Association of CETP Taq1B and -629C > A polymorphisms with coronary artery disease and lipid levels in the multi-ethnic Singaporean population.

BACKGROUND: Hyperlipidaemia is a major risk factor for coronary artery disease (CAD) and cholesteryl ester transfer protein (CETP) gene polymorphisms are known to be associated with lipid profiles. METHODS: In this study, we investigated the association of two polymorphisms in the CETP, Taq1B (rs708272) and -629C > A (rs1800775), with CAD and lipid levels HDL-C in 662 CAD + cases and 927 controls from the Singapore population comprising Chinese, Malays and Indians. RESULTS: TaqB2 frequency was significantly lowest in the Malays (0.43) followed by Chinese (0.47) and highest in the Indians (0.56) in the controls. The B2 allele frequency was significantly lower in the Chinese CAD + cases compared to the controls (p = 0.002). The absence of the B2 allele was associated with CAD with an OR 2.0 (95% CI 1.2 to 3.4) after adjustment for the confounding effects of age, smoking, BMI, gender, hypertension, dyslipidemia and diabetes mellitus. The B2 allele was significantly associated with higher plasma HDL-C levels in the Chinese men after adjusting for confounders. Associations with plasma apoA1 levels were significant only in the Chinese men for Taq1B and -629C > A. In addition, the Taq1B polymorphism was only associated with plasma Apo B and Lp(a) in the Malay men. Significant associations were only found in non-smoking subjects with BMI <50th percentile. In this study, the LD coefficients between the Taq1B and -629C > A polymorphisms seemed to be weak. CONCLUSION: The absence the Taq1B2 allele was associated with CAD in the Chinese population only and the minor allele of the Taq1B polymorphism of the CETP gene was significantly associated with higher plasma HDL-C levels in Chinese men.

Mitochondrial DNA analysis reveals diverse histories of tribal populations from India.

We analyzed 370 bp of the first hypervariable region of the mitochondrial DNA (mtDNA) control region in 752 individuals from 17 tribal and four nontribal groups from the Indian subcontinent, to address questions concerning the origins, genetic structure and relationships of these groups. Southern Indian tribes showed reduced diversity and large genetic distances, both among themselves and when compared with other groups, and no signal of prehistoric demographic expansions. These results probably reflect enhanced genetic drift because of small population sizes and/or bottlenecks in these groups. By contrast, northern groups exhibited more diversity and signals of prehistoric demographic expansions. Phylogenetic analyses revealed that southern and northern groups (except northeastern ones) have related mtDNA sequences albeit at different frequencies, further supporting the larger impact of drift on the genetic structure of southern groups. The Indian mtDNA gene pool appears to be more closely related to the east Eurasian gene pool (including central, east and southeast Asian populations) than the west Eurasian one (including European and Caucasian populations). Within India, northeastern tribes are quite distinct from other groups; they are more closely related to east Asians than to other Indians. This is consistent with linguistic evidence in that these populations speak Tibeto-Burman languages of east Asian origin. Otherwise, analyses of molecular variance suggested that caste and tribal groups are genetically similar with respect to mtDNA variation.

Variation of the platelet glycoprotein IIIa PI(A1/A2) allele frequencies in the three ethnic groups of Singapore.

BACKGROUND: Polymorphisms of the glycoprotein IIIa receptor have been shown to be associated with differences in platelet aggregability. The PI(A2) variant of the polymorphism has been reported to be an inherited risk factor for acute coronary events. Although the allele frequency of this polymorphism is well documented in Caucasian populations, studies involving Asian Indians, Malays and Chinese are lacking. We studied 706 random male individuals to determine the genotypic distribution of this polymorphism in Singapore. METHODS: Male subjects included in this study were drawn from those undergoing routine annual medical examinations offered by their employers. Venous blood was obtained from these patients after an overnight fast and from which genomic DNA was extracted. Genotyping was carried out by polymerase chain reaction (PCR) followed by digestion with restriction enzyme NciI. Personal and family medical history of the subjects were also taken. RESULTS: The genotype distribution of the individuals studied was in accordance to a population at Hardy Weinberg equilibrium. The frequency of the PI(A2) allele was 0.1, 0.01 and 0.01 in the Indians, Malays and Chinese, respectively. The differences in frequencies of the PI(A2) variant are significant among different ethnic groups (P<0.001 for Indians vs. Chinese and Indians vs. Malays). CONCLUSIONS: We observed a significantly higher frequency of the PI(A2) allele among Indians relative to the Chinese and Malays in Singapore. The effect of this genotype may partially explain the higher rate of ischaemic heart disease seen among Indians compared to the Chinese and Malay ethnic groups.

Ethnic variations of a retinoblastoma susceptibility gene (RB1) polymorphism in eight Asian populations.

An A --> G single nucleotide polymorphism (SNP) at nucleotide 153,104 in the retinoblastoma susceptibility locus (RB1) at 13q14 was previously reported to be present only in Asians. In this study, we determined the distribution of this SNP in normal Southeast Asian populations (Chinese, Malay, Javanese, Thai, Filipino), in South Asian populations (Bangladeshi, Pakistani Pushtun and Indian) and in Chinese retinoblastoma cases and control subjects. The RB1 SNP was present in all populations at an overall frequency of =/< 0.18. Heterozygosity was higher in the Southeast Asian groups (0.14-0.34) than in the South Asian groups (Bangladeshi and Indian) (0.04-0.06). Significant differences in allele frequencies were found between the two population groups. Interestingly, our Pakistani population comprised of ethnic Pushtuns from northwest Pakistan was significantly different from the neighbouring Bangladeshi and Indian populations. No significant difference was found between Chinese case patients and control subjects. This RB1 SNP appears to be an ethnic variant prevalent in Southeast Asian populations and may be useful for studying RB1 inheritance by pedigree analysis.

Acyl-CoA: cholesterol acyltransferase-2 gene polymorphisms and their association with plasma lipids and coronary artery disease risks.

Acyl-CoA: cholesterol acyltransferase-2 (ACAT2), an intracellular cholesterol esterification enzyme found only in the intestine and liver, has been demonstrated to be associated with hypercholesterolemia and atherosclerosis in mice. To explore the possible impact of ACAT2 gene variants on CAD susceptibility and plasma lipid levels, three polymorphisms, 41A>G (Glu>Gly), 734C>T (Thr>Ile), and IVS4-57_58 ins48 bp (D/I), were genotyped in 809 CAD patients (CAD+) and 1,304 controls (CAD-) from three distinct Singaporean ethnic groups (1,228 Chinese, 367 Malays and 518 Indians). The 734T allele frequency was significantly lower in CAD+ (0.20) than CAD- (0.26) in Chinese (P=0.003) and I allele of D/I was significantly higher in CAD+ (0.17) than CAD- (0.10) in Indians (P=0.011). The 41G allele was significantly more frequent among normolipidemic (0.19) than dyslipidemic (0.13) individuals in Chinese (P=0.008). In normolipidemic females, 734C>T was associated with apoA1, apoB and lipoprotein (a) in Indians, and with apoA1 in Malays, whereas 41A>G is associated with total cholesterol in Indians. The 734C>T polymorphism was in almost complete linkage disequilibrium (LD) with the IVS4-57_58 ins48 bp and in very strong LD with 41A>G in all the three ethnic groups. In the normolipidemic females, the AG/CT had much higher apoB than AA/CC in Indians. We found that the three ACAT2 polymorphisms studied are associated with CAD risk and plasma lipid levels but their effects are not consistent across genders and ethnic groups.

The northeast Indian passageway: a barrier or corridor for human migrations?

The northeast Indian passageway connecting the Indian subcontinent to East/Southeast Asia is thought to have been a major corridor for human migrations. Because it is also an important linguistic contact zone, it is predicted that northeast India has witnessed extensive population interactions, thus, leading to high genetic diversity within groups and heterogeneity among groups. To test this prediction, we analyzed 14 biallelic and five short tandem-repeat Y-chromosome markers and hypervariable region 1 mtDNA sequence variation in 192 northeast Indians. We find that both northeast Indian Y chromosomes and mtDNAs consistently show strikingly high homogeneity among groups and strong affinities to East Asian groups. We detect virtually no Y-chromosome and mtDNA admixture between northeast and other Indian groups. Northeast Indian groups are also characterized by a greatly reduced Y-chromosome diversity, which contrasts with extensive mtDNA diversity. This is best explained by a male founder effect during the colonization of northeast India that is estimated to have occurred within the past 4,000 years. Thus, contrary to the prediction, these results provide strong evidence for a genetic discontinuity between northeast Indian groups and other Indian groups. We, therefore, conclude that the northeast Indian passage way acted as a geographic barrier rather than as a corridor for human migrations between the Indian subcontinent and East/Southeast Asia, at least within the past millennia and possibly for several tens of thousand years, as suggested by the overall distinctiveness of the Indian and East Asian Y chromosome and mtDNA gene pools.

The impact of factor XIIIa V34L polymorphism on plasma factor XIII activity in the Chinese and Asian Indians from Singapore.

Factor XIII (FXIII) is a plasma transglutaminase that is essential for normal haemostasis and fibrinolysis. A few polymorphic sites have been identified in the gene, one of them being a point mutation (V34L) in exon 2 of the FXIIIa subunit gene leading to an amino acid change of valine to leucine. We have examined the role of this polymorphism in relation to plasma FXIII activity in a total of 532 healthy individuals belonging to two ethnic groups in Singapore. The frequency of the L34 allele was significantly higher ( P<0.001) among the Asian Indians (0.08) when compared with the Chinese (0.005). No significant difference in frequency of the L34 allele was observed between Asian Indian CAD patients and controls. The mean FXIII levels were significantly higher ( P<0.0005) among the Asian Indians (148.4%+/-35.5) when compared with Chinese (111.2%+/-26.7). The L34 variant was associated with increased FXIII activity among Asian Indian females. This study shows that both racial and genetic components play a significant role in determining plasma FXIII activity. The effect of V34L polymorphism on FXIII activity in the Indian females is independent of the effects of the P564L and E651Q polymorphic sites in the FXIIIa gene.

ABCA1 gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore.

Mutations in the ATP-binding cassette transporter ABCA1 underlie Tangier disease and familial hypoalphaliproteinemia (FHA), disorders that are characterised by reduced high-density lipoprotein-cholesterol (HDL-C) concentration and cholesterol efflux, and increased coronary artery disease (CAD). We explored if polymorphisms in the ABCA1 gene are associated with CAD and variations in plasma lipid levels, especially HDL-C, and whether the associations may depend on ethnicity. Male cases and controls from the Singapore Chinese, Malay and Indian populations were genotyped for five ABCA1 single nucleotide polymorphisms. Various single-locus frequency distribution differences between cases and controls were detected in different ethnic groups: the promoter -14C>T in Indians, exon 18 M883I in Malays, and 3'-untranslated (UTR) region 8994A>G in Chinese. For the Malay population, certain haplotypes carrying the I825- A (exon 17) and M883- G alleles were more frequent among cases than controls, whereas the converse was true for the alternative configuration of V825- G and I883- A, and this association was reinforced in multi-locus disequilibrium analysis that utilized genotypic data. In the healthy controls, associations were found for -14C>T genotypes with HDL-C in Chinese; 237indelG (5'UTR) with apolipoprotein A1 (apoA1) in Malays and total cholesterol (TC) in Indians; M883I with lipoprotein(a) [Lp(a)] in Malays and apolipoprotein B (apoB) in Chinese; and 8994A>G with Lp(a) in Malays, and TC, low-density lipoprotein-cholesterol (LDL-C) as well as apoB in Indians. While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1.