Background Bone strength and thus, the likelihood of fracture, is a complex trait likely influenced by a number of different genes. The number, locations and effects of the individual genes contributing to natural variation in skeletal fragility are all unknowns. Methods To begin to identify the heritable determinants of bone strength, we have examined femoral shaft failure load (FL) in a genetically heterogeneous F2 population of mice (N=997) derived from C57BL/6 (B6) and DBA/2 (D2) inbred progenitor strains. Femora from sixteen-week-old mice were harvested and tested to failure in 3-point bending. Mice were genotyped with microsatellite markers chosen from the MIT database at an average spacing of 15 centiMorgans (cM). Results Genome-wide quantitative trait locus (QTL) analysis of the B6D2F2 population revealed regions on five different chromosomes that were very strongly linked to FL (chromosomes 3, 7, 8, 14, and 17) in both genders. Evidence of gender-specific genetic influences on FL was also identified at three other chromosomal sites (chromosomes 2, 12, and X). It is interesting to note that the chromosome 2, 3, 8, 12, 14, and 17 QTLs identified here contain genomic regions thought to be homologous with 20p, 1q, 16q, 2p, and 13q regions of the human genome that are associated with osteoporosis risk. Conclusions These results suggest that the genetic determinants of the complex phenotype of skeletal fracture can be effectively studied by analysis of primary skeletal characteristics. The identification of the genes responsible for biomechanical differences in murine skeletal development should reveal fundamentally important processes in the control of skeletal integrity. Based on the considerable linkage conservation between mouse and human genomes, findings in this animal model should aid in the identification of specific osteoporosis candidate genes for study in human populations.

The β-amyloids (abetas) are the major components of the plaque observed in the brains of patients with Alzheimer’s disease. The conundrum is that although they are produced in everyone during the posttranslational processing in the endoplasmic reticulum (ER) of the amyloid precursor protein (APP), deposits are only observed in the elderly. Our work suggests that normals have a carrier protein(s) keeping them in solution. Based on immunoblotting studies of cerebrospinal fluid (CSF) from normals, we find that the bulk of the abetas are bound to the ER chaperones, ERp57 and calreticulin, suggesting that these may be carrier proteins which prevent aggregation of the abetas and that the deposits are due to faulty ER posttranslational processing of APP with the failure to form this complex. If membrane protein synthesis is similarly affected, it could explain the neuronal dysfunction characteristic of Alzheimer’s disease.

Normal bronchial epithelial cells (NBECs) are at risk for damage from inhaled and endogenous oxidative species and from epoxide metabolites of inhaled polycyclic aromatic hydrocarbons. Epidemiological and in vitro data suggest that interindividual variation in this risk may result from variation in NBEC expression of enzymes that inactivate reactive species by conjugating them to glutathione. Quantitative competitive reverse transcription-PCR was used to measure mRNA levels of glutathione transferases (GSTs) and glutathione peroxidases (GSHPxs) in primary NBECs from subjects with or without bronchogenic carcinoma. Mean expression levels (mRNA/10(3) beta-actin mRNA) in NBECs from 23 subjects without bronchogenic carcinoma compared to those from 11 subjects with bronchogenic carcinoma respectively (in parentheses) were: mGST (26.0, 6.11), GSTM3 (0.29, 0.09), combined GSTM1,2,4,5 (0.98, 0.60), GSTT1 (0.84, 0.76), GSTP1 (287, 110), GSHPx (140, 62.1), and GSHPxA (0.43, 0.34). Levels of GSTP1, GSTM3, and GSHPx were significantly (P < 0.05) lower in NBECs from subjects with bronchogenic carcinoma. Further, the gene expression index formed by multiplying the values for mGST x GSTM3 x GSHPx x GSHPxA x GSTP1 had a sensitivity (90%) and specificity (76%) for detecting NBECs from bronchogenic carcinoma subjects that was better than any individual gene. In cultured NBECs derived from eight individuals without bronchogenic carcinoma and incubated under identical conditions such that environmental effects were minimized, the mean level of expression and degree of interindividual variation for each gene evaluated was less than that observed in primary NBECs. Data from these studies support the hypotheses that (a) interindividual variation in risk for bronchogenic carcinoma results in part from interindividual variation in NBEC expression of antioxidant genes; (b) gene expression indices will better identify individuals at risk for bronchogenic carcinoma than individual gene expression values; and (c) both hereditary and environmental exposures contribute to the level of and interindividual variation in gene expression observed in primary NBECs. Many epidemiological studies have been designed to evaluate risk associated with polymorphisms or gene expression levels of putative susceptibility genes based on measurements in surrogate tissues, such as peripheral blood lymphocytes. Based on data presented here, it will be important to include the assessment of NBECs in future studies. Measurement of antioxidant gene expression in NBECs may identify the 5-10% of individuals at risk for bronchogenic carcinoma. Bronchoscopic sampling of NBECs from smokers and ex-smokers then will allow susceptible individuals to be entered into surveillance and/or chemoprevention studies.