Peter Elfström (2009): Associated disorders in celiac disease. Örebro Studies in Medicine 27, 83 pages. Background: Celiac disease (CD) is an autoimmune disorder that affects genetically susceptible individuals and is induced by dietary gluten. Treatment consists of a lifelong gluten-free diet. CD is common and affects about 1% of the general population. The classic symptoms include diarrhea and malabsorption, but many patients have only mild symptoms or no symptoms at all. The proportion of individuals presenting with atypical symptoms or discovered only when investigating an associated condition of CD is increasing. Aims: The aim of this thesis was to investigate the risk of possible associated disorders through Swedish population-based registers. The objective was to gain more information on the consequences of having CD and to identify high risk groups where screening may be considered. Materials and methods: We used the Swedish hospital discharge register to examine the risk of liver disease, autoimmune heart disease, Addison’s disease and thyroid disorders in a cohort of about 14,000 individuals with CD and an age and sexmatched reference population of 70,000 individuals. In the last study we used all regional pathology registers and the cancer registry to examine the risk of hematopoietic cancer, including lymphoma in three different cohorts: I) 28,810 individuals with CD; II) 12,681 individuals with small intestinal mucosal inflammation but without villous atrophy; and III) 3552 individuals with latent CD (a positive serology test for CD with a normal small intestinal biopsy). Results: CD is statistically significantly associated with an increased risk of liver disease, Addison’s disease, thyroid disease and lymphoma. We also found an increased risk of lymphoma in individuals with small intestinal mucosal inflammation. There was no statistically significant association between autoimmune heart disease or leukemia and CD. Latent CD was not associated with any hematopoietic cancers. Conclusion: This thesis found a positive association between CD and a number of autoimmune and inflammatory disorders. Clinicians need to have a high awareness of this association and to test for these conditions when symptoms appear.

El síndrome metabólico (SM) y la hiperlipidemia familiar combinada (HLFC) comparten una parte importante de sus rasgos clínicos, y se ha postulado para ambos una etiología parcialmente coincidente. Se considera que su expresión está afectada por múltiples loci genéticos, existiendo adicionalmente interacción gen-ambiente. En este trabajo se explora la posible implicación en el desarrollo de SM de USF1, un gen previamente asociado con HLFC.Se desarrolló un estudio caso-control en el que se analizó la variabilidad genética en USF1 mediante genotipado por pirosecuenciación de los SNP rs2516837, rs2516838, rs6686076, rs2516839, rs2073653, rs2774276, rs2073656, rs2073658 y rs3737787. Se estudiaron 192 sujetos con SM según los criterios ATPIII y 197 sujetos control. Se analizaron las frecuencias alélicas y genotípicas y se estimaron los haplotipos compuestos por los citados polimorfismos. Se analizó estadísticamente la asociación de SNP aislados y haplotipos estimados con el desarrollo de SM.Las frecuencias de los 9 SNP estudiados mostraron que se encontraban en equilibrio de Hardy-Weinberg tanto en casos como en controles. Se apreció un importante grado de desequilibrio de unión entre ellos, pero las diferencias en su distribución entre casos y controles no alcanzaron significación estadística. La estimación de haplotipos de los SNP analizados en los grupos estudiados detectó 6 haplotipos principales, pero ninguno de ellos mostró una asociación estadísticamente significativa con la condición de SM.En la muestra de pacientes estudiados no se ha observado una asociación de la variabilidad genética en el locus USF1 con el desarrollo de SM definido según los criterios ATPIII.Metabolic syndrome (MS) and familial combined hyperlipidemia (FCHL) share many clinical features and a partially overlapping etiology for these two entities has been postulated. The expression of these disorders may be affected by multiple genetic loci in addition to gene-environment interaction. This study explored the possible involvement of the USF1 gene, which has previously been associated with FCHL, in the development of MS.A case-control study was performed to analyze genetic variation in USF1 defined by SNPs rs2516837, rs2516838, rs6686076, rs2516839, rs2073653, rs2774276, rs2073656, rs2073658, and rs3737787. SNP genotypes were determined by pyrosequencing in 192 subjects with MS according to the Adult Treatment Panel (ATP)-III criteria and 197 control subjects. Allelic and genotypic frequencies were analyzed for each SNP isolated, and haplotypes were estimated for the combined polymorphisms. A statistical analysis was performed of the association of the SNPs and haplotypes with the development of MS.The frequencies of the nine SNPs studied showed that they were in Hardy-Weinberg equilibrium in both cases and controls. There was a considerable degree of linkage disequilibrium between the SNPs but the differences in their distribution between cases and controls did not reach statistical significance. Estimation of the haplotypes of the SNPs analyzed in the study groups identified six main haplotypes, but none showed a statistically significant association with SM.In the sample of patients studied, no association was observed between genetic variation in the USF1 locus and the development of MS defined by ATP-III criteria.

BACKGROUND:The aim of the study was to investigate the effect of functional polymorphisms in promoters of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9, MMP-12 and plasminogen activator inhibitor (PAI) 1 genes on the growth rate of small abdominal aortic aneurysms (AAA).METHODS:Some 455 individuals with a small AAA (4.0-5.5 cm) were monitored for aneurysm growth by ultrasonography (mean follow-up 2.6 years). They also provided a DNA sample for analysis of the -1306 C > T, -1171 5A > 6A, -1562 C > T, -82 A > G and -675 4G > 5G alleles of MMP-2, MMP-3, MMP-9, MMP-12 and PAI-1, respectively. Mean linear AAA growth rates were calculated by flexible modelling; the sample size was sufficient to detect variants that influenced the growth rate by 25 per cent.RESULTS:For MMP-2, MMP-9 and MMP-12 genotypes, growth rates were similar to the mean linear growth rate of 3.08 mm per year. For MMP-3, growth rates were 3.05 (for 5A5A), 3.19 (for 5A6A) and 2.90 (for 6A6A) mm per year. For PAI-1, patients with 4G4G, 4G5G and 5G5G genotypes had growth rates of 3.18, 2.92 and 3.47 mm per year, respectively, for aneurysms with a baseline diameter of 45.1, 44.6 and 46.2 mm. The increased growth rate for patients with PAI-1 5G5G genotype was not statistically significant (P = 0.061), although these patients had the lowest plasma PAI-1 concentrations (P = 0.018).CONCLUSION:There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect.

Objective: The purpose of this study was to investigate the plausibility of serum sex hormone-binding globulin (SHBG) concentration as a risk marker for venous thromboembolism (VTE) during use of combined oral contraceptives (COC).Study design: This was a prospective, randomized cross-over study. Thirty-five women were treated with COCs containing the same amount of ethinyl estradiol and either levonorgestrel (LNG/EE) or desogestrel (DG/EE). Serum SHBG and markers of hemostasis were determined before and after 2 months on each treatment.Results: SHBG increased significantly with both preparations. Treatment with DG/EE caused more pronounced prothrombotic changes in hemostatic parameters than LNG/EE. With both treatment regimens, there was a significant correlation between changes in resistance to activated protein C (APCr) and changes in plasma SHBG.Conclusion: The correlation between SHBG and the well-established risk factor APCr might indicate the usefulness of SHBG as a risk marker for VTE during COC treatment. (C) 2004 Elsevier Inc. All rights reserved.

Background Atherosclerosis is the most common complication of diabetes. Correction of hyperglycaemia helps to prevent microvascular complications but has little effect on macrovascular disease. Post-hoc analyses of diabetic subpopulations in lipid intervention trials suggest that correction of lipoprotein abnormalities will lead to a decrease in coronary-artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS) was specifically designed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes.Methods 731 men and women with type 2 diabetes were screened by metabolic and angiographic criteria. 418 were randomly assigned micronised fenofibrate (200 mg/day) or placebo for at least 3 years. They were in good glycaemic control (mean haemoglobin A(10) 7.5%), had mild lipoprotein abnormalities, typical of type 2 diabetes, and at least one visible coronary lesion. Half had no previous clinical coronary disease. Initial and final angiograms followed a standard protocol and were analysed by a computer-assisted quantitative approach. Missing data for the primary endpoints (minimum lumen diameter, mean segment diameter, and mean percentage stenosis) were imputed. Analyses were by intention to treat.Findings Total plasma cholesterol, HDL-cholesterol. LDL-cholesterol, and triglyceride concentrations all changed significantly more from baseline in the fenofibrate group (n=207) than in the placebo group (n=211). The fenofibrate group showed a significantly smaller increase in percentage diameter stenosis than the placebo group (mean 2.11 [SE 0.594] vs 3.65 [0.608]%, p=0.02), a significantly smaller decrease in minimum lumen diameter (-0.06 [0.016] vs -0.10 [0.016] mm, p=0.029), and a non-significantly smaller decrease in mean segment diameter (-0.06 [0.017] vs -0.08 [0.018] mm, p=0.171). The trial was not powered to examine clinical endpoints, but there were fewer in the fenofibrate group than the placebo group (38 vs 50).Interpretation DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes. This effect is related, at least partly, to the correction of lipoprotein abnormalities, even those previously judged not to need treatment.

BACKGROUND:Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis. METHODS AND RESULTS:Single-strand conformation polymorphism analysis was carried out to search the promoter region of the gene encoding gelatinase B for naturally occurring genetic variation. As a result, an unreported common polymorphism was detected, which arose from a cytosine (C) to thymidine (T) transition at position -1562 relative to the start of transcription. Transient transfection experiments and DNA-protein interaction assays indicated that the T allele had a higher promoter activity than the C allele, which appeared to be due to preferential binding of a putative transcription repressor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects were genotyped. The allele frequencies were not significantly different between the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying 1 or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes had triple-vessel disease. CONCLUSIONS:These data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.

Summary To determine whether perturbations of haemostatic function and lipoprotein metabolism prevail long after preeclampsia and increase the risk of future coronary heart disease (CHD), we conducted a follow-up study in women with (cases, n = 25) or without (controls, n = 24) a history of preeclampsia. Blood samples were taken in the follicular and in the luteal phases of a menstrual cycle. Levels of blood pressure (BP) and proteinuria measured during the index pregnancy were included in the evaluation. Compared to control women who had undergone a normal pregnancy, the formerly preeclamptic patients had higher systolic (p <0.01) and diastolic (p <0.05) BPs and increased plasma levels of von Willebrand factor (vWF), fibrinogen, cholesterol, triglycerides and very low density lipoprotein (VLDL) (all p <0.05). The lipid, vWF, and fibrinogen levels were positively related to the degree of BP elevation but not to the degree of proteinuria during the index pregnancy. Except for the increase in vWF level, all biochemical perturbations were only present in the luteal but not in the follicular phase samples. In conclusion, persistent endothelial dysfunction with ensuing dysregulation of blood pressure, haemostatic perturbation and dyslipoproteinemia after preeclampsia may indicate a proneness to future CHD.

Summary The factor V (Arg506→Gln) mutation confers an increased risk of deep vein thrombosis, whereas its role in saphenous vein graft closure after coronary artery bypass grafting (CABG) remains unclear. This study examined the anticoagulant response to activated protein C (APC ratio) in relation to the surgical trauma and the significance of the factor V Leiden mutation in determining postoperative thrombin generation and fibrin formation and the risk of early vein graft occlusion. A total of 108 men undergoing elective CABG for exertional angina pectoris (mean age 61.1 ± 8.7 years) were examined. The patency of saphenous vein grafts was studied at routine reangiography three months after CABG. Of 100 patients who underwent reangiography, 23 had one or more occluded vein grafts at reangiography. Heterozygosity for the factor V (Arg506→Gln) mutation tended to be associated with early saphenous vein graft occlusion (5/11 carriers vs. 18/89 non-carriers with graft occlusion, व2 = 3.52, p = 0.06), whereas pre- and postoperative APC ratios did not. Pre- and postoperative determinations of prothrombin fragment 1+2, thrombin-antithrombin complexes and soluble fibrin levels did not differ between patients with and without the mutation. Early saphenous vein graft occlusion after CABG could tentatively be added to deep vein thrombosis as a vascular complication that can be attributed to the factor V (Arg506→Gln) mutation.

Diabetic patients with acute myocardial infarction have a poor prognosis, which has been attributed to a higher incidence of congestive heart failure and fatal reinfarction. This study reports on the one-year morbidity and mortality in a randomized study with the aim of testing whether insulin-glucose infusion initiated as soon as possible after onset of myocardial infarction and followed by long-term subcutaneous insulin treatment may have a beneficial effect on outcome in diabetic patients. In all, 306 patients were recruited to the insulin-treated group, while 314 patients served as controls. The overall mortality after one year was 19% in the insulin group compared to 26% among controls (P < 0.05). The treatment effect was most pronounced in patients without prior insulin medication and at low cardiovascular risk. In this stratum the in-hospital mortality was reduced by 58% (P < 0.05) and the one-year mortality by 52% (P < 0.02). The most frequent cause of death in all patients was congestive heart failure (66%), but cardiovascular mortality (congestive heart failure, fatal reinfarction, sudden death and stroke) tended to be decreased in insulin-treated patients. However, this difference did not reach the level of statistical significance. The number of reinfarctions was 53 (28% fatal) in the insulin group compared to 55 (45% fatal) in the control group. The two groups did not differ as regards need for hospital care or coronary revascularization during the year of follow-up. In summary, left ventricular failure and fatal reinfarctions contribute to increased mortality in diabetic patients following acute myocardial infarction. Intensive insulin treatment lowered this mortality during one year of follow-up.

The importance of the haemostatic system in predisposing to or precipitating coronary heart disease has gained increasing recognition. Major advances have been made in our understanding of the mechanisms resulting in hypercoagulability and impaired fibrinolytic function. Emphasis is placed on the role of dyslipoproteinaemia and insulin resistance.

Association studies were carried out in a sample of 86 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) AI-CIII-AIV gene cluster on among-individual differences in plasma lipid and lipoprotein traits, the five high density lipoprotein (HDL) subclasses (2b to 3c), lipoprotein lipase (LPL) activity and presence and progression of atherosclerosis. Individuals were genotyped for four polymorphisms; 5'apoAI (G/A-75), 3'apoAI (PstI; P +/-), apoCIII (C/T1100) and apoCIII (PvuII; V +/-), using PCR-based techniques. Allele frequencies were similar in healthy individuals and patients (frequencies of alleles in combined population: 5'apoAI-A-75 = 0.14, 3'apoAI-P- = 0.05, apoCIII-T1100 = 0.27 and apoCIII-V- = 0.18). In the healthy individuals, levels of low density lipoprotein (LDL) triglycerides were significantly associated with genotypes of the apoCIII-PvuII polymorphism (p = 0.02), but no other associations were found between lipids or HDL subclasses and single polymorphisms in the apoAI-CIII-AIV gene cluster. Levels of triglycerides and very low density lipoprotein (VLDL) triglycerides were significantly higher in the presence of the haplotype defined by the presence of apoCIII-T1100 and common alleles of the other three polymorphisms, explaining 5.8% and 7.8% (p = 0.03 and 0.01), respectively, of sample variance. In the patients, no associations were found between lipids or HDL subclasses and variation at the apoAI-CIII-AIV gene cluster. Associations were also examined between levels of HDL subclasses and variation at the apoE (common isoforms), apoB (signal peptide and XbaI polymorphisms) and lipoprotein lipase (PvuII, HindIII and Serine447/Stop polymorphisms) gene loci. In the patient group only, levels of protein in HDL2b, HDL2a and HDL3b subclasses were significantly associated with genotypes of the LPL-HindIII polymorphism (22.1, 19.3 and 11.4%, respectively, of sample variance; p < 0.05). Finally, associations were examined between genotypes at the apoAI-CIII-AIV gene cluster and the extent of coronary atherosclerosis. Global severity of atherosclerosis at the first angiography was weakly associated with genotypes of the apoCIII-C/T1100 polymorphism, presence of the T1100 allele being associated with 53% lower median score (1.6 vs 0.75; p = 0.09).(ABSTRACT TRUNCATED AT 400 WORDS)

Repeated coronary angiographies and single photon emission computed tomographies (SPECT) were performed at 9 and 33 months after myocardial infarction (MI) in 47 young men. Coronary lesions were classified in eight grades with respect to the reduction of the luminal diameter. The progression and regression of two steps or more in lesions of grade 2 or more, the recanalization of coronary thrombosis and an increase in collaterals were recorded. Patients were divided into three groups with regard to (A) deterioration, (B) improvement and (C) no changes in the three major coronary regions, respectively. Overall, 23 patients (49%) showed changes between the first and the second investigation. A simplified method using summarized short-axis slices for evaluation of the thallium-201 SPECT showed a significant difference in change of regional myocardial uptake of thallium-201 between groups A and B (P = 0.047) but not between the groups A and C, in lateral myocardial regions. No significant differences were found between any of the groups in respect of the anterior or inferior myocardial regions. These findings were not explained by changes in clinical status, maximum heart rate or workload, or by changes in medication. Our results suggest that substantial changes in coronary morphology can take place during the 2 years following MI without consistent changes in clinical symptoms or regional myocardial perfusion.