Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish

Background: Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels. Methods: To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals. Results: From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-Clevels (P < 10^-68). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100,whichwas alsostronglyassociatedwithLDL-Cinthereplicationsample (P < 10^-36). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10^-6 in both) and accounted for 26% and 7% of the variation in LDL-Clevels andCAC,respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dLhigher, a 4.41-fold higher odds(95%confidence interval, 2.69-7.21) of having detectableCAC,anda9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400). Conclusion: The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.