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Background: Aldosterone synthase (CYP11B2) is a key enzyme involved in the terminal steps of aldosterone biosynthesis. Genetic variability in CYP11B2 gene has been associated with heterogeneous aldosterone production, which can affect sodium homeostasis and thereby regulation of blood pressure. Hence, the present study was aimed to explore the single-locus variations, haplotype and epistasis patterns of CYP11B2 (C-344T, intron-2 gene conversion and Lys173Arg) gene polymorphisms, and the risk contributed by them to the development of essential hypertension (EHT)., Methods: A total of 279 hypertensive patients and 200 normotensive controls were enrolled in this study. C-344T and Lys173Arg polymorphisms of CYP11B2 gene were genotyped by PCR-RFLP method and intron-2 gene conversion (IC) polymorphism by allele-specific PCR analysis., Results: Single-locus analysis revealed significant association of CYP11B2 C-344T and Lys173Arg polymorphisms with EHT (p < 0.05). Considering the sexes, Lys173 allele was found to be at risk for hypertension in males (OR 1.40; 95% CI = 1.01-1.96). Unphased haplotype analysis revealed H1 (T-Conv-Lys; p = 0.0017) to have significant risk for EHT, while haplotype H4 (T-Wt-Arg) had a significant protective effect. Multifactor dimensionality reduction (MDR) interaction analysis found the overall best model with C-344T and IC polymorphisms exhibiting strong synergistic effect., Conclusion: The present study revealed a strong synergistic effect of CYP11B2 C-344T and IC polymorphisms causing susceptibility to EHT and haplotype H1 (-344T-Conv-Lys173) as the risk-conferring factor for hypertension predisposition.

The northern region of the Indian subcontinent is a vast landscape interlaced by diverse ecologies, for example, the Gangetic Plain and the Himalayas. A great number of ethnic groups are found there, displaying a multitude of languages and cultures. The Tharu is one of the largest and most linguistically diverse of such groups, scattered across the Tarai region of Nepal and bordering Indian states. Their origins are uncertain. Hypotheses have been advanced postulating shared ancestry with Austroasiatic, or Tibeto-Burman-speaking populations as well as aboriginal roots in the Tarai. Several Tharu groups speak a variety of Indo-Aryan languages, but have traditionally been described by ethnographers as representing East Asian phenotype. Their ancestry and intra-population diversity has previously been tested only for haploid (mitochondrial DNA and Y-chromosome) markers in a small portion of the population. This study presents the first systematic genetic survey of the Tharu from both Nepal and two Indian states of Uttarakhand and Uttar Pradesh, using genome-wide SNPs and haploid markers. We show that the Tharu have dual genetic ancestry as up to one-half of their gene pool is of East Asian origin. Within the South Asian proportion of the Tharu genetic ancestry, we see vestiges of their common origin in the north of the South Asian Subcontinent manifested by mitochondrial DNA haplogroup M43.

Androgens in breast cancer have been studied alone and in correlation with estrogens as estrogen to testosterone ratio. 5-α-reductase is one of the important enzymes participating in androgen metabolism, which affects androgen activity by affecting conversion of testosterone to dihydrotestosterone. We hypothesized that polymorphisms in the SRD5A2 gene (encoding 5-α-reductase) may affect breast cancer risk by affecting total androgen activity. Complete coding region of the SRD5A2 gene was sequenced in a group of 628 patients and 244 control samples from three southern states (Tamil Nadu, Andhra Pradesh, and Karnataka) of India. We observed three common polymorphisms in this gene; namely, A49T, V89L, and (TA)n repeats. A49T locus was monomorphic in the study population, but V89L showed a strong correlation with breast cancer (P = 0.03, OR = 1.40, CI = 1.02-1.91). (TA)0/(TA)9 and (TA)9/(TA)9 genotypes were at a lower risk of breast cancer (P = 0.01, OR = 0.64, CI = 0.46-0.90). We conclude that SRD5A2 genotypes significantly affect breast cancer risk in the South Indian populations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The current study was aimed to elucidate the association of thymidylate synthase (TYMS) 5'- UTR 28bp tandem repeat and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T polymorphisms with acute leukemia in South Indian subjects. A total of 812 subjects [523 healthy controls, 148 acute lymphoblastic leukemia (ALL) cases and 141 acute myeloid leukemia (AML) cases] were screened for TYMS 5'-UTR 28bp tandem repeat and cSHMT C1420T using PCR-AFLP and PCR-with confronting two-pair primers (CTPP) approaches. TYMS 5'-UTR 2R allele frequencies of controls, ALL and AML cases were 35.3%, 28.0% and 30.1% respectively. This polymorphism conferred protection against ALL (OR: 0.71, 95%CI: 0.53-0.96) while showing no statistically significant association with AML (OR: 0.79, 95%CI: 0.58, 1.07). The cSHMT variant allele (T-) frequencies of ALL and AML cases (6.42% and 5.68% respectively) were significantly lower compared to controls (58.3%). This polymorphism conferred protection against ALL (OR: 0.049, 95%CI: 0.029-0.081) and AML (OR: 0.043, 95%CI: 0.025-0.074). The TYMS 5'-UTR 2R2R genotype was associated with a lower total leukocyte count, smaller percentage of blasts, and more adequate platelet count compared to 2R3R and 3R3R genotypes in ALL cases. No such genotype-dependent differences were observed in AML cases. ALL cases carrying the cSHMT C1420T polymorphism showed higher disease free survival compared to those with the wild genotype. To conclude, the TYMS 5'-UTR 28bp tandem repeat reduces risk for ALL while cSHMT C1420T reduces risk for both ALL and AML. Both also influence disease progression in ALL.

The m.10398G>A polymorphism in the MT-ND3 gene has been linked to the manifestation of several neurodegenerative disorders and cancers. Several research groups have analyzed the association between m.10398G>A polymorphism and breast cancer; however, the results do not follow a consensus. We have studied this polymorphism in three Dravidian populations from South India. Analysis on 716 cases and 724 controls found no association between m.10398G>A polymorphism and breast cancer [OR = 0.916 (0.743-1.128); P = 0.409]. Menopausal stratification also revealed no significant association in either pre-menopausal or post-menopausal breast cancer groups. In addition, we undertook a meta-analysis on 16 study groups, comprising a total of 7202 cases and 7490 controls. The pooled odds ratio suggested no significant association of m.10398G>A substitution with breast cancer [OR = 1.016 (0.85-1.22); P = 0.86]. In conclusion, there is no evidence of association between m.10398G>A polymorphism and breast cancer risk among South Indian women. Meta-analysis suggested no overall correlation between this polymorphism and breast cancer risk., (© 2013.)

Introduction: TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear., Methods: We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA., Results: c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001)., Conclusion: c.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.

Entire mitochondrial DNA (mtDNA) sequencing was carried out in 101 primary breast cancer patients and 90 controls of south Indian origin. We identified 69 novel mutations in breast cancer patients and 637 reported polymorphisms in patients and/or controls. PolyPhen-2 analysis predicted 5 out of 14 novel missense mutations as 'probably damaging variants'. Haplogrouping analysis identified a significant association between haplogroup M5 and breast cancer risk. Microsatellite instability and tumor specific large scale mtDNA deletions were not observed in tumor tissues from the patients. In conclusion, mtDNA mutations and haplogroups may constitute an inheritable risk factor for pathogenesis of breast cancer., (Copyright © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

The present study was designed to explore the association between the SNP +405G>C of the VEGF gene with the risk of endometriosis, and endometriosis associated with adenomyosis and chocolate cysts. Following extraction of genomic DNA, genotyping of the +405 G>C polymorphisms of the VEGF gene was performed by PCR - RFLP analysis. The genotype (X2 =21.713, 2 df, P = < 0.0001) and allele (X2 =10.697, 1 df, P = 0.0011) frequencies of endometriosis patients were significantly different from those of the control women. The genotype and allele frequencies significantly differed in all the clinical subgroups of endometriosis patients. The significant differences in allele frequencies were the result of an increased proportion of homozygote GG genotype carriers. No significant difference was observed between the clinical subgroups with respect to the genotype and allele frequencies of the VEGF +405G>C polymorphism. These findings suggest that the VEGF +405 G>C polymorphism is associated with the risk of endometriosis, and endometriosis associated with adenomyosis and chocolate cysts.

Purpose: Myopia is a common vision problem affecting almost one third of the world's population. It can occur as an isolated genetic condition or be associated with other anomalies and/or syndromes. Seventeen myopia loci have been identified on various chromosomes; however, no specific gene mutations have yet been identified., Methods: Two large multigeneration Asian Indian pedigrees (UR006 and UR077) with isolated, nonsyndromic myopia were studied, in which the condition appeared to segregate as an X-linked recessive trait (MYP1; MIM 310460). The degree of myopia was variable in both families, ranging from -6 to -23 D (mean, -8.48 D) with the majority >7.0 D. To map the myopia locus in these families, polymorphic microsatellite markers covering the entire X chromosome were used in linkage analyses performed on 42 genomic DNA samples (13 affected and 29 normal) from both families., Results: Marker DXYS154, which is located within the pseudoautosomal region in distal Xq28 (PAR2; pseudoautosomal region 2), gave a combined maximum LOD score of 5.3 at = 0 under an autosomal recessive model. Other markers in the region (near but not within the PAR2 region) that showed no recombination with the phenotype in both the families included DXS1108, DXS8087, and F8i13., Conclusions: Observation of recombination in family UR006 refined the disease locus to a ∼1.25-Mb region flanked by the proximal marker DXS1073 and distal marker DXYS154. Mutation search in exons and splice junctions of candidate genes CTAG2, GAB3, MPP1, F8Bver, FUNDC2, VBP1, RAB39B, CLIC2, TMLHE, SYBL, IL9R, SPRY3, and CXYorf1 did not detect a pathogenic or predisposing variant.