Decreased bone mineral density in subjects carrying familial defective apolipoprotein B-100.

Context: Although numerous epidemiologic studies have documented associations between osteoporosis and cardiovascular disease, the mechanisms underlying this association remain to be clarified. One hypothesis is that hyperlipidemia may be a common predisposing factor to both atherosclerotic heart disease and bone fragility. Objective: To evaluate this, we compared bone mineral density (BMD) between subjects with and without the R3500Q APOB mutation, the cause of familial defective apolipoprotein B-100, which has been previously shown to markedly increase low-density lipoprotein cholesterol (LDL-C). We hypothesized that R3500Q carriers would have lower BMD due to lifetime, elevated LDL-C. Design: This was a a cross-sectional study in the Old Order Amish (OOA) population. Participants: The R3500Q APOB mutation is present at a high frequency (similar to 6% vs <0.5%) in the OOA population due to a founder effect. Therefore, we conducted analysis on 1097 Amish individuals of whom 125 were R3500Q carriers. Main Outcome Measure: BMD was measured by dual-energy x-ray absorptiometry. Results: After adjusting for age, age(2), sex, body mass index, and family structure, carriers for the Q risk allele had significantly lower BMD than noncarriers at the femoral neck (P = .037), lumbar spine (P = .035) and whole body (P = .016). Adjusting for LDL-C attenuated the association between R3500Q genotype and BMD but did not completely explain the relationship. Subgroup analyses showed no significant interactions with sex, age, or presence of metabolic syndrome. Conclusion: These results use the unique genetic architecture of the OOA population to provide a novel line of evidence supporting a causal role for elevated LDL-C in lowering BMD.