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

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, John Shelton, Jeffrey R. O'Connell, Alan R. Shuldiner, Braxton D. Mitchell

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
Pages (from-to)1850-1855
Number of pages6
JournalArchives of internal medicine
Volume170
Issue number20
DOIs
StatePublished - Nov 8 2010

ASJC Scopus subject areas

  • Internal Medicine

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    Shen, H., Damcott, C. M., Rampersaud, E., Pollin, T. I., Horenstein, R. B., McArdle, P. F., Peyser, P. A., Bielak, L. F., Post, W. S., Chang, Y. P. C., Ryan, K. A., Miller, M., Rumberger, J. A., Sheedy, P. F., Shelton, J., O'Connell, J. R., Shuldiner, A. R., & Mitchell, B. D. (2010). Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish. Archives of internal medicine, 170(20), 1850-1855. https://doi.org/10.1001/archinternmed.2010.384