M.P. Sachdeva

Evidence of a common founder for SCA12 in the Indian population.

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5′ region of the PPP2R2B gene on chromosome 5q31–5q32. We found that it accounts for ∼16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51–69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning ∼137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice.

A validation study of type 2 diabetes-related variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of North India.

The aim of this study was to validate the single nucleotide polymorphisms (SNPs) of four candidate genes (TCF7L2, HHEX, KCNJ11, and ADIPOQ) related to type 2 diabetes (T2D) in an endogamous population of north India; the Aggarwal population, having 18‐clans. This endogamous population model was heavily supported by recent land mark work and we also verified the homogeneity of this population by clan‐based stratification analysis. Two SNPs (rs4506565; rs7903146) in TCF7L2 were found to be significant (p‐value = 0.00191; p‐value = 0.00179, respectively), and odds ratios of 2.1 (dominant‐model) and 2.0 (recessive‐model) respectively, were obtained for this population. The TTT haplotype in the TCF7L2 gene was significantly associated with T2D. Waist‐Hip ratio (WHR), systolic blood pressure (SBP), and age were significant covariates for increasing risk of T2D. Single‐SNP, combined‐SNPs and haplotype analysis provides clear evidence that the causal mutation is near to or within the significant haplotype (TTT) of the TCF7L2 gene. In spite of a culturally‐learned sedentary lifestyle and fat‐enriched dietary habits, WHR rather than body‐mass‐index emerged as a robust predictor of risk for T2D in this population.

MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among north Indian women

Abstract Aim: The present study attempts to understand the role of methylenetetrahydrofolate reductase C677T (MTHFR C677T) in recurrent pregnancy losses in North Indian women because of hyperhomocysteinemia in light of serum folate and vitamin B12. Methods: One hundred and seven women with three or more consecutive unexplained recurrent pregnancy losses and 343 women with two or more successful and uncomplicated pregnancies were recruited. Plasma homocysteine, serum folate and vitamin B12 were analyzed using chemiluminescence. MTHFR C677T detection was completed in all subjects. Results: MTHFR genotypic distribution among cases and controls showed no significant difference (P=0.409). However, MTHFR C677T polymorphism was found to be significantly associated with increased homocysteine in the case group (P=0.031). Hyperhomocysteinemia and vitamin B12 deficiency were found to be significant risk factors for recurrent pregnancy loss (RPL) (OR=7.02 and 16.39, respectively). Folate deficiency was more common in controls (63.47%) as compared to the case group (2.56%). Conclusion: Low vitamin B12 increases homocysteine, specifically among T allele carrying case mothers, suggesting T allele is detrimental with B12 deficiency. The study emphasizes the importance of vitamin B12 in the prevention of RPL in North Indian women.

Spectrum of MTHFR gene SNPs C677T and A1298C: a study among 23 population groups of India.

Elevated homocysteine is a risk factor for many complex disorders. The role of methylenetetrahydrofolate reductase (MTHFR) gene in methylation of homocysteine makes it one of the most important candidate genes for these disorders. Considering the heterogeneity in its distribution in world populations, we screened MTHFR C677T and A1298C single nucleotide polymorphisms in a total of 23 Indian caste, tribal and religious population groups from five geographical regions of India and belonging to four major linguistic groups. The frequencies of MTHFR 677T and 1298C alleles were found to be 10.08 and 20.66%, respectively. MTHFR homozygous genotype 677TT was absent in eight population groups and homozygous 1298CC was absent in two population groups. 677T allele was found to be highest among north Indian populations with Indo-European tongue and 1298C was high among Dravidian-speaking tribes of east India and south India. The less common mutant haplotype 677T-1298C was observed among seven population groups and overall the frequency of this haplotype was 0.008, which is similar to that of African populations. cis configuration of 677T and 1298C was 0.94%. However, we could not find any individual with four mutant alleles which supports the earlier observation that presence of more than two mutant alleles may decrease the viability of foetus and possibly be a selective disadvantage in the population.

A Genomic Insight into Diversity Among Tribal and Nontribal Population Groups of Manipur, India

Twenty autosomal markers, including linked markers at two gene markers, are used to understand the genomic similarity and diversity among three tribal (Paite, Thadou, and Kom) and one nontribal communities of Manipur (Northeast India). Two of the markers (CD4 and HB9) are monomorphic in Paite and one (the CD4 marker) in Kom. Data suggest the Meitei (nontribal groups) stand apart from the three tribal groups with respect to higher heterozygosity (0.366) and presence of the highest ancestor haplotypes of DRD2 markers (0.228); this is also supported by principal co-ordinate analysis. These populations are found to be genomically closer to the Chinese population than to other Indian populations.

Diversified genomic contribution among south Indian populations–A study on four endogamous groups of Andhra Pradesh

Background: The present study examines genomic variation among three tribal (Nayakpod, Thoti and Kolam) and a caste (Niyogi Brahmin) population groups of Andhra Pradesh, south India. Aim: The present study examined the genomic diversity of the populations in relation to other population groups of India using 20 autosomal loci. Subjects and methods: A total of 204 blood samples from the population groups described above were collected and analysis was carried out following standard protocols. Results: All markers were found to be polymorphic in these groups except AluCD4 among Thotis. High average heterozygosity values (0.3927 among Thotis to 0.4268 among Brahmins) are comparable with the available autosomal (Alu and restriction site polymorphisms) data for the Nilgiri hill tribes of Tamil Nadu, south India. The gene differentiation value (Gst) was found to be 4.2. The principal coordinate analysis (PCO) based on data from the 20 markers presents a smaller cluster of presently studied populations than that of the Nilgiri hill tribes of Tamil Nadu, south India. Conclusion: Although the presently studied populations of Andhra Pradesh have heterozygosity similar to that of Nilgiri hill populations, the former are more closely placed on the PCO plot than the latter, who are more scattered. Also the gene differentiation (Gst) of the former is much lower than that of the latter, indicating considerable regional variation in the inflow of genes from diverse ethnic groups within south India.

Association of TCF7L2 and ADIPOQ with Body Mass Index, Waist–Hip Ratio, and Systolic Blood Pressure in an Endogamous Ethnic Group of India

Despite the increasing burden of type 2 diabetes (T2D) and its established association with anthropometric and physiological traits as a risk factor, genetic studies focusing on the association of T2D-related genes with quantitative traits like body mass index (BMI), waist-hip ratio (WHR), and systolic blood pressure (SBP) are only a few for western populations and rare for Indian populations. The present study tested the association of TCF7L2, HHEX, KCNJ11, and ADIPOQ with BMI, SBP, and WHR in men and women of the Aggarwal population of India and found a differential association of TCF7L2 (rs7903146, rs4506565, and rs12256372) and ADIPOQ (rs2241766 and rs1501299) genes with increasing BMI, SBP, and WHR between the two sexes. We conclude that TCF7L2 and ADIPOQ together might play an important role in explaining these traits and to understand the biological and genetic mechanisms underlying T2D, and the role of other T2D genes must also be evaluated with these continuous traits.

Population Severance in Manipur at Dopamine Receptor D2 Locus

INTRODUCTION Tibeto-Burman language-speaking Mongoloid groups of northeast India are reported to be genetically highly heterogeneous. Manipur, one of the states of this region sharing a major International border with Myanmar, is also expected to be diversified as seen by its large number of tribal and nontribal groups. A number of genomic markers, that is, autosomal, mitochondrial, and Y chromosomal ones, have been used to understand the peopling of the northeast region. AIMS In this article, an attempt is made to understand the peopling of Manipur using three sites (Taq1A, Taq1B, and Taq1D) on the dopamine receptor D2 (DRD2) gene through allele and haplotype frequencies and their distribution patterns. METHODS In total, 367 blood samples were collected from eight populations of which three (Meitei, Muslims, and Bamon) are nontribal groups and five (Aimol, Kabui, Paite, Kom, and Thadou) are tribal groups. RESULTS All the three sites are polymorphic in all the studied populations with relatively lower heterozyosities indicating a genetic discontinuity between the populations of mainland India and northeast India, suggesting the unlikeliness of eastward migration of people from Africa through India. CONCLUSION High heterogeneity and predominance of ancestral haplotype (B2D2A1) among the Meitei suggest an admixture of incoming mongoloid groups with an already existing protoastroloid element. The study also highlights the distinctiveness of Manipuri population groups with respect to DRD2 gene polymorphism.

Emergence of TCF7L2 as a Most Promising Gene in Predisposition of Diabetes Type II

Abstract The genetics of the complex disorder like Diabetes Type II, which is clinically diagnosed as disease of insulin resistance and impaired insulin secretion leading to impaired glucose homeostasis in body, remains a nightmare for geneticists. But the recent progress in identification of a most promising marker in predisposition of diabetes Type II, namely, TCF7L2 with its large effect size and its global presence in various ethnically and geographically different populations offers some hope as the robust genetic approach like genome-wide association studies seem to corroborate the evidence in favour of association of this gene with predisposition to the disease. This paper presents a comprehensive review of studies on the association of this gene with type II diabetes.

‘Mendelian randomization’: an approach for exploring causal relations in epidemiology

OBJECTIVES To assess the current status of Mendelian randomization (MR) approach in effectively influencing the observational epidemiology for examining causal relationships. METHODS Narrative review on studies related to principle, strengths, limitations, and achievements of MR approach. RESULTS Observational epidemiological studies have repeatedly produced several beneficiary associations which were discarded when tested by standard randomized controlled trials (RCTs). The technique which is more feasible, highly similar to RCTs, and has the potential to establish a causal relationship between modifiable exposures and disease outcomes is known as MR. The technique uses genetic variants related to modifiable traits/exposures as instruments for detecting causal and directional associations with outcomes. CONCLUSIONS In the last decade, the approach of MR has methodologically developed and progressed to a stage of high acceptance among the epidemiologists and is gradually expanding the landscape of causal relationships in non-communicable chronic diseases.