Abstract 3483: The APOB R3500Q Polymorphism Is Common In The Old Order Amish And Is Associated With Low Density Lipoprotein Cholesterol Concentrations And Coronary Artery Calcification
Low density lipoprotein cholesterol (LDL-C) is a major cardiovascular disease (CVD) risk factor. Reduction in LDL-C levels reduces the incidence of CVD. To identify the genetic determinants of this trait, we carried out a whole genome association (WGA) scan in 861 relatively healthy Amish subjects aged 20 – 80 yrs from Lancaster County, PA, recruited for a study of cardiovascular health. Fewer than 2% of subjects reported a prior history of a cardiovascular event. The WGA scan, carried out using the Affymetrix 500K platform, revealed a cluster of single nucleotide polymorphisms (SNPs) in the region of the APOB gene on chromosome 2p24.1 to be strongly associated with both LDL-C levels (p < 10−60) and coronary artery calcification (CAC) score (p < 10−9), as measured by EBCT scan. Following sequencing of APOB exons revealed the presence of a mutation in exon 26 (R3500Q), whose allele frequency in European Caucasians was reported to be 0.04% to 0.2%. Subsequent genotyping of this mutation in more Amish individuals (n = 1,533) revealed an allele frequency of 6.1% and a carrier frequency of 12%. The mutation was strongly associated in additive fashion with levels of both LDL-C (P < 10−93) and CAC (P < 10−15) and accounted for 45% of the variation in LDL-C levels and 6% of the variation in CAC score. Carriers of the R3500Q mutation had approximately 60 mg per deciliter higher LDL-C levels and had a 4.33-fold higher odds (95% C.I.: 2.46 –7.62) of having any CAC compared to noncarriers. This allele accounted for 10% of severe CAC in the population.
Conclusion: The high frequency of the APOB R3500Q variant in the Amish population likely represents a founder effect. It is present in 1 of 8 –9 individuals in this population, causing hypercholesterolemia and increasing the risk of subclinical CVD.