Differential risk factors and morbidity/mortality pattern in type 2 diabetes: A study among two Mendelian populations with different ancestry (India).

BACKGROUND AND AIMS: Association studies of type 2 diabetes mellitus (T2DM) with risk factors have shown variable results. Moreover, population-specific comparative investigations are negligible. Therefore, the present study aimed to evaluate the association of dyslipidemia and obesity with impaired fasting glucose (IFG) and T2DM among two ethnically, geographically and culturally different populations in India. METHODS: This was a cross-sectional study among Jats and Meiteis, each inhabiting a separate geographical region. A total of 2371 individuals, age ≥30 years were recruited through household survey. Obesity variables were captured using anthropometric measurements while fasting blood (2.5 mL) was drawn to measure lipid and glucose levels using enzymatic assay by spectrophotometer. Participants were categorized under normal, IFG and T2DM groups, indicative of diabetes progression stages. Statistical analysis was performed using SPSS 16.0 version. RESULTS: Significant differential distribution of lipid and obesity variables among IFG and T2DM in both populations were observed. Odds ratio revealed high TC and all obesity variables except BMI posed significant increased risk for T2DM among Jats. Abnormal TG, VLDL, WC, and WHtR posed significant increased risk for T2DM among Meiteis. Age-cohort wise prevalence of T2DM showed increasing trend at ≥60 years among Jats and decreasing trend at ≥60 years among Meiteis, suggesting a potential higher morbidity in the former and mortality in latter because of T2DM. CONCLUSIONS: The present study observed a differential association of risk factors for T2DM among Jats and Meiteis. This study emphasize the need to implement community-specific intervention programs for prevention, treatment and management of T2DM.

Loss of function mutation in the P2X7, a ligand-gated ion channel gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited heart failure condition, mostly found to have genetic abnormalities, and is a leading cause of sudden death in young adults. Whole exome sequencing should be given consideration as a molecular diagnostic tool to identify disease-causing mutation/s. In this study, a HCM family with multiple affected members having history of sudden death were subjected to exome sequencing along with unaffected members. Quality passed variants obtained were filtered for rarity (MAF > 0.5%), evolutionary conservation, pathogenic prediction, and segregation in affected members after removing shared variants present in unaffected members. Only one non-synonymous mutation (p. Glu186Lys or E186K) in exon 6 of P2X7 gene segregated in HCM-affected individuals which was absent in unaffected family members and 100 clinically evaluated controls. The site of the mutation is highly conserved and led to complete loss of function which is in close vicinity to ATP-binding site-forming residues, affecting ATP binding, channel gating, or both. Mutations in candidate genes which were not segregated define clinical heterogeneity within affected members. P2X7 gene is highly expressed in the heart and shows direct interaction with major candidate genes for HCM. Our results reveal a significant putative HCM causative gene, P2X7, for the first time and show that germ-line mutations in P2X7 may cause a defective phenotype, suggesting purinergic receptor involvement in heart failure mediated through arrhythmias which need further investigations to be targeted for therapeutic interventions.

Prevalence of MTHFR, Factor V, ACE and APOE gene polymorphisms among Muslims of Manipur, India.

BACKGROUND: Chronic metabolic disorders such as cardiovascular disease and diabetes have become an emerging public health problem in India, in both rural and urban settings. Genetic markers like MTHFR, FV, ACE and APOE are important candidates involved in the development of these disorders. AIM: The present study aims to understand the distribution of allele frequencies of the SNPs in the above-mentioned genes in Manipuri Muslims, an endogamous religious community constituting ~8% of the Manipur population. SAMPLE AND METHODS: Blood samples were collected from 107 unrelated healthy individuals. Genotyping were done by PCR (for ACE I/D and MTHFR A1298C) followed by restriction digestion (for MTHFR C677T, FV G1691A and APOE). RESULTS AND DISCUSSION: All four SNPs, with the exception of FVL, were found to be polymorphic, with allele frequencies of 15.1%, 17%, 36.1% and 7.7% for MTHFR 677T, MTHFR 1298C, ACE D and APOE E4, respectively. The D allele of ACE I/D polymorphism was found to be significantly higher among males and also among the young age group compared with females and the old age groups, respectively. This study has highlighted the necessity of looking at the clinical implications of these SNPs in future studies of Manipuri Muslims.

Prevalence of ß-Thalassemia and hemoglobin E in two migrant populations of Manipur, North East India.

Hemoglobinopathies are a group of inherited single-gene disorders found commonly in the Mediterranean region, Middle East, Indian subcontinent, Burma, and South East Asia. As many as 229 mutation variants of ß-thalassemia are reported in the world, many community/region-specific mutations. Very little on thalassemia has been reported in Manipur, a North Eastern Indian state. Thus, a community genetic approach through population screening can be applied to the people of Manipur and a total of 602 blood samples from unrelated Meitei Brahmins (n=300) and Meitei Muslims (n=302) were screened for abnormal hemoglobins by Naked Eye Single Tube Red Cell Osmotic Fragility Test (NESTROFT). HBA(2) level was estimated by using high-performance liquid chromatography and molecular analysis was done by using PCR. Sequencing was also carried out to confirm the mutations. High frequencies of NESTROFT positive (10%) and NESTROFT doubtful (11%) cases were found among the Meitei Brahmins in comparison to the Meitei Muslims [NESTROFT positive (3.31%) and NESTROFT doubtful (1.33%)]. The allele frequency of HB*E was 0.022 and 0.012 among the Meitei Brahmin and Meitei Muslim, respectively. Sequencing of the ß-globin gene confirmed a very rare ß-thalassemia [-90 C→T (0.33%)] among the Meitei Brahmins of Manipur. This mutation with hemoglobin E in one of the present population hints the presence of the Mongoloid stock among them, possibly from China. There is a need for further studies on other populations of Manipur and the neighboring North East Indian states using such genetic markers.

Haptoglobin polymorphism among fourteen populations of India.

Haptoglobin (HP) is a serum protein that has the capability of binding the extracorpuscular haemoglobin released during haemolysis. It plays an important role in protection of haemolytic disease by reducing the oxidative and peroxidative potential at free haemoglobin. The present study was aimed to determine the prevalence of HP polymorphism among different Indian populations, anthropologically belonging to diverse ethnicity. The polymorphism was screened among 642 unrelated individuals belonging to 14 population groups of India including both tribal and non-tribal caste groups from different geographical regions of India with distinct linguistic affiliations. An attempt is also made to understand the distribution of HP polymorphism among the studied populations. The result reveals the HP gene to be polymorphic in all the studied populations. Except the two tribal populations (Thotis of Andhra Pradesh and Patelias of Rajasthan) and one caste population (Rajput of Himachal Pradesh), all the studied populations are found to obey the Hardy-Weinberg equilibrium. The significance of the present study is elucidated with the prevalence of high mutant HP*2 allele frequency in India. Selection could be one of the most plausible explanations for this high HP frequency because of its uniformly high occurrence among all the studied populations.

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.

APOE, MTHFR, LDLR and ACE polymorphisms among Angami and Lotha Naga populations of Nagaland, India.

Several common polymorphisms in the ApoE, ACE, MTHFR and LDLR genes have been implicated in the pathogenesis of common complex diseases across world populations. This study investigates the prevalence of five known and clinically important common polymorphisms in Angami and Lotha Naga populations. A total of 112 unrelated healthy volunteers (52 Lotha Nagas and 60 Angami Nagas) participated in the study. All the five genes were found to be polymorphic in the studied populations. The Lotha Nagas displayed higher mutant allele frequencies than the Angami Nagas except for the T allele frequency of the AvaII polymorphism of the LDLR gene, though chi square did not reveal any significant population differences by genotypes. In view of the relatively high mutant allele frequencies in both the populations, they are likely to be at a high risk of developing various complex diseases as they shift from an active and rigorous lifestyle to a more sedentary one.

The genomic similarities with linguistic difference: a study among the Oraon and Munda tribes of the Ranchi district, Jharkhand, India.

AIMS: The present study was conducted on two tribal communities, the Oraon and Munda, inhabiting the Ranchi district of Jharkhand state, India. The study was designed to elucidate genetic similarity, if any, shared between these tribes as they belong to the common Proto-Australoid stock but bear different linguistic affiliations. For this, a total of 98 intravenous blood samples (48 Oraon and 50 Munda) were collected from unrelated individuals of either sex up to first cousins, with their prior informed written consent. The DNA was extracted and studied for a total of 20 autosomal markers, including 7 Alu Indels, 3 DRD2 TaqI sites, 3 ß-globin sites, and 7 restriction site polymorphisms. RESULTS: All the 20 studied molecular markers were found to be polymorphic in both the tribal population groups and showed similarities with respect to allele frequencies, with a low coefficient of gene differentiation (G(ST)) value. Moreover, sharing and distribution patterns of haplotypes of the ß-globin gene cluster suggest that the Oraon and Munda share a common ancestry. However, small differences between them with reference to the linkage disequilibrium (LD) pattern indicate that the Munda might have emerged as a result of admixture between Proto-Australoids and Austro-Asiatic-speaking Mongoloids as supported by the principal co-ordinate analysis, wherein the Munda are closely placed with the Dravidian-speaking Proto-Australoid tribes of India. CONCLUSION: A common genetic substratum (Proto-Australoid stock) of the Oraon and Munda was evident in the present study, although these tribes are distinct linguistically.

A genomic insight into the peopling of Manipur, India.

INTRODUCTION: manipur, one of the northeastern states of India, lies on the ancient silk route and serves as a meeting point between the Southeast Asia and South Asia. AIMS: this study was conducted to understand and estimate the genomic diversity among various population groups of Manipur, with a major goal of getting an insight into the peopling of India. METHODS: seven human-specific Alu insertion/deletion polymorphisms were screened on 366 individuals belonging to eight ethnic groups of Manipur, including both tribal (Aimol, Kabui, Kom, Paite, and Thadou) and nontribal populations (Bamon, Muslims, and Meitei). RESULTS: all the biallelic loci are polymorphic except CD4, which is monomorphic in six out of the eight studied populations. The average heterozygosity values are low (0.309-0.395), with relatively higher average heterozygosity values among Bamons and Muslims than other studied populations, suggesting admixture in these two populations. Lower heterozygosity values of the tribal populations place them closer to the Chinese and Southeast Asian populations, indicating their late arrival in India coupled with geographical isolation. CONCLUSION: this study provides evidence for the genetic heterogeneity of the Manipur populations. It also supports the hypothesis, based on the archeological and linguistic findings, that the northeastern populations of India have a close genetic affinity with the southeastern and East Asian populations. The genetic discontinuity observed between the studied populations and the other non-Northeast Indian populations suggests the role of northeast border as a "barrier" rather than a corridor.

Brief communication: Allelic and haplotypic structure at the DRD2 locus among five North Indian caste populations.

The dopamine D2 receptor (DRD2) gene, with its known human-specific derived alleles that can facilitate haplotype reconstruction, presents an important locus for anthropological studies. The three sites (TaqIA, TaqIB, and TaqID) of the DRD2 gene are widely studied in various world populations. However, no work has been previously published on DRD2 gene polymorphisms among North Indian populations. Thus, the present study attempts to understand the genetic structure of North Indian upper caste populations using the allele and haplotype frequencies and distribution patterns of the three TaqI sites of the DRD2 gene. Two hundred forty-six blood samples were collected from five upper caste populations of Himachal Pradesh (Brahmin, Rajput and Jat) and Delhi (Aggarwal and Sindhi), and analysis was performed using standard protocols. All three sites were found to be polymorphic in all five of the studied populations. Uniform allele frequency distribution patterns, low heterozygosity values, the sharing of five common haplotypes, and the absence of two of the eight possible haplotypes observed in this study suggest a genetic proximity among the selected populations. The results also indicate a major genetic contribution from Eurasia to North Indian upper castes, apart from the common genetic unity of Indian populations. The study also demonstrates a greater genetic inflow among North Indian caste populations than is observed among South Indian caste and tribal populations.

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.

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.