Familial Defective Apolipoprotein B-100 and Increased Low-density Lipoprotein Cholesterol and Coronary Artery Calcification in the Old Order Amish

Overview

Journal Arch Intern Med

Specialty General Medicine

Date 2010 Nov 10

PMID 21059979

Citations 45

Authors

Haiqing Shen

Coleen M Damcott

Evadnie Rampersaud

Toni I Pollin

Richard B Horenstein

Patrick F McArdle

Patricia A Peyser

Lawrence F Bielak

Wendy S Post

Yen-Pei C Chang

Kathleen A Ryan

Michael Miller

John A Rumberger

Patrick F Sheedy 2nd

John Shelton

Jeffrey R OConnell

Alan R Shuldiner

Braxton D Mitchell

Affiliations

Soon will be listed here.

Abstract

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.

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