Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese

Abstract: Background: Familial combined hyperlipidaemia (FCH) is the most common genetic dyslipidaemia associated with coronary artery disease. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A4/A5 gene cluster are associated with FCH in Caucasians and with elevated triglycerides (TG) in various ethnic groups. We examined these associations with FCH in Hong Kong Chinese. Methods: Fifty-six Chinese FCH patients and 176 unrelated controls were studied. Thirteen SNPs in the APOA1/C3/A4/A5 cluster were genotyped. Results: Four alleles in APOA5 were associated with FCH (P <0.001). The −1131T>C (rs662799) and −3A>G (rs651821) SNPs in APOA5 were in almost complete linkage disequilibrium (LD, r 2 =0.99), and their minor alleles were more frequent (P <0.001) in FCH than controls (0.60 vs. 0.24). The odds ratio (OR) for FCH was 6.2 (95% CI, 2.6–14.8) and 6.1 (2.6–14.6) per copy of −1131C and −3G, respectively, and 24.6 (8.4–72.0) and 24.4 (8.4–70.9) in −1131C and −3G homozygotes, respectively, as compared to wild-type homozygotes. The 1891T>C (rs2266788) SNP was in LD (r 2 =0.68) with −1131T>C and −3A>G, and the minor allele was more frequent in FCH than controls (0.42 vs. 0.19, P <0.001). The 553G>T (rs2075291) nonsynonymous variant was also associated with FCH (0.15 vs. 0.04, P =0.001) and, along with −3A>G (or −1131T>C) and 1891T>C, contributed to haplotypes predicting FCH. The two tightly linked SNPs, −1131T>C and −3A>G polymorphism were significantly associated with lipid traits in all subjects combined, with variant homozygous subjects having higher TG and LDL-C and lower HDL-C levels. Conclusions: Some common polymorphisms and haplotypes in APOA5 are closely associated with FCH in Hong Kong Chinese, and these differ from those found in Caucasians. [Copyright &y& Elsevier]