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 < 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).


CONCLUSIONS
The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Haiqing
H
Shen
Coleen M
CM
Damcott
Evadnie
E
Rampersaud
Toni I
TI
Pollin
Richard B
RB
Horenstein
Patrick F
PF
McArdle
Patricia A
PA
Peyser
Lawrence F
LF
Bielak
Wendy S
WS
Post
Yen-Pei C
YP
Chang
Kathleen A
KA
Ryan
Michael
M
Miller
John A
JA
Rumberger
Patrick F
PF
Sheedy
John
J
Shelton
Jeffrey R
JR
O'Connell
Alan R
AR
Shuldiner
Braxton D
BD
Mitchell
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053299:Apolipoprotein B-100 / Q000097:blood / Q000235:genetics*; D002114:Calcinosis / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D003718:Denmark / Q000208:ethnology; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010414:Pennsylvania / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D004247:DNA