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

Arch Intern Med. 2010 Nov 8;170(20):1850-5. doi: 10.1001/archinternmed.2010.384.


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 < 10(-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 < 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-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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoprotein B-100 / blood
  • Apolipoprotein B-100 / genetics*
  • Calcinosis / blood
  • Calcinosis / ethnology
  • Calcinosis / genetics*
  • Cholesterol, LDL / blood*
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / ethnology
  • Coronary Artery Disease / genetics*
  • DNA / genetics*
  • Denmark / ethnology
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Pennsylvania / epidemiology
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Retrospective Studies
  • Risk Factors
  • Young Adult


  • Apolipoprotein B-100
  • Cholesterol, LDL
  • DNA