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-C levels ( P −68 ). Additional genotyping revealed the presence of R3500Q , the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample ( P −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 −6 in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-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.