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Decreased bone mineral density in subjects carrying familial defective apolipoprotein B-100
Laura M Yerges-Armstrong1, Haiqing Shen, Kathleen A Ryan
1Baltimore, MD 21201. lyerges@medicine.umaryland.edu.
Insights
Individuals with a specific gene mutation (R3500Q APOB) linked to high cholesterol had lower bone mineral density (BMD). This suggests elevated LDL-C may causally impact bone health, potentially linking cardiovascular disease and osteoporosis.
Area of Science:
- Endocrinology
- Genetics
- Bone Biology
Background:
- Osteoporosis and cardiovascular disease share potential links, with hyperlipidemia hypothesized as a common risk factor.
- Familial defective apolipoprotein B-100, caused by the R3500Q APOB mutation, is known to elevate low-density lipoprotein cholesterol (LDL-C).
Purpose of the Study:
- To investigate the relationship between the R3500Q APOB mutation and bone mineral density (BMD).
- To test the hypothesis that carriers of the R3500Q mutation have lower BMD due to lifelong elevated LDL-C.
Main Methods:
- Cross-sectional study conducted in the Old Order Amish (OOA) population, chosen for its high frequency of the R3500Q APOB mutation.
- Analysis included 1097 Amish individuals (125 R3500Q carriers), with BMD measured using dual-energy x-ray absorptiometry.
Main Results:
- R3500Q carriers exhibited significantly lower BMD at the femoral neck, lumbar spine, and whole body compared to non-carriers, even after adjusting for covariates.
- Adjusting for LDL-C levels partially attenuated the association between the R3500Q genotype and BMD, but did not fully account for the observed difference.
Conclusions:
- This study provides novel evidence, utilizing the unique genetic makeup of the OOA population, supporting a causal role for elevated LDL-C in reducing bone mineral density.
- The findings contribute to understanding the complex interplay between lipid metabolism and bone health, potentially linking cardiovascular disease risk factors to osteoporosis.
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 (∼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.
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