The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore

Abstract

Singapore comprises three ethnic groups: Chinese (76.7%), Malays (14%), and Asian-Indians (7.9%). Overall, Singaporeans experience coronary heart disease rates similar to those found in the United States. However, there is a dramatic interethnic gradient, with Asian-Indians having significantly higher risk than Chinese and Malays. These differences are associated with HDL cholesterol levels and cannot be solely explained by environmental exposure, and may be driven by genetic factors. The gene encoding apolipoprotein A-V ( APOA5 ) has been located on chromosome 11, and it is emerging as an important candidate gene for lipoprotein metabolism. We investigated associations between APOA5 polymorphisms and plasma lipids in 3,971 Singaporeans to establish whether they accounted for some of the ethnic differences in plasma lipids. We found significant associations between the minor alleles at each of four common polymorphisms and higher plasma triglycerides (TGs) across ethnic groups. Haplotype analyses showed significant associations with TGs, explaining 6.9%, 5.2%, and 2.7% of the TG variance in Malays, Asian-Indians, and Chinese, respectively. Conversely, we observed significant inverse associations between the minor alleles and HDL cholesterol concentrations for Chinese and Malays. These data suggest that APOA5 plays a role in the ethnic differences observed for plasma TG and HDL cholesterol concentrations. -Lai, C-Q., E-S. Tai Singapore is a highly developed country in Southeast Asia, populated by ‫ف‬ 4.5 million people living in a mostly urbanized area of ‫ف‬ 700 km 2 and representing three ethnic groups (Chinese 76.7%, Malay 14%, and Indian 7.9%, with other minor ethnicities making up the other 1.4%). Despite their ethnic and cultural differences from Western populations, Singaporeans suffer from high cardiovascular disease (CVD) rates similar to those found in the United States and Australia (1). Most interestingly, the effects of urbanization have not affected all three major ethnic groups equally. Asian-Indians have the highest rate of CVD, followed at a significant distance by Malays and Chinese (1-4). In addition, the ethnic difference is further reflected by the diverse lipid profile among these ethnic groups. In particular, HDL cholesterol levels mirror CVD rates, with Asian-Indians having the lowest, followed by the Malays, and with the Chinese displaying the highest concentrations. Conversely, plasma triglyceride (TG) concentration is the highest in Malays and Asian-Indians and the lowest in Chinese. These differences occur despite the high socioeconomic status and the consumption of diets that have similar biochemical and nutritional compositions regardless of the ethnic origin (2,5). This provides an ideal situation in which to examine the contribution of genetic factors to disease risk heterogeneity and to study the interaction between genetic and environmental factors.High TG and LDL cholesterol and low HDL cholesterol concentrations are independent risk factors for CVD (6, 7). Identifying ...

Different effects of apolipoprotein A5 SNPs and haplotypes on triglyceride concentration in three ethnic origins

“…33,34 Pervious studies reported that the allele frequency ranged from 6 to 8% for Caucasian and Africans, 1,4,7 from 4 to 8% in African Americans, 4,35 was 15% in Hispanics 4,7 and was very rare, that is, 1-3%, in Chinese and Japanese. 10,31,32 The frequencies of the other four SNPs ranged from 9 to 11% for Caucasians, 4,7 13 to 16% for Hispanics, 4,36 6 to 9% for African Americans 1,4 and are in common frequencies of 27 to 37% among East Asian populations. 10,31,[36][37][38] Although all four common polymorphisms at the ApoA5 locus were associated with plasma TG concentrations in Yemenite and Ashkenazi, the possibility that any one of them represents a functional variant is very small because; they are in a strong LD with one or more functional variants that directly affect the TG plasma concentration.…”

“…10,31,32 The frequencies of the other four SNPs ranged from 9 to 11% for Caucasians, 4,7 13 to 16% for Hispanics, 4,36 6 to 9% for African Americans 1,4 and are in common frequencies of 27 to 37% among East Asian populations. 10,31,[36][37][38] Although all four common polymorphisms at the ApoA5 locus were associated with plasma TG concentrations in Yemenite and Ashkenazi, the possibility that any one of them represents a functional variant is very small because; they are in a strong LD with one or more functional variants that directly affect the TG plasma concentration. Several other polymorphisms in the ApoC-III gene have been shown to be associated with plasma TG concentration in different studies, 39 the most prominent being SNP 1100C4T in axon 3.…”

“…The analysis includes five SNPs that were reported previously on Caucasian populations and other ethnic groups. 1,4,5,7,10 Their description is as follows: rs662799 (À1131T4C) in the 5¢ region and previously reported as SNP3; rs651821 (À3A4G) in the 5¢ region and previously reported as a start codon or kozak; rs3135506 (c. 56C4G) in the third exon and previously reported as S19W or SNP5; rs2072560 (IVS3+476G4A) in intron 3 and previously reported as SNP 2 and rs2266788 (1259T4C) in exon 4 previously reported as SNP 1.…”

“…1, [4][5][6][7] They were found to affect postprandial lipemia, 8 and to increase the risk of cardiovascular disease (CVD). 5 Five common single nucleotide polymorphisms (SNPs) within this locus (rs662799, rs651821, rs3135506, rs2072560 and rs2266788) have been identified in studies of different designs and in some race-specific populations associated with TG, VLDL-C and HDL-C. 5,9,10 The frequencies of the minor alleles and haplotypes vary significantly among ethnic origins. Most studies show a 15-30% increase in TG concentrations with the presence of the minor allele at these polymorphisms and there is no clear evidence that ethnic origin determines the magnitude of the above increase.…”

A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese

“…Figure 2a shows the results of the meta-analysis of our findings on rs662799 together with previous reports on healthy Chinese subjects. [19][20][21][22][23][24][25] The combined estimate of the standardized mean difference in plasma triglyceride level between the TT and CC genotypes was 0.58 (95% CI: 0.43-0.74) in a random effects model. In a meta-analysis of four studies on healthy European subjects with sample sizes greater than 300, [26][27][28][29] the corresponding estimate between TT and TC/CC genotypes was 0.33 (95% CI: 0.24-0.43) (Figure 2b).…”