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Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir–India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid Arthritis (RA) is a systemic, chronic, inflammatory, and autoimmune disease which is characterised by the progressive ruination of joint structures. The Human Leukocyte Antigens (HLA) genes: HLA-DRB1 and HLA-DQB1, belonging to HLA family, presented on human chromosome six, are involved in the immune system. Various studies involving Genome-wide Association Studies (GWAS), meta-analysis, and replication studies have shown the association of HLA-DRB1 variant rs13192471 and HLA-DQB1 variant rs6457617 with RA susceptibility in different population groups. Aim: To perform a replication case-control based association study of variants rs13192471 and rs6457617, in order to determine their association with RA, in an independent cohort from the population of North-western India. Materials and Methods: The Case-control study conducted at Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India, duration of the study was, from May 2019 to June 2022. In this study, Deoxyribonucleic Acid (DNA) was isolated from 188 RA cases and 310 healthy controls, followed by qualitative and quantitative analyses. The genotyping was performed on a Real Time-polymerase Chain Reaction (RT-PCR) using TaqMan Allele Discrimination Assay. Statistical power of the study was estimated using PS: Power and sample size calculator version 3.1. Results: The statistical analysis of the genotyping data showed a significant association (p=0.005) of variant rs13192471 with RA susceptibility, whereas the variant rs6457617 did not show an association (p=0.275) with RA in the studied population cohort. Conclusion: The present study successfully replicated the association of HLA-DRB1 variant rs13192471 in the population group of North-western India. It is pertinent to screen these variants for RA susceptibility in other population groups of India before their use as potential genetic biomarkers in the Indian population. [ABSTRACT FROM AUTHOR]

Background: Leucine-rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome-wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease.Materials and Methods: In the present case-control study, 166 cases and 459 controls were included. Taqman assay technique using real-time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy-Weinberg equilibrium for rs2494938 was assessed using the Chi-square test. The allele- and genotype-specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI).Results: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23-2.04 at 95% CI, P = 0.0003).Conclusion: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India. [ABSTRACT FROM AUTHOR]

Rare diseases (RDs) are the clinical conditions affecting a few percentage of individuals in a general population compared to other diseases. Limited clinical information and a lack of reliable epidemiological data make their timely diagnosis and therapeutic management difficult. Emerging Next-Generation DNA Sequencing technologies have enhanced our horizons on patho-physiological understanding of many of the RDs and ushered us into an era of diagnostic and therapeutic research related to this ignored health challenge. Unfortunately, relevant research is meager in developing countries which lack a reliable estimate of the exact burden of most of the RDs. India is to be considered as the "Pandora's Box of genetic disorders." Owing to its huge population heterogeneity and high inbreeding or endogamy rates, a higher burden of rare recessive genetic diseases is expected and supported by the literature findings that endogamy is highly detrimental to health as it enhances the degree of homozygosity of recessive alleles in the general population. The population of a low resource region Jammu and Kashmir (J&K) – India, is highly inbred. Some of its population groups variably practice consanguinity. In context with the region's typical geographical topography, highly inbred population structure and unique but heterogeneous gene pool, a huge burden of known and uncharacterized genetic disorders is expected. Unfortunately, many suspected cases of genetic disorders remain undiagnosed or misdiagnosed due to lack of appropriate clinical as well as diagnostic resources in the region, causing patients to face a huge psycho-socio-economic crisis and many a time suffer life-long with their ailment. In this review, the major challenges associated with RDs are highlighted in general and an account on the methods that can be adopted for conducting fruitful molecular genetic studies in genetically vulnerable and low resource regions is also provided, with an example of a region like J&K – India. [ABSTRACT FROM AUTHOR]

Many major rival models of the origin of the Hindu caste system co-exist despite extensive studies, each with associated genetic evidences. One of the major factors that has still kept the origin of the Indian caste system obscure is the unresolved question of the origin of Y-haplogroup R1a1*, at times associated with a male-mediated major genetic influx from Central Asia or Eurasia, which has contributed to the higher castes in India. Y-haplogroup R1a1* has a widespread distribution and high frequency across Eurasia, Central Asia and the Indian subcontinent, with scanty reports of its ancestral (R*, R1* and R1a*) and derived lineages (R1a1a, R1a1b and R1a1c). To resolve these issues, we screened 621 Y-chromosomes (of Brahmins occupying the upper-most caste position and schedule castes/tribals occupying the lower-most positions) with 55 Y-chromosomal binary markers and seven Y-microsatellite markers and compiled an extensive dataset of 2809 Y-chromosomes (681 Brahmins, and 2128 tribals and schedule castes) for conclusions. A peculiar observation of the highest frequency (up to 72.22%) of Y-haplogroup R1a1* in Brahmins hinted at its presence as a founder lineage for this caste group. Further, observation of R1a1* in different tribal population groups, existence of Y-haplogroup R1a* in ancestors and extended phylogenetic analyses of the pooled dataset of 530 Indians, 224 Pakistanis and 276 Central Asians and Eurasians bearing the R1a1* haplogroup supported the autochthonous origin of R1a1 lineage in India and a tribal link to Indian Brahmins. However, it is important to discover novel Y-chromosomal binary marker(s) for a higher resolution of R1a1* and confirm the present conclusions.Journal of Human Genetics (2009) 54, 47–55; doi:10.1038/jhg.2008.2; published online 9 January 2009 [ABSTRACT FROM AUTHOR]

Background: Y-chromosomal haplogroup (Y-HG) Q is suggested to originate in Asia and represent recent founder paternal Native American radiation into the Americas. This group is delineated into Q1, Q2 and Q3 subgroups defined by biallelic markers M120, M25/M143 and M3, respectively. Recently, a novel subgroup Q4 has been identified which is defined by bi-allelic marker M346, representing HG Q (0.41%, 3/728) in Indian population. With scanty details of HG Q in Asia, especially India, it was pertinent to explore the status of the Y-HG Q in Indian population to gather an insight to determine the extent of diversity within this region. Results: We observed 15/630 (2.38%) Y-HG Q individuals in India with an ancestral state at M120, M25, M3 and M346 markers, indicating an absence of already known Q1, Q2, Q3 and Q4 subhaplogroups. Interestingly, we further observed a novel 4 bp deletion/insertion polymorphism (ss4 bp, rs41352448) at 72,314 position of human arylsulfatase D pseudogene, defining a novel sublineage Q5 (in 5/15 individuals, i.e., 33.3 % of the observed Y-HG Q) with distributions independent of the social, cultural, linguistic and geographical affiliations in India. Conclusion: The study adds another sublineage Q5 in the already existing arrangement of Y-HG Q in literature. It was quite interesting to observe an ancestral state Q* and a novel sub-branch Q5, not reported elsewhere, in Indian subcontinent, though in low frequency. A novel subgroup Q4 was identified recently which is also restricted to Indian subcontinent. The most plausible explanation for these observations could be an ancestral migration of individuals bearing ancestral lineage Q* to Indian subcontinent followed by an autochthonous differentiation to Q4 and Q5 sublineages later on. However, other explanations of, either the presence of both the sub haplogroups (Q4 and Q5) in ancestral migrants or recent migrations from central Asia, cannot be ruled out till the distribution and diversity of these subgroups is explored extensively in Central Asia and other regions. [ABSTRACT FROM AUTHOR]

We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India. [ABSTRACT FROM AUTHOR]

Four binary polymorphisms and four multiallelic short tandem repeat (STR) loci from the nonrecombining region of the human Y-chromosome were typed in different Indian population groups from Uttar Pradeh (UP), Bihar (BI), Punjab (PUNJ), and Bengal (WB) speaking the Indo-Aryan dialects and from South India (SI) with the root in the Dravidian language. We identified four major haplogroups [(P) 1+, (C and F) 2+, (R1a) 3, (K) 26+] and 114 combinations of Y-STR haplotypes. Analyses of the haplogroups indicated no single origin from any lineage but a result of a conglomeration of different lineages from time to time. The phylogenetic analyses indicate a high degree of population admixture and a greater genetic proximity for the studied population groups when compared with other world populations. [ABSTRACT FROM AUTHOR]

Objective: To replicate the association of newly identified variants of TMEM163 (transmembrane protein 163) and COBLL1 (cordon-bleu protein-like 1) with type 2 diabetes (T2D) in Northwest Indian population.Methods: We performed a replication study of variants rs998451 and rs6723108 of gene TMEM163 and rs7607980 of gene COBLL1. The variations were genotyped using Taqman allele discrimination assay in 1209 Northwest Indians (651 T2D cases and 558 controls). The association of each SNP with the disease was evaluated using logistic regression.Results: All the three SNPs examined in this study did not show any significant association with T2D. For rs998451 and rs6723108 of TMEM163 the observed odds ratios were 0.71 with a 95% CI of 0.28-1.84 (p=0.484) and 1.80 with a 95% CI of 0.74-4.40 (p=0.196), respectively. For rs7607980 the estimated odds ratio was 1.01 with 95% CI of 0.70-1.44 (p=0.946).Conclusion: We conclude that lack of association could be because of population structure of Indian Population that is conglomeration of various ethnic groups. For a conclusive association study of T2D in India, it is critical that such studies are carried out among endogamous ethnic groups rather than conventional practice of pooling samples based on Geographical/regional or linguist affiliations like Asian Indian, North or South Indian etc. [ABSTRACT FROM AUTHOR]

Gastric Carcinoma (GC) is one of the most common malignancies, which accounts for 6.8% of total cancer population worldwide. In India, the northeastern region has the highest gastric cancer incidence, and the Kashmir Valley has a very high incidence of gastric cancer as compared to other parts of Northern India. It exceeds 40% of total cancers with an incidence rate of 3-6-fold higher than other metro cities of India. Gastric cancer is a heterogeneous disease where most of the cases are sporadic, and <15% are due to obvious familial clustering. The heterogeneous nature of the disease can be associated with differences in genetic makeup of an individual. A better understanding of genetic predisposition toward GC will be helpful in promoting personalized medicine. The aim of this review is to analyze the development and progression of GC and to explore the genetic perspectives of the disease with special emphasis on Jammu and Kashmir, India., Competing Interests: None

Background: Leucine-rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome-wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease., Materials and Methods: In the present case-control study, 166 cases and 459 controls were included. Taqman assay technique using real-time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy-Weinberg equilibrium for rs2494938 was assessed using the Chi-square test. The allele- and genotype-specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI)., Results: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23-2.04 at 95% CI, P = 0.0003)., Conclusion: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India., Competing Interests: None

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D.

Adiponectin is a prime determinant of the status of insulin resistance. Association studies between adiponectin (ADIPOQ) gene single nucleotide polymorphisms (SNPs) and metabolic diseases have been reported earlier. However, results are ambiguous due to apparent contradictions. Hence, we investigated (1) the association between ADIPOQ SNPs: -11377C/G, +10211T/G, +45T/G and +276G/T for the risk towards type 2 diabetes (T2D) and, (2) genotype-phenotype association of these SNPs with various biochemical parameters in two cohorts. Genomic DNA of diabetic patients and controls from Gujarat and, Jammu and Kashmir (J&K) were genotyped using PCR-RFLP, TaqMan assay and MassArray. Transcript levels of ADIPOQ were assessed in visceral adipose tissue samples, and plasma adiponectin levels were estimated by qPCR and ELISA respectively. Results suggest: (i) reduced HMW adiponectin/total adiponectin ratio in Gujarat patients and its association with +10211T/G and +276G/T, and reduced ADIPOQ transcript levels in T2D, (ii) association of the above SNPs with increased FBG, BMI, TG, TC in Gujarat patients and (iii) increased GGTG haplotype in obese patients of Gujarat population and, (iv) association of -11377C/G with T2D in J&K population. Reduced HMW adiponectin, in the backdrop of obesity and ADIPOQ genetic variants might alter metabolic profile posing risk towards T2D.

Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents. The patients present with early-onset, progressive extrapyramidal dysfunction, and brain Magnetic Resonance imaging (MRI) suggestive of symmetrical iron deposition in the globus pallidi. Screening the PANK2 gene in the patients as well as their unaffected family members revealed a functional single nucleotide variation, perfectly segregating in the patient's family in an autosomal recessive mode of inheritance. We also provide the results of in-silico analyses, predicting the functional consequence of the identified PANK2 variant.

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP&#95;003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.

Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p<5.5E-04) with T2D susceptibility in combined population. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E-08) in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial) levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR)<1.38 increased to OR = 2.44, (95%CI = 1.67-3.59) when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

Our previous studies have implicated genes mainly involved in the activity of pancreatic β cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic β cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the high-expressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in >80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1α, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR) = 8.91; p = 6.5×10(-11)]. The risk level was considerably low in the genotype backgrounds of TX (OR = 6.68; p = 2.71×10(-12)) and CX (OR = 3.74; p = 4.0×10(-3)). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease.

Many major rival models of the origin of the Hindu caste system co-exist despite extensive studies, each with associated genetic evidences. One of the major factors that has still kept the origin of the Indian caste system obscure is the unresolved question of the origin of Y-haplogroup R1a1*, at times associated with a male-mediated major genetic influx from Central Asia or Eurasia, which has contributed to the higher castes in India. Y-haplogroup R1a1* has a widespread distribution and high frequency across Eurasia, Central Asia and the Indian subcontinent, with scanty reports of its ancestral (R*, R1* and R1a*) and derived lineages (R1a1a, R1a1b and R1a1c). To resolve these issues, we screened 621 Y-chromosomes (of Brahmins occupying the upper-most caste position and schedule castes/tribals occupying the lower-most positions) with 55 Y-chromosomal binary markers and seven Y-microsatellite markers and compiled an extensive dataset of 2809 Y-chromosomes (681 Brahmins, and 2128 tribals and schedule castes) for conclusions. A peculiar observation of the highest frequency (up to 72.22%) of Y-haplogroup R1a1* in Brahmins hinted at its presence as a founder lineage for this caste group. Further, observation of R1a1* in different tribal population groups, existence of Y-haplogroup R1a* in ancestors and extended phylogenetic analyses of the pooled dataset of 530 Indians, 224 Pakistanis and 276 Central Asians and Eurasians bearing the R1a1* haplogroup supported the autochthonous origin of R1a1 lineage in India and a tribal link to Indian Brahmins. However, it is important to discover novel Y-chromosomal binary marker(s) for a higher resolution of R1a1* and confirm the present conclusions.

Mitochondrial DNA alterations in recent years have been suggested as modifier events, providing a possible proliferative advantage to the tumor cells. In order to provide further insight into the process of tumorigenesis, a study of whole mitochondria genome was conducted in 134 tissue samples obtained from 2 unrelated cancers (tumor and adjacent normal tissues from 36 breast cancer and 31 esophageal squamous cell carcinoma (ESCC) patients) with known p53 somatic mutation background. Fifteen of 36 (41.66%) breast and 12 of 31 (38.71%) ESCC tumors were found to contain at least 1 mtDNA somatic mutation, which correlated significantly with the concomitant presence of somatic mutation in DNA binding domain of the p53 gene (Breast cancer, p = 0.006; ESCC, p = 0.002). Interestingly, mutations in the non D-loop region of the mtDNA contributed significantly (Breast cancer, p = 0.004; ESCC, p = 0.032) in comparison to the hotspot-D-Loop-region. The concomitant presence of mutations in p53 and mtDNA were also predominant in breast cancer tumors with poor prognosis, that is, with the advanced stage, grade and the ER/PR negativity. Also, the observation made was apparently well explained in 10398A bearing N haplogroup genetic background with increased presence of novel and pathogenic germline mutation in mtDNA. Our study suggests that the concomitant presence of somatic alteration in mtDNA and the DNA binding domain of the p53 gene facilitates cell survival and tumorigenesis, requiring specialized therapeutic intervention because of a possible resistance to conventional chemotherapy., ((c) 2008 Wiley-Liss, Inc.)

Mitochondria are the major source of Reactive Oxygen Species (ROS) and mtDNA G10398A (Ala-->Thr) polymorphism, proposed to be involved in increased ROS production, has been shown in association with invasive breast cancer in African-American (AA) women [J.A. Canter, A.R. Kallianpur, F.F. Parl, R.C. Millikan, Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 65 (2005) 8028-8033] and prostate cancer in AA men [M.P. Mims, T.G. Hayes, S. Zheng, S.M. Leal, A. Frolov, M.M. Ittmann, et al., Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 66 (2006) 1880; author reply 1880-1881]. The role of mitochondria, however, in cancer development has been in question recently [A. Salas, Y.G. Yao, V. Macaulay, A. Vega, A. Carracedo, H.J. Bandelt, A critical reassessment of the role of mitochondria in tumorigenesis, PLoS Med. 2 (2005) e296], which has made it pertinent to analyze the data and test the hypotheses by conducting fresh case-control studies. This study, therefore, makes an attempt to validate the exclusive presence of mtG10398A (Ala-->Thr) polymorphism in a haplotype constituting mtDNA haplogroup N and its sublineages, imparting this group a higher risk for breast cancer, based on the re-analyses of approximately 1000 complete human mtDNA sequences worldwide and collated information on 2334 individuals belonging to 18 regions in India. The conclusion drawn of mt10398A allele providing a risk towards cancer is confirmed in a case-control comparison study of 124 sporadic breast cancer patients and 273 controls; and 55 squamous cell carcinoma of esophagus, ESCC, and 163 controls, matched for age, ethnicity and sex from north India. It is further apparent from the study that such a mtDNA polymorphism background provides a higher risk for the cancers of the tissues which could be affected by environmental insults directly as in the ESCC, observed with a high acquired (somatic) rate of mutation in p53 when compared to the breast cancer, suggesting that the mtDNA variants that arose as energetic adaptations, influence our health differentially under different environment conditions and a given genetic background of the mt genome.

The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes, ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77-4.00); cohort2 (OR = 1.76 95%CI 1.12-2.77)]. The analysis of G10398A/T16189C haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together.