For biomolecules in solution, changes in configurational entropy are thought to contribute substantially to the free energies of processes like binding and conformational change. In principle, the configurational entropy can be strongly affected by pairwise and higher-order correlations among conformational degrees of freedom. However, the literature offers mixed perspectives regarding the contributions that changes in correlations make to changes in configurational entropy for such processes. Here we take advantage of powerful techniques for simulation and entropy analysis to carry out rigorous in silico studies of correlation in binding and conformational changes. In particular, we apply information-theoretic expansions of the configurational entropy to well-sampled molecular dynamics simulations of a model host-guest system and the protein bovine pancreatic trypsin inhibitor. The results bear on the interpretation of NMR data, as they indicate that changes in correlation are important determinants of entropy changes for biologically relevant processes and that changes in correlation may either balance or reinforce changes in first-order entropy. The results also highlight the importance of main-chain torsions as contributors to changes in protein configurational entropy. As simulation techniques grow in power, the mathematical techniques used here will offer new opportunities to answer challenging questions about complex molecular systems.

ObjectivesChronic stress, characteristic of police work, affects the hypothalamic‐pituitary‐adrenal axis' control of cortisol production. Capacity to vary cortisol may be the appropriate measurement to interpret associations with chronic diseases, including obesity, best measured by variability within a person, not central tendency.MethodsOn each of 217 policemen, 18 saliva specimens were obtained for cortisol. Statistical models examined the associations of within‐subjects (W‐S) cortisol standard deviation (SD) and W‐S cortisol mean with waist circumference and four body composition indexes: BMI, and three derived from DEXA: fat‐mass, and trunk and extremities lean‐mass. Explained variance and the functional nature of associations are reported.ResultsAssociations of anthropometrics with W‐S cortisol mean were not statistically significant at P < 0.05; all associations with W‐S cortisol SD were significant. The association of trunk lean mass index (LMIt) with W‐S cortisol SD dominated all models. Associations of W‐S cortisol SD with other indexes vanished when models contained LMIt ; when any other index was included in models predicting LMIt, associations with W‐S cortisol SD remained significant. The functional association between LMIt and W‐S cortisol SD is progressively “hockey stick,” monotonic increasing, and flattens at joint high values.ConclusionsResults support inferences that LMIt measures visceral adiposity and W‐S cortisol variability appears to be an appropriate construct to measure in association with visceral adiposity. The “hockey stick” character of the association is consistent with other investigations suggesting obesity is associated with less W‐S cortisol variation; however, the monotonic increase and flattening of association at increasing W‐ScortisolSD values suggests a more complex association, potentially interpretable by allostasis models of causation. Am. J. Hum. Biol. 25:499–507, 2013. © 2013 Wiley Periodicals, Inc.

ABSTRACTObjectivesThis study examines cross‐sectional associations of indices of adiposity, lean body mass, and physical activity, with heart rate variability (HRV), a marker for parasympathetic cardiac vagal control.MethodsThe study population consists of 360 officers from the Buffalo New York Police Department. Indices of adiposity include body mass index, waist circumference, and a fat‐mass index taken from dual‐energy X‐ray absorptiometry (DEXA) measurements. Lean body mass indices were derived from DEXA measurements of trunk mass and extremity lean mass. Physical activity was measured using a 7‐day self‐report questionnaire. HRV was obtained from 5‐min electrocardiogram measurements by means of parametric spectral analysis resulting in estimates for high‐frequency (HF) and low‐frequency (LF) HRV.ResultsBoth HF and LF HRV were significantly associated with markers for adiposity, two components of lean mass and physical activity with all associations being in the expected direction except that for trunk lean mass. This unexpected result is explained by the possibility that trunk mass is a marker for visceral adiposity rather than lean mass. Body mass index did not explain any additional variance in HRV above and beyond waist circumference and the DEXA indices.ConclusionsHigher levels of physical activity, lower levels of markers for central adiposity and higher lean mass in the extremities predict higher levels of HRV in this population of police officers. This association between modifiable risk factors and markers for autonomic function suggest possible interventions that may improve health and performance. Am. J. Hum. Biol. 25:370–377, 2013. © 2013 Wiley Periodicals, Inc.

OBJECTIVES:The body mass index (BMI), a ratio of weight/height(2) , dominates estimation of adiposity in population studies. BMI, however, does not distinguish among fat, muscle, or bone mass. Accordingly, its usage to assess and manage obesity in the population is limited. This study compares the use of BMI with direct measures of fat- and lean-mass to predict established cardiovascular and diabetes risk factors: blood pressure, lipids, and glucose.METHODS:The entire Buffalo Police Department was the object of recruitment to a baseline study of physiological and psychological stress. Four hundred nine officers constitute the sample for this analysis. Regression methods focusing on explained variance in blood pressure, high density lipoprotein (HDL) cholesterol, and blood glucose compare the use of BMI to that of fat- and lean-mass indexes derived from dual energy X-ray absorptiometry (DEXA).RESULTS:DEXA indexes explain 1.6%-3.3% (P < 0.05, all risk factors) more variance than BMI. Fat mass drives the association for blood pressure, trunk lean mass for HDL cholesterol, and both for blood glucose. High degrees of multicollinearity complicate interpretation of predictive models jointly containing BMI and DEXA indexes.CONCLUSIONS:In police officers, DEXA indexes are better predictors of cardiovascular disease and diabetes risk factors. However, populations with different distributions of fitness, diet, and health conditions may demonstrate differentfeatures. In contrast to BMI, DEXA-derived measurements suggest avenues to explore metabolic processes, which relate to an index's underlying association with risk and may suggest more effective intervention strategies.

Virtually unknown in the West, the physician Nikolai Vigdorchik is recognized in Russian-Soviet history for his role in introducing social security into Russia. He rose from Jewish working-class origins to a career that combined activism in labour rights and public health with extensive and path-breaking publications in social security occupational safety and public health. He contributed more than 30 years of leadership to Soviet research and educational institutions devoted to occupational safety and health. Vigdorchik's 1935 publication on lead and hypertension is illustrative of his contribution to modern epidemiological methods, describing a statistical bias in the study of hospitalized patients. It predates by 11 years Joseph Berkson's paper, after whom the bias is named. Vigdorchik's life illustrates a modem-day conundrum: social activism comes with political cost - by virtue of its evidence-based orientation, public health science is safer but both are necessary to move a culture towards health and stability

The Caerphilly Collaborative Heart Disease Study is based on a large cohort of men (2,398) aged 49-66 years at the time of study. Platelet aggregation induced by collagen, thrombin, and ADP was measured in fasting blood samples and was related to prevalent angina, past myocardial infarction, and electrocardiographic evidence of ischemic heart disease. A number of subjects had taken aspirin, other nonsteroidal anti-inflammatory drugs, or other drugs affecting platelet aggregation 7 days before blood sample collection; after the exclusion of these subjects, data were available for 1,811 men. No relations were demonstrated with angina, but significant relations were shown between past myocardial infarctions and electrocardiographic evidence of ischemia and ADP-induced aggregation (both primary and secondary) and between electrocardiographic evidence of ischemia and thrombin-induced aggregation. The strongest relation indicated more than a twofold increase in the odds of a past myocardial infarction in subjects of the highest fifth of ADP-induced primary platelet aggregation compared with the lowest fifth. No significant relations were detected with collagen-induced aggregation. Accounting for a number of possible confounding factors had a relatively small impact on the relations between platelet aggregation and ischemic heart disease. Other evidence, including the well-established effect of aspirin on reducing the incidence of ischemic heart disease, indicates that the relations we describe are unlikely to be simply an effect ofIHD on platelets. (Circulation 1991;83:38-44)

Increased westernization with Japanese migration to the U.S. in the early 20th century isthought to have altered the risk of cardiovascular disease.Whether similar effects include changes in the risk ofParkinson’s disease (PD) is not clear. This report describes therelations between environmental, life-style, and physicalattributes and the incidence of PD that have been observed inthe Honolulu-Asia Aging Study.

CONTEXT:Parkinson disease (PD) has an unknown cause; however, convincing evidence is emerging that indicates pesticides can selectively injure the dopaminergic system in laboratory animals. Retrospective studies in humans demonstrate a link between exposure to agricultural lifestyle factors and PD.OBJECTIVE:To determine whether working on a plantation in Hawaii and exposure to pesticides are associated with an increased risk of PD decades later.DESIGN AND SETTING:Prospective cohort study based on the island of Oahu, Hawaii, with 30 years of follow-up. Years of work on a plantation were assessed by questionnaire at study enrollment in 1965. Self-reported information on pesticide exposure was collected at a separate examination 6 years later.PARTICIPANTS:Participants were 7986 Japanese American men born between 1900 and 1919 who were enrolled in the longitudinal Honolulu Heart Program.MAIN OUTCOME MEASURES:Incident PD was determined by medical record review or by an examination conducted by a study neurologist at a later date.RESULTS:During follow-up, 116 men developed PD. Age-adjusted incidence increased significantly among men who worked more than 10 years on a plantation. The relative risk of PD was 1.0 (95% confidence interval, 0.6-1.6), 1.7 (95% confidence interval, 0.8-3.7), and 1.9 (95% confidence interval, 1.0-3.5) for men who worked on a plantation 1 to 10 years, 11 to 20 years, and more than 20 years compared with men who never did plantation work (P =.006, test for trend). Age-adjusted incidence of PD was higher in men exposed to pesticides than in men not exposed to pesticides although this was not statistically significant (P =.10, test for trend).CONCLUSION:These longitudinal observations regarding plantation work in Hawaii support case-control studies suggesting that exposure to pesticides increases the risk of PD.

Background-It has been hypothesized that immunoreactivity to beta (2)-glycoprotein 1 (beta 2GP1)-dependent anticardiolipin antibody (aCL), but not beta 2GP1 -independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI).Methods-We performed a nested case-control study examining aCL as a risk factor for ischernic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured beta 2GP1-dependent and beta 2GP1-independent aCL and anti-beta 2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI. and in a control group of 1360 men who remained free of both conditions.Results-Only beta 2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor-adjusted relative odds for men with a positive versus a negative beta 2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years.Conclusions-These data suggest that aCL IgG, particularly the beta 2GP1 -dependent variety, is an important predictor of future stroke and MI in men.

BACKGROUND:Elderly people frequently report the presence of chronically disturbed sleep. However, most data are derived from predominantly Caucasian populations. The current study is an investigation of the prevalence and correlates of sleep disturbances in a cohort of elderly Japanese American men residing in Hawaii. The importance of this population lies in its representation of an ethnic group living in a culture different from their ancestry.METHODS:This study is a cross-sectional cohort analysis of data pertaining to sleep disturbances and their potential correlates from 3,845 elderly Japanese American men residing in Hawaii (mean age. 78 years; range, 71-93 years) who participated in the fourth survey of the Honolulu Heart Program (1991-1994), which is the baseline exam for the Honolulu-Asia Aging Study. Information collected included an extensive survey of medication use, medical history, and assessments of physical and mental function, quality of life, and sleep.RESULTS:The prevalence of insomnia (DIMS) was 32.6%, a rate similar to that reported in predominantly Caucasian populations. Depression, benzodiazepine use, and several chronic health problems were the most important factors associated with DIMS. In contrast, excessive daytime sleepiness (EDS) had a prevalence of 8.9%, a rate lower than that found in elderly Caucasian populations but close to that reported among native Japanese. Important factors related to EDS were symptoms of nocturnal respiratory disturbance, depression, perception of adverse quality of life, Parkinson's disease, and digitalis use.CONCLUSIONS:Elderly Japanese men are less likely than elderly Caucasian men to report excessive daytime sleepiness. However, their insomnia rates are similar.

To the Editor: p53 has a critical role in cell-cycle control. As such, it has been identified as an important target in human carcinogenesis. However, since human p53 was cloned, ≥10 DNA-sequence polymorphisms have been identified (Matlashewski et al. Matlashewski et al., 1987Matlashewski GJ Tuck S Pim D Lamb P Schneider J Crawford LV Primary structure polymorphism at amino acid residue 72 of human p53.Mol Cell Biol. 1987; 7: 961-963Crossref PubMed Scopus (446) Google Scholar; Weston and Godbold Weston and Godbold, 1997Weston A Godbold JH Polymorphisms of HRAS-1 and p53 in breast cancer and lung cancer: a meta-analysis.Environ Health Perspect. 1997; 105: 919-926PubMed Google Scholar). The codon 72 polymorphism (arginine/proline: G/C), the first to be described, has been the subject of ≥31 epidemiological case-control studies that have explored a potential association with cancer (Olschwang et al. Olschwang et al., 1991Olschwang S Laurent-Puig P Vassal A Salmon Rémy J Thomas G Characterization of a frequent polymorphism in the coding sequence of the Tp53 gene in colonic cancer patients and a control population.Hum Genet. 1991; 86: 369-370Crossref PubMed Scopus (51) Google Scholar; Weston et al. Weston et al., 1992Weston A Perrin LS Forrester K Hoover RN Trump BF Harris CC Caporaso NE Allelic frequency of a p53 polymorphism in human lung cancer.Cancer Epidemiol Biomarkers Prev. 1992; 1: 481-483PubMed Google Scholar, Weston et al., 1994Weston A Ling-Cawley HM Caporaso NE Bowman ED Hoover RN Trump BF Harris C Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer.Carcinogenesis. 1994; 15: 583-587Crossref PubMed Scopus (92) Google Scholar, Weston et al., 1997Weston A Pan CF Ksieski HB Wallenstein S Berkowitz GS Tartter PI Bleiweiss IJ et al.p53 haplotype determination in breast cancer.Cancer Epidemiol Biomarkers Prev. 1997; 6: 105-112PubMed Google Scholar; Zhang et al. Zhang et al., 1992Zhang W Hu G Deisseroth A Polymorphism at codon 72 of the p53 gene in human acute myelogenous leukemia.Gene. 1992; 117: 271-275Crossref PubMed Scopus (36) Google Scholar; Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Birgander et al. Birgander et al., 1995Birgander R Själander A Rannug A Alexandrie AK Sundberg MI Seidegard J Tornling G et al.p53 polymorphisms and haplotypes in lung cancer.Carcinogenesis. 1995; 16: 2233-2236Crossref PubMed Scopus (120) Google Scholar, Birgander et al., 1996bBirgander R Själander A Zhou Z Fan C Beckman L Beckman G p53 polymorphisms and haplotypes in nasopharyngeal cancer.Hum Hered. 1996; 46: 49-54Crossref PubMed Scopus (53) Google Scholar; Jin et al. Jin et al., 1995Jin X Wu X Roth JA Amos CI King TM Branch C Honn SE et al.Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.Carcinogenesis. 1995; 16: 2205-2208Crossref PubMed Scopus (155) Google Scholar; Själander et al. Själander et al., 1995aSjälander A Birgander R Athlin L Stenling R Rutegard J Beckman L Beckman G p53 germ-line haplotypes associated with increased risk for colorectal cancer.Carcinogenesis. 1995; 16: 1461-1464Crossref PubMed Scopus (97) Google Scholar, Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar; Wu et al. Wu et al., 1995Wu W Kakehi Y Habuchi T Kinoshita H Ogawa O Terachi T Huang C-H et al.Allelic frequency of p53 gene codon 72 polymorphism in urologic cancers.Jpn J Cancer Res. 1995; 86: 730-736Crossref PubMed Scopus (55) Google Scholar; Murata et al. Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar; To-Figueras et al. To-Figueras et al., 1996To-Figueras J Gene M Gomez-Catalan J Galan C Firvida J Fuentes M Rodamilans M et al.Glutathione-S-transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility.Cancer Epidemiol Biomarkers Prev. 1996; 5: 337-342PubMed Google Scholar; Golovleva et al. Golovleva et al., 1997Golovleva I Birgander R Själander A Lundgren E Beckman L Interferon-alpha and p53 alleles involved in nasopharyngeal carcinoma.Carcinogenesis. 1997; 18: 645-647Crossref PubMed Scopus (20) Google Scholar; Weston and Godbold Weston and Godbold, 1997Weston A Godbold JH Polymorphisms of HRAS-1 and p53 in breast cancer and lung cancer: a meta-analysis.Environ Health Perspect. 1997; 105: 919-926PubMed Google Scholar; Yung et al. Yung et al., 1997Yung WC Ng MH Sham JS Choy DT p53 codon 72 polymorphism in nasopharyngeal carcinoma.Cancer Genet Cytogenet. 1997; 93: 181-182Abstract Full Text PDF PubMed Scopus (16) Google Scholar; Hayes et al. Hayes et al., 1998Hayes VM Hofstra RMW Buys CHCM Hollema H van der Zee AGJ Homozygous arginine-72 in wild type p53 and risk of cervical cancer.Lancet. 1998; 352: 1756Abstract Full Text Full Text PDF PubMed Google Scholar; Helland et al. Helland et al., 1998Helland A Langerod A Johnsen H Olsen OA Skovlund E Borresen-Dale A-L p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (110) Google Scholar; Hildesheim et al. Hildesheim et al., 1998Hildesheim A Schiffman M Brinton LA Fraumeni JF Herrero R Concepcion-Bratti M Schwartz P et al.p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (124) Google Scholar; Josefsson et al. Josefsson et al., 1998Josefsson AM Magnusson PKE Ylitalo N Quarforth-Tubbin P Pontén J Adami HO Gyllensten UB p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (11) Google Scholar; Lanham et al. Lanham et al., 1998Lanham S Campbell I Watt P Gornall R p53 polymorphism and risk of cervical cancer.Lancet. 1998; 352: 1631Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar; Minaguchi et al. Minaguchi et al., 1998Minaguchi T Kanamori Y Matsushima M Yoshikawa H Taketani Y Nakamura Y No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection.Cancer Res. 1998; 58: 4585-4586PubMed Google Scholar; Rosenthal et al. Rosenthal et al., 1998Rosenthal AN Ryan A Al-Jehani RM Storey A Harwood CA Jacobs IJ p53 codon 72 polymorphism and risk of cervical cancer in UK.Lancet. 1998; 352: 871-872Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar; Storey et al. Storey et al., 1998Storey A Thomas M Kalita A Harwood C Gardiol D Mantovani F Breuer J et al.Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.Nature. 1998; 393: 229-234Crossref PubMed Scopus (843) Google Scholar; Tagawa et al. Tagawa et al., 1998Tagawa M Murata M Kimura H Prognostic value of mutations and a germ line polymorphism of the p53 gene in non-small cell lung carcinoma: association with clinicopathological features.Cancer Lett. 1998; 128: 93-99Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar; Wang-Gohrke et al. Wang-Gohrke et al., 1998Wang-Gohrke S Rebbeck TR Besenfelder W Kreienberg R Runnebaum IB p53 germline polymorphisms are associated with an increased risk for breast cancer in German women.Anticancer Res. 1998; 18: 2095-2099PubMed Google Scholar). Although they err on the side of caution by citing Weston and Godbold (Weston and Godbold, 1997Weston A Godbold JH Polymorphisms of HRAS-1 and p53 in breast cancer and lung cancer: a meta-analysis.Environ Health Perspect. 1997; 105: 919-926PubMed Google Scholar), Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, p. 293), referring to the codon 72 polymorphism, state that “overall, the available data in the literature suggest that p53 variants may be considered as risk factors for some of the major neoplastic diseases in humans, such as lung, colorectal, breast and cervical cancer and are expected to affect survival.” With respect to codon 72, we contend that this is probably not the case. In the available data, lung cancer is the subject of eight studies (Weston et al. Weston et al., 1992Weston A Perrin LS Forrester K Hoover RN Trump BF Harris CC Caporaso NE Allelic frequency of a p53 polymorphism in human lung cancer.Cancer Epidemiol Biomarkers Prev. 1992; 1: 481-483PubMed Google Scholar, Weston et al., 1994Weston A Ling-Cawley HM Caporaso NE Bowman ED Hoover RN Trump BF Harris C Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer.Carcinogenesis. 1994; 15: 583-587Crossref PubMed Scopus (92) Google Scholar; Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Birgander et al. Birgander et al., 1995Birgander R Själander A Rannug A Alexandrie AK Sundberg MI Seidegard J Tornling G et al.p53 polymorphisms and haplotypes in lung cancer.Carcinogenesis. 1995; 16: 2233-2236Crossref PubMed Scopus (120) Google Scholar; Jin et al. Jin et al., 1995Jin X Wu X Roth JA Amos CI King TM Branch C Honn SE et al.Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.Carcinogenesis. 1995; 16: 2205-2208Crossref PubMed Scopus (155) Google Scholar; Murata et al. Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar; To-Figueras et al. To-Figueras et al., 1996To-Figueras J Gene M Gomez-Catalan J Galan C Firvida J Fuentes M Rodamilans M et al.Glutathione-S-transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility.Cancer Epidemiol Biomarkers Prev. 1996; 5: 337-342PubMed Google Scholar; Tagawa et al. Tagawa et al., 1998Tagawa M Murata M Kimura H Prognostic value of mutations and a germ line polymorphism of the p53 gene in non-small cell lung carcinoma: association with clinicopathological features.Cancer Lett. 1998; 128: 93-99Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Three studies claim a statistically significant association: in one study, a subset analysis suggested a relationship in lung cancer cases diagnosed at age <53 years (Jin et al. Jin et al., 1995Jin X Wu X Roth JA Amos CI King TM Branch C Honn SE et al.Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.Carcinogenesis. 1995; 16: 2205-2208Crossref PubMed Scopus (155) Google Scholar); in the other two, the allelic frequencies were almost identical (and the difference was not significant) between cases and controls (Kawajiri et al. [Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar] observed a proline-allele frequency of .35 for controls and .36 for cases [n = 347 and 328, respectively]). Murata et al. (Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar) observed a proline-allele frequency of .40 for controls and .35 for cases (n = 152 and 191, respectively), but associations of cancer risk were claimed on the basis of higher numbers of homozygotes (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Murata et al. Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar). One study (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar) implicated proline; the other (Murata et al. Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar), arginine. Most recently, the relationship between cervical cancer, human papillomavirus (HPV) infection, and inheritance of the arginine allele has received considerable attention. The initial study, cited by Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), showed a high degree of correlation between inheritance of the arginine allele and cervical cancer risk when HPV infection was present but not when it was absent (Storey et al. Storey et al., 1998Storey A Thomas M Kalita A Harwood C Gardiol D Mantovani F Breuer J et al.Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.Nature. 1998; 393: 229-234Crossref PubMed Scopus (843) Google Scholar). There are now eight studies of cervical cancer, but only one shows any association and seven are null (Hayes et al. Hayes et al., 1998Hayes VM Hofstra RMW Buys CHCM Hollema H van der Zee AGJ Homozygous arginine-72 in wild type p53 and risk of cervical cancer.Lancet. 1998; 352: 1756Abstract Full Text Full Text PDF PubMed Google Scholar; Helland et al. Helland et al., 1998Helland A Langerod A Johnsen H Olsen OA Skovlund E Borresen-Dale A-L p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (110) Google Scholar; Hildesheim et al. Hildesheim et al., 1998Hildesheim A Schiffman M Brinton LA Fraumeni JF Herrero R Concepcion-Bratti M Schwartz P et al.p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (124) Google Scholar; Josefsson et al. Josefsson et al., 1998Josefsson AM Magnusson PKE Ylitalo N Quarforth-Tubbin P Pontén J Adami HO Gyllensten UB p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (11) Google Scholar; Lanham et al. Lanham et al., 1998Lanham S Campbell I Watt P Gornall R p53 polymorphism and risk of cervical cancer.Lancet. 1998; 352: 1631Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar; Minaguchi et al. Minaguchi et al., 1998Minaguchi T Kanamori Y Matsushima M Yoshikawa H Taketani Y Nakamura Y No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection.Cancer Res. 1998; 58: 4585-4586PubMed Google Scholar; Rosenthal et al. Rosenthal et al., 1998Rosenthal AN Ryan A Al-Jehani RM Storey A Harwood CA Jacobs IJ p53 codon 72 polymorphism and risk of cervical cancer in UK.Lancet. 1998; 352: 871-872Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). There are five breast cancer studies (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Själander et al. Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar; Weston et al. Weston et al., 1997Weston A Pan CF Ksieski HB Wallenstein S Berkowitz GS Tartter PI Bleiweiss IJ et al.p53 haplotype determination in breast cancer.Cancer Epidemiol Biomarkers Prev. 1997; 6: 105-112PubMed Google Scholar; Helland et al. Helland et al., 1998Helland A Langerod A Johnsen H Olsen OA Skovlund E Borresen-Dale A-L p53 polymorphism and risk of cervical cancer.Nature. 1998; 396: 530-531Crossref PubMed Scopus (110) Google Scholar; Wang-Gohrke et al. Wang-Gohrke et al., 1998Wang-Gohrke S Rebbeck TR Besenfelder W Kreienberg R Runnebaum IB p53 germline polymorphisms are associated with an increased risk for breast cancer in German women.Anticancer Res. 1998; 18: 2095-2099PubMed Google Scholar); only one reached significance. Of the other published studies, a positive association has been claimed in 0/2 for nasopharyngeal cancer (Birgander et al. Birgander et al., 1996bBirgander R Själander A Zhou Z Fan C Beckman L Beckman G p53 polymorphisms and haplotypes in nasopharyngeal cancer.Hum Hered. 1996; 46: 49-54Crossref PubMed Scopus (53) Google Scholar; Golovleva et al. Golovleva et al., 1997Golovleva I Birgander R Själander A Lundgren E Beckman L Interferon-alpha and p53 alleles involved in nasopharyngeal carcinoma.Carcinogenesis. 1997; 18: 645-647Crossref PubMed Scopus (20) Google Scholar; Yung et al. Yung et al., 1997Yung WC Ng MH Sham JS Choy DT p53 codon 72 polymorphism in nasopharyngeal carcinoma.Cancer Genet Cytogenet. 1997; 93: 181-182Abstract Full Text PDF PubMed Scopus (16) Google Scholar), 0/4 for colon cancer (Olschwang et al. Olschwang et al., 1991Olschwang S Laurent-Puig P Vassal A Salmon Rémy J Thomas G Characterization of a frequent polymorphism in the coding sequence of the Tp53 gene in colonic cancer patients and a control population.Hum Genet. 1991; 86: 369-370Crossref PubMed Scopus (51) Google Scholar; Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Jin et al. Jin et al., 1995Jin X Wu X Roth JA Amos CI King TM Branch C Honn SE et al.Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.Carcinogenesis. 1995; 16: 2205-2208Crossref PubMed Scopus (155) Google Scholar; Själander et al. Själander et al., 1995aSjälander A Birgander R Athlin L Stenling R Rutegard J Beckman L Beckman G p53 germ-line haplotypes associated with increased risk for colorectal cancer.Carcinogenesis. 1995; 16: 1461-1464Crossref PubMed Scopus (97) Google Scholar), 0/2 for bladder/urologic cancer (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Wu et al. Wu et al., 1995Wu W Kakehi Y Habuchi T Kinoshita H Ogawa O Terachi T Huang C-H et al.Allelic frequency of p53 gene codon 72 polymorphism in urologic cancers.Jpn J Cancer Res. 1995; 86: 730-736Crossref PubMed Scopus (55) Google Scholar), 0/1 for acute myelogenous leukemia (Zhang et al. Zhang et al., 1992Zhang W Hu G Deisseroth A Polymorphism at codon 72 of the p53 gene in human acute myelogenous leukemia.Gene. 1992; 117: 271-275Crossref PubMed Scopus (36) Google Scholar), and 1/1 for stomach cancer (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar). Again, for stomach cancer, the allelic frequencies were not different for cases and controls, and an association of cancer risk with the arginine variant was claimed on the basis of higher numbers of arginine homozygotes in cases (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; this report used the same control group noted above, and the proline-allele frequency in stomach cancer was .28 [n=140]). We contend, therefore, that the balance of the results of human molecular epidemiological association studies suggests that codon 72 allelism does not have an impact on human cancer risk. Specifically, at most, only 6 of 31 positive associations have been reported, and none have received consistent support in attempts to replicate them (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar; Jin et al. Jin et al., 1995Jin X Wu X Roth JA Amos CI King TM Branch C Honn SE et al.Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.Carcinogenesis. 1995; 16: 2205-2208Crossref PubMed Scopus (155) Google Scholar; Murata et al. Murata et al., 1996Murata M Tagawa M Kimura M Kimura H Wantanabe S Saisho H Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history.Carcinogenesis. 1996; 17: 261-264Crossref PubMed Scopus (120) Google Scholar; Själander et al. Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar; Storey et al. Storey et al., 1998Storey A Thomas M Kalita A Harwood C Gardiol D Mantovani F Breuer J et al.Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.Nature. 1998; 393: 229-234Crossref PubMed Scopus (843) Google Scholar). Moreover, there is no obvious, plausible biological basis for an association of cancer risk with the codon 72 polymorphism. The impact of proline on the tertiary structure of a protein is disruption of α-helices. A proline residue resides at the monomeric position codon 71; therefore, at codon 72 there is no obvious consequence to proline. Results were reported for p53, codon 72, genotype frequencies in healthy Italian centenarians and younger controls (Bonafè et al. Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). The expectation was of allelic winnowing in the case of a codon 72 variant associated with cancer susceptibility and subsequent survival. The frequency of proline-allele carriers was .539 in controls and .506 in centenarians, 3.3% lower (and the corresponding allelic frequency was 2.7% lower, but the difference was not significant). We conjecture that their comparison of centenarians (n=176) with younger controls (n=204) is too crude to detect the predicted allelic winnowing (Bonafè et al. Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). First, the cause of death from cancer in the Italian population is ∼23% (WHO WHO, 1987WHO World health statistics annual. World Health Organization, Geneva1987: 247-249Google Scholar; Lopez Lopez, 1990Lopez AD Competing causes of death: a review of recent trends in mortality in industrialized countries with special reference to cancer.Ann N Y Acad Sci. 1990; 609: 58-76Crossref PubMed Scopus (20) Google Scholar). Second, even though we do not agree that there is good evidence for an association between inheritance at codon 72 and cancer susceptibility, because of the molecular epidemiological data reviewed above, let us assume that the proline variant carries a relative risk of 1.5–2.0 (Kawajiri et al. Kawajiri et al., 1993Kawajiri K Nakachi K Imai K Watanabe J Hayashi S-I Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.Carcinogenesis. 1993; 14: 1085-1089Crossref PubMed Scopus (220) Google Scholar). On the basis of this assumption we might expect a reduction of 3.0%–4.8% in proline-allele carriers as the population ages (table 1 shows a simulated 2×2 table for a standard population of 1,000 persons, given a relative risk of 1.5 and a cancer death rate of 23% [WHO WHO, 1987WHO World health statistics annual. World Health Organization, Geneva1987: 247-249Google Scholar; Lopez Lopez, 1990Lopez AD Competing causes of death: a review of recent trends in mortality in industrialized countries with special reference to cancer.Ann N Y Acad Sci. 1990; 609: 58-76Crossref PubMed Scopus (20) Google Scholar]). In the letter by Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), a reduction of 3.3% in the frequency of proline-allele carriers among centenarians was reported. This reduction is consistent with their hypothesis, although the authors suggest that it is not (Bonafè et al. Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Moreover, our corresponding projected reduction in allelic frequency is 2.8% for a relative risk of 1.5; Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar) observed a 2.7% reduction in frequency. However, to have, at a significance level of .05, 80% power to detect a 3.0%–4.8% reduction in the prevalence of proline-allele carriers, a minimum of 2,002–3,178 people would be needed, given a relative risk of 2.0; and 5,176–8,182 would be needed, given a relative risk of 1.5 (results of power calculations are given in table 2).Table 1Simulated Relative-Risk Calculation for a Standard Population of 1,000 PersonsNo. of Cancer DeathsNo. of SurvivorsTotalProline-allele carriers147392539Arginine homozygotes83378461 Total2307701,000Note.—On the basis of the control genotypic frequencies reported by Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), a relative risk of 1.5, and a cancer death rate of 23% (WHO WHO, 1987WHO World health statistics annual. World Health Organization, Geneva1987: 247-249Google Scholar; Lopez Lopez, 1990Lopez AD Competing causes of death: a review of recent trends in mortality in industrialized countries with special reference to cancer.Ann N Y Acad Sci. 1990; 609: 58-76Crossref PubMed Scopus (20) Google Scholar), the frequency of proline-allele carriers in survivors is .509 (a reduction of 3.0%). If the relative risk is raised to 2.0, the frequency of proline-allele carriers in survivors is .491 (a reduction of 4.8%). This model addresses only a role for p53 allelism in cancer as a cause of death. If limited to the major neoplasms indicated by Bonafè et al. (1999) (lung, colon, breast, and cervical), with a relative risk of 2.0, the frequency of proline-allele carriers in survivors is .526 (a reduction of only 1.3%). Also note that, if any association is limited to proline homozygotes, then, for a relative risk of 1.5, this fraction of the population would be expected to drop from .088 to .076 (a reduction of 1.2%). Bonafè et al. (1999), in fact, observed a drop of 2.0%, from .088 to .068. Open table in a new tab Table 2Power CalculationsNo. of Centenarians Required for Hypothesis Testing When Frequency of Proline-Allele Carriers IsaPercentages are derived from calculations in table 1.OR3.0%4.8%1.54,0912,5882.01,5891,001a Percentages are derived from calculations in table 1. Open table in a new tab Note.—On the basis of the control genotypic frequencies reported by Bonafè et al. (Bonafè et al., 1999Bonafè M Olivieri F Mari D Baggio G Mattace R Sansoni P DeBenedictis G et al.p53 variants predisposing to cancer are present in healthy centenarians.Am J Hum Genet. 1999; 64: 292-295Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), a relative risk of 1.5, and a cancer death rate of 23% (WHO WHO, 1987WHO World health statistics annual. World Health Organization, Geneva1987: 247-249Google Scholar; Lopez Lopez, 1990Lopez AD Competing causes of death: a review of recent trends in mortality in industrialized countries with special reference to cancer.Ann N Y Acad Sci. 1990; 609: 58-76Crossref PubMed Scopus (20) Google Scholar), the frequency of proline-allele carriers in survivors is .509 (a reduction of 3.0%). If the relative risk is raised to 2.0, the frequency of proline-allele carriers in survivors is .491 (a reduction of 4.8%). This model addresses only a role for p53 allelism in cancer as a cause of death. If limited to the major neoplasms indicated by Bonafè et al. (1999) (lung, colon, breast, and cervical), with a relative risk of 2.0, the frequency of proline-allele carriers in survivors is .526 (a reduction of only 1.3%). Also note that, if any association is limited to proline homozygotes, then, for a relative risk of 1.5, this fraction of the population would be expected to drop from .088 to .076 (a reduction of 1.2%). Bonafè et al. (1999), in fact, observed a drop of 2.0%, from .088 to .068. Notwithstanding these conclusions and observations, we believe that p53 allelism is an important cancer-susceptibility factor but that it is more complex than that simply defined by the polymorphism at codon 72. A series of studies by a Swedish group (Beckman et al. Beckman et al., 1994Beckman G Birgander R Själander A Saha N Holmberg PA Kivela A Beckman L Is p53 polymorphism maintained by natural selection?.Hum Hered. 1994; 44: 266-270Crossref PubMed Scopus (317) Google Scholar; Birgander et al. Birgander et al., 1995Birgander R Själander A Rannug A Alexandrie AK Sundberg MI Seidegard J Tornling G et al.p53 polymorphisms and haplotypes in lung cancer.Carcinogenesis. 1995; 16: 2233-2236Crossref PubMed Scopus (120) Google Scholar, Birgander et al., 1996aBirgander R Själander A Beckman G Beckman L Effect of p53 alleles on placental weight.Hum Hered. 1996; 46: 290-297Crossref PubMed Scopus (4) Google Scholar, Birgander et al., 1996bBirgander R Själander A Zhou Z Fan C Beckman L Beckman G p53 polymorphisms and haplotypes in nasopharyngeal cancer.Hum Hered. 1996; 46: 49-54Crossref PubMed Scopus (53) Google Scholar; Själander et al. Själander et al., 1995aSjälander A Birgander R Athlin L Stenling R Rutegard J Beckman L Beckman G p53 germ-line haplotypes associated with increased risk for colorectal cancer.Carcinogenesis. 1995; 16: 1461-1464Crossref PubMed Scopus (97) Google Scholar, Själander et al., 1995bSjälander A Birgander R Kivela A Beckman G p53 polymorphisms and haplotypes in different ethnic groups.Hum Hered. 1995; 45: 144-149Crossref PubMed Scopus (132) Google Scholar, Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar, Själander et al., 1996bSjälander A Birgander R Saha N Beckman L Beckman G p53 polymorphisms and haplotypes show distinct differences between major ethnic groups.Hum Hered. 1996; 46: 41-48Crossref PubMed Scopus (84) Google Scholar) indicated that a constellation of three p53 polymorphisms (intron 3, codon 72, and intron 6) constituted a haplotype predictive of increased breast cancer risk (odds ratio [OR] = 2.9, 95% confidence interval [CI] = 1.4–6.3 [Själander et al. Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar]). Haplotypes were deduced on the basis of population frequencies of the individual polymorphisms. First, estimates of pairwise haplotype frequencies were calculated, and extended haplotype frequencies were deduced from this information. A subsequent study examined the same question but used a PCR-based method for physical determination of the haplotypes (Weston et al. Weston et al., 1997Weston A Pan CF Ksieski HB Wallenstein S Berkowitz GS Tartter PI Bleiweiss IJ et al.p53 haplotype determination in breast cancer.Cancer Epidemiol Biomarkers Prev. 1997; 6: 105-112PubMed Google Scholar, Weston et al., 1998Weston A Wolff MS Morabia A True extended haplotypes of p53: indicators of breast cancer risk.Cancer Genet Cytogenet. 1998; 102: 153-154Abstract Full Text PDF PubMed Google Scholar). The results of the latter study were consistent with those reported in the study by Själander et al. (Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar) (OR = 2.5, 95% CI = 1.3–4.8, in postmenopausal women) and further implicated a specific haplotype, designated “p531-2-1.” More recently, a third study, estimating extended haplotypes of these three polymorphisms in a German population, provided results consistent with an elevated breast cancer risk associated with inheritance of p531-2-1 (OR = 2.0, 95% CI = 1.0–3.9 [Wang-Gohrke et al. Wang-Gohrke et al., 1998Wang-Gohrke S Rebbeck TR Besenfelder W Kreienberg R Runnebaum IB p53 germline polymorphisms are associated with an increased risk for breast cancer in German women.Anticancer Res. 1998; 18: 2095-2099PubMed Google Scholar]). It is to be noted that this latest report has adopted an allelic nomenclature different from that developed by Beckman et al. (Beckman et al., 1994Beckman G Birgander R Själander A Saha N Holmberg PA Kivela A Beckman L Is p53 polymorphism maintained by natural selection?.Hum Hered. 1994; 44: 266-270Crossref PubMed Scopus (317) Google Scholar) and adopted by others (Själander et al. Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar; Weston et al. Weston et al., 1997Weston A Pan CF Ksieski HB Wallenstein S Berkowitz GS Tartter PI Bleiweiss IJ et al.p53 haplotype determination in breast cancer.Cancer Epidemiol Biomarkers Prev. 1997; 6: 105-112PubMed Google Scholar, Weston et al., 1998Weston A Wolff MS Morabia A True extended haplotypes of p53: indicators of breast cancer risk.Cancer Genet Cytogenet. 1998; 102: 153-154Abstract Full Text PDF PubMed Google Scholar). The balance of the results of human breast cancer studies of molecular epidemiological haplotype association—specifically, three positive associations in three studies—suggests that inheritance of the p531-2-1 haplotype does have an impact on human breast cancer risk (Själander et al. Själander et al., 1996aSjälander A Birgander R Hallmans G Cajander S Lenner P Athlin L Beckman G et al.p53 polymorphisms and haplotypes in breast cancer.Carcinogenesis. 1996; 17: 1313-1316Crossref PubMed Google Scholar; Wang-Gohrke et al. Wang-Gohrke et al., 1998Wang-Gohrke S Rebbeck TR Besenfelder W Kreienberg R Runnebaum IB p53 germline polymorphisms are associated with an increased risk for breast cancer in German women.Anticancer Res. 1998; 18: 2095-2099PubMed Google Scholar; Weston et al. Weston et al., 1998Weston A Wolff MS Morabia A True extended haplotypes of p53: indicators of breast cancer risk.Cancer Genet Cytogenet. 1998; 102: 153-154Abstract Full Text PDF PubMed Google Scholar). However, more research is needed to resolve this question. In our laboratory, we have adopted a complementary molecular epidemiological and basic-science approach. First, we are trying again to replicate the epidemiological studies of breast cancer, by using the PCR-based physical haplotype method in a population-based case-control study that has sufficient power. Second, we have derived normal human mammary cell strains with known haplotypes and plan to test their response to suspect breast carcinogens. Our grateful thanks to Helen Michael for assistance with preparation of the manuscript.

We have investigated the role of cholesteryl ester transfer protein (CETP) and scavenger receptor B1 (HDL receptor, SRB) in high-density lipoprotein (HDL) metabolism and atherogenesis. Studies in Japanese-American subjects indicate that heterozygous CETP deficiency (D442G mutation) is associated with moderately increased HDL levels but increased CHD risk; however, when CETP deficiency is associated with high HDL levels (HDL chol> 60 mg/dl), CHD prevalence is low. Recently, we have investigated the impact of the ileu405:val CETP polymorphism, found in many ethnic groups. Subjects with the VV polymorphism were found to have higher HDL chol and lower plasma CETP levels; this effect was primarily observed in subjects with plasma TG> 160 mg/dl. Hypertriglyceridemic VV subjects had increased CHD risk compared to normotriglyceridemic VV or II subjects (p < 0.05). CETP distribution was bimodal in VV subjects but unimodal in II subjects, suggesting that a functionally significant CETP gene mutation has arisen on a subset of chromosomes containing V alleles. SRB transgenic mice (liver-specific promoter) had profound reductions in HDL cholesterol and apoA-I levels, confirming that SRB1 is a functional HDL receptor. CHO cells transfected with SRB1 showed increased selective uptake of HDL CE, C and phospholipid and were also found to have a 2- to 4-fold increase in the initial rate of HDL-mediated free cholesterol efflux. In situ hybridization showed that SRB1 mRNA was expressed by macrophage-like cells in atheroma of apoEO mice. Thus, SRB1 may also be involved in HDL-mediated cholesterol efflux from cells in the arterial wall, as well as in the uptake of HDL C and CE by the liver.

PURPOSE: The purpose of this report is to describe levels of total cholesterol and high-density-lipoprotein cholesterol (HDL-C) in a group of elderly men and to compare these levels to those that were observed 20 years earlier. METHODS: From 1965–1968, the Honolulu Heart Program began following 8006 men of Japanese ancestry living on the island of Oahu, Hawaii, in a prospective study of coronary heart disease and stroke. This report presents data for 971 men who participated in a separate fasting study of lipids and lipoproteins that first occurred from 1970–1972 and in those who received repeat examinations 10 and 20 years later. Men were aged 71–93 years at the last examination. RESULTS: Over the 20-year period, total cholesterol declined by 1.6–1.8 mg/dL per year (P < 0.001), from average baseline values of 219–222 mg/dL. Levels of HDL-C rose 0.2–0.3 mg/dL per year (P < 0.001), from average baseline values of 44–46 mg/dL. After adjustment for baseline cholesterol levels, men with prevalent coronary heart disease at the end of the 20-year follow-up experienced significantly greater reductions in total cholesterol levels than men without disease (P < 0.001). Men who developed coronary heart disease within the first 10 years of follow-up had the greatest yearly decline in total cholesterol (1.9 mg/dL), followed by men who developed heart disease later (1.8 mg/dL) and men who remained disease free (1.5 mg/dL). Differences between men with recent and earlier disease were not statistically significant, although men without coronary disease experienced a significantly smaller decrease in total cholesterol than either of these groups (P < 0.05). CONCLUSIONS: Changes in total cholesterol and HDL-C levels with advancing age may be part: of a natural aging process. Some changes, however, such as large reductions in total cholesterol, may signal occult disease or declines in overall health. Selective survival may contribute to these findings since improvements in lipid and lipoprotein levels that are beneficial in younger ages were common in this long-lived cohort of men.

Annals of the New York Academy of SciencesVolume 811, Issue 1 p. 178-184 Cholesteryl Ester Transfer Protein and Atherogenesis A. TALL, Corresponding Author A. TALL Division of Molecular Medicine Department of Medicine Columbia University New York, New York 10032Address correspondence to: A. Tall, Division of Molecular Medicine, Columbia University, 630 West 168th Street, PH 8 101, New York, NY 10032.Search for more papers by this authorD. SHARP, D. SHARP Honolulu Heart Program Kuakini Medical Center 347 North Kuakini Street Honolulu, Hawaii 96817Search for more papers by this authorS. ZHONG, S. ZHONG Federal Drug Administration Center for Biologics Evaluation and Research Division of Cellular and Gene Therapies National Institutes of Health Building, 29B 29 Lincoln Drive MSC 4555 Bethesda, Maryland 20892Search for more papers by this authorT. HAYEK, T. HAYEK Rambam Medical Center Israel Institute of Technology Faculty of Medicine Haifa 31096, IsraelSearch for more papers by this authorL. MASUCCI-MAGOULAS, L. MASUCCI-MAGOULAS Division of Molecular Medicine Department of Medicine Columbia University New York, New York 10032Search for more papers by this authorE. M. RUBIN, E. M. RUBIN Cell and Molecular Biology Division Lawrence Berkeley Laboratory University of California One Cyclotron Road (M/S 74/157) Berkeley, California 94720Search for more papers by this authorJ. L. BRESLOW, J. L. BRESLOW Rockefeller University 1230 York Avenue New York, New York 10021Search for more papers by this author A. TALL, Corresponding Author A. TALL Division of Molecular Medicine Department of Medicine Columbia University New York, New York 10032Address correspondence to: A. Tall, Division of Molecular Medicine, Columbia University, 630 West 168th Street, PH 8 101, New York, NY 10032.Search for more papers by this authorD. SHARP, D. SHARP Honolulu Heart Program Kuakini Medical Center 347 North Kuakini Street Honolulu, Hawaii 96817Search for more papers by this authorS. ZHONG, S. ZHONG Federal Drug Administration Center for Biologics Evaluation and Research Division of Cellular and Gene Therapies National Institutes of Health Building, 29B 29 Lincoln Drive MSC 4555 Bethesda, Maryland 20892Search for more papers by this authorT. HAYEK, T. HAYEK Rambam Medical Center Israel Institute of Technology Faculty of Medicine Haifa 31096, IsraelSearch for more papers by this authorL. MASUCCI-MAGOULAS, L. MASUCCI-MAGOULAS Division of Molecular Medicine Department of Medicine Columbia University New York, New York 10032Search for more papers by this authorE. M. RUBIN, E. M. RUBIN Cell and Molecular Biology Division Lawrence Berkeley Laboratory University of California One Cyclotron Road (M/S 74/157) Berkeley, California 94720Search for more papers by this authorJ. L. BRESLOW, J. L. BRESLOW Rockefeller University 1230 York Avenue New York, New York 10021Search for more papers by this author First published: 17 December 2006 https://doi.org/10.1111/j.1749-6632.1997.tb52000.xCitations: 12Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume811, Issue1Atherosclerosis IVApril 1997Pages 178-184 RelatedInformation

Hyperinsulinemia has been associated with cardiovascular disease (CVD), but whether this relation is independent of other CVD risk factors is uncertain. Most studies have focused on coronary heart disease (CHD), but few have included peripheral vascular disease (PVD) and stroke. Moreover, evidence in elderly and minority populations is limited. Between 1991 and 1993, 3562 elderly (71 to 93 years) Japanese-American men from the Honolulu Heart Program were examined and had fasting insulin levels measured. Hyperinsulinemia, defined as a fasting insulin > or =95th percentile among nonobese men with normal glucose tolerance and no diabetic history or medication use, was observed in 22% of the population. Subjects with hyperinsulinemia had a more adverse CVD risk factor profile and had higher age-adjusted prevalences of CHD, angina, PVD, thromboembolic stroke, and hemorrhagic stroke compared with those without hyperinsulinemia. Age-adjusted fasting insulin levels but not 2-hour levels were also significantly elevated (P<.01) in those with prevalent CVD compared with those without. In logistic regression analyses, adjustment for multiple CVD risk factors attenuated the relations of hyperinsulinemia with CHD, angina, and PVD to nonsignificant levels, whereas those involving thromboembolic and hemorrhagic stroke were strengthened and remained significant (odds ratios=2.27 and 7.53, 95% confidence intervals=1.25 to 4.13 and 1.65 to 34.25, respectively). When multivariate analyses were restricted to nondiabetic subjects, associations were slightly weaker and in general nonsignificant. Nondiabetic men with thromboembolic stroke were twice as likely to have hyperinsulinemia as those who were stroke-free, although this association was of borderline significance (odds ratio= 1.99, 95% confidence interval=0.95 to 4.17, P=.069). In subjects with elevated total cholesterol levels, somewhat stronger associations were observed for PVD and stroke but not for CHD. Although further prospective studies are indicated, particularly for PVD and stroke, these cross-sectional results are consistent with an indirect role for insulin in CVD, wherein hyperinsulinemia or an underlying insulin-resistant state may adversely affect other CVD risk factors or serve as a marker for an atherogenic or thrombogenic state.

"Fish Consumption May Limit the Damage of Smoking on the Lung: To the Editor." American Journal of Respiratory and Critical Care Medicine, 151(5_pt_1), p. 1688