A two-step genetic study on quantitative precursors of coronary artery disease in a homogeneous Indian population: Case–control association discovery and validation by transmission-disequilibrium test.

In spite of its strong familiality, gene identification for coronary artery disease (CAD) has not yielded a consistent picture. One major reason for this is that families or cases and controls were not recruited from a homogeneous population. We, therefore, attempted to map genes underlying 10 quantitative traits (QTs) that are known precursors of CAD in a homogeneous population (Marwari) of India. The QTs are apolipoprotein B (ApoB), C-reactive protein (CRP), fibrinogen (FBG), homocysteine (HCY), lipoprotein (a) (LPA), cholesterol – total (CHOL-T), cholesterol – HDL (CHOL-H), cholesterol – LDL (CHOL-L), cholesterol – VLDL (CHOL-V) and triglyceride (TG). We assayed 209 SNPs in 31 genes among members of Marwari families. After log-transformation and covariate-adjustment of the QTs, a two-step analysis was performed. In Step-1, data on unrelated individuals were analysed for association with the SNPs. In Step-2, for validation of Step-1 results, a quantitative transmission-disequilibrium test on parent– offspring data was performed for each SNP found to be significantly associated with a QT in Step-1 on an independent sample set drawn from the same population. Statistically significant results found for the various QTs and SNPs were: rs3774933, rs230528, rs230521, rs1005819 and rs1609798 (intronic, NFKB1) with APOB; rs5361 (Missense, R>S, SELE) and rs4648004 (Intronic, NFKB1) with FBG; rs4220 (Missense, K>R, FGB) with HCY; and rs3025035 (Intronic, VEGFA) with CHOL-H. SNPs in SELE, VEGFA, FGB and NFKB1 genes impact significantly on levels of quantitative precursors of CAD in Marwaris.

Patterns of nucleotide sequence variation in ICAM1 and TNF genes in twelve ethnic groups of India: roles of demographic history and natural selection.

We have studied DNA sequence variation in and around the genes ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India, with a view to investigating the relative roles of demographic history and natural selection in shaping the observed patterns of variation. The total numbers of single nucleotide polymorphisms (SNPs) detected at the ICAM1 and TNF loci were 29 and 12, respectively. Haplotype and allele frequencies differed significantly across populations. The site frequency spectra at these loci were significantly different from those expected under neutrality, and showed an excess of intermediate-frequency variants consistent with balancing selection. However, as expected under balancing selection, there was no significant reduction of F(ST) values compared to neutral autosomal loci. Mismatch distributions were consistent with population expansion for both loci. On the other hand, the phylogenetic network among haplotypes for the TNF locus was similar to expectations under population expansion, while that for the ICAM1 was as expected under balancing selection. Nucleotide diversity at the ICAM1 locus was an order of magnitude lower in the promoter region, compared to the introns or exons, but no such difference was noted for the TNF gene. Thus, we conclude that the pattern of nucleotide variation in these genes has been modulated by both demographic history and selection. This is not surprising in view of the known allelic associations of several polymorphisms in these genes with various diseases, both infectious and noninfectious.

High prevalence of metabolic syndrome and its correlates in two tribal populations of India and the impact of urbanization.

BACKGROUND AND OBJECTIVES: Metabolic syndrome is one of the major causes of morbidity and mortality in the world. The prevalence of this syndrome is high among Asians, including Indians, and is rising, particularly with the adoption of a modernized life style. Whether traditional societies in India have a low prevalence and the extent to which a transition to a modern life style contributes to the increase in prevalence are unknown. To examine the role of environmental and genetic factors in metabolic syndrome we conducted a study in two sub-Himalayan tribal populations with shared ancestry (Toto and Bhutia). The Toto live exclusively in a rural area, whereas a section of the Bhutia has adopted a modern life style. METHODS: Fasting (12 h) blood samples of Toto (n=258); rural Bhutia (n=75) and urban Bhutia (n=230) were collected, with written informed consent. Lipid profile, blood pressures, body fat and other anthropometric parameters were assessed. Criteria suggested by National Cholesterol Education Programme (NCEP) Adult Treatment Panel III (2001) were used for assessment of metabolic syndrome. RESULTS: The prevalence of metabolic syndrome was high (about 30-50%) among the Bhutia, with no significant rural-urban difference. Among the Toto, though the prevalence of metabolic syndrome was low (about 4-9%), their lipid levels were alarmingly adverse (about 37-67% had low HDLcholesterol or high triglyceride levels). There was an additional adverse impact of adoption of urban life-styles (perhaps primarily mediated through dietary changes) on cardiovascular risk factors. INTERPRETATION AND CONCLUSION: Our study suggested that metabolic syndrome and its correlates could be a major health problem even in traditional societies, indicating that this syndrome was not necessarily a result of modernization. Further, our study indicates that genetic factors that adversely affect the levels of such variables have long antiquities in Indian ethnic groups.

A comparison of two popular statistical methods for estimating the time to most recent common ancestor (TMRCA) from a sample of DNA sequences.

We have compared two statistical methods of estimating the time to most recent common ancestor (TMRCA) from a sample of DNA sequences, which have been proposed by Templeton (1993) and Bandelt et al. (1995). Monte-Carlo simulations were used for generating DNA sequence data. Different evolutionary scenarios were simulated and the estimation procedures were evaluated. We have found that for both methods (i) the estimates are insensitive to demographic parameters and (ii) the standard deviations of the estimates are too high for these methods to be reliably used in practice.