Vettriselvi Venkatesan

South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer.

AbstractThe androgen receptor (AR) gene possesses polymorphic CAG tandem repeats and the repeat length has been inversely related to the risk of prostate cancer (PCa). The distinct ethnic variation in the CAG repeat length may be correlated to differences in PCa risk in different populations. To evaluate the CAG repeat length in the AR gene and the implications for PCa, we screened 87 PCa patients and 120 control subjects from South India. The mean CAG repeat length in PCa patients was significantly smaller than that of controls (17.0 vs 20.7; P<0.001). Men with≤19 CAG repeats had a significantly increased risk of cancer compared to those with >19 CAG repeats (age-adjusted OR=7.01; 95% CI=3.52-13.94; P<0.001). However, no significant association was observed between CAG repeats and age of onset or prostate-specific antigen levels. Although there was a trend towards shorter CAG repeat length in high grades of cancer, it was not significant (P=0.085). Thus, our results suggest an association between short CAG repeats in the AR gene and PCa risk in South Indian men. Further, we propose that CAG repeats could be used as a prognostic marker for PCa diagnosis.

Establishing integrated rural–urban cohorts to assess air pollution-related health effects in pregnant women, children and adults in Southern India: an overview of objectives, design and methods in the Tamil Nadu Air Pollution and Health Effects (TAPHE) study

Introduction In rapidly developing countries such as India, the ubiquity of air pollution sources in urban and rural communities often results in ambient and household exposures significantly in excess of health-based air quality guidelines. Few efforts, however, have been directed at establishing quantitative exposure–response relationships in such settings. We describe study protocols for The Tamil Nadu Air Pollution and Health Effects (TAPHE) study, which aims to examine the association between fine particulate matter (PM2.5) exposures and select maternal, child and adult health outcomes in integrated rural–urban cohorts. Methods and analyses The TAPHE study is organised into five component studies with participants drawn from a pregnant mother–child cohort and an adult cohort (n=1200 participants in each cohort). Exposures are assessed through serial measurements of 24–48 h PM2.5 area concentrations in household microenvironments together with ambient measurements and time-activity recalls, allowing exposure reconstructions. Generalised additive models will be developed to examine the association between PM2.5 exposures, maternal (birth weight), child (acute respiratory infections) and adult (chronic respiratory symptoms and lung function) health outcomes while adjusting for multiple covariates. In addition, exposure models are being developed to predict PM2.5 exposures in relation to household and community level variables as well as to explore inter-relationships between household concentrations of PM2.5 and air toxics. Finally, a bio-repository of peripheral and cord blood samples is being created to explore the role of gene–environment interactions in follow-up studies. Ethics and dissemination The study protocols have been approved by the Institutional Ethics Committee of Sri Ramachandra University, the host institution for the investigators in this study. Study results will be widely disseminated through peer-reviewed publications and scientific presentations. In addition, policy-relevant recommendations are also being planned to inform ongoing national air quality action plans concerning ambient and household air pollution.

Differential expression of microRNAs let-7a, miR-125b, miR-100, and miR-21 and interaction with NF-kB pathway genes in periodontitis pathogenesis

Periodontitis is a chronic inflammatory disease which is caused by destruction of the tissues that surrounds and supports the tooth. Deregulation of microRNAs has been reported to cause several inflammatory diseases such as autoimmune disease, chronic periodontitis, and cancer. In the present study, we have investigated the expression pattern of microRNAs let‐7a, miR‐125b, miR‐100, miR‐21, and RNA‐binding protein LIN‐28A among healthy individuals and chronic periodontitis patients. Total RNA was isolated from gingival tissue samples collected from 100 healthy individuals and 100 chronic periodontitis patients. The expression of microRNAs and LIN‐28 was performed by qPCR. Target prediction for the microRNAs was done using miRWalk and miRTarbase online databases and the experimentally validated targets were analyzed for their molecular function, biological processes, and related pathways using gProfiler software. The expression analysis revealed that let‐7a and miR‐21 were upregulated, whereas, miR‐100, miR‐125b, and LIN‐28 were down regulated. The age dependent expression analysis revealed that the expression levels of all the microRNAs and LIN‐28 were found to increase with age (more than 50 years), thereby suggesting an increased risk to chronic periodontitis. Among the various targets predicted using miRWalk and miRTarbase databases, NFKB was found to be a common target among all the four microRNAs. gProfiler revealed several functions such as NF‐ĸB signaling pathway, cytokine‐cytokine receptor interaction, osteoclast differentiation, etc., all of which specific to inflammation and periodontitis.

HLA-DRB1 shared epitope alleles in patients with rheumatoid arthritis: relation to autoantibodies and disease severity in a south Indian population

To investigate the presence of the ‘shared epitope’ (SE) in the HLA‐DRB1 alleles in patients with RA and to ascertain the frequency of the HLA‐DRB1 alleles with autoantibodies (anti‐cyclic citrullinated peptide [anti‐CCP] rheumatoid factor [RF]) and disease severity.

Reciprocal Microduplication of the Williams-Beuren Syndrome Chromosome Region in a 9-Year-Old Omani Boy

BACKGROUND Microdeletions of the 7q11.23 Williams-Beuren syndrome chromosome region (WBSCR) are reported with a frequency of 1 in 10,000, whereas microduplications of the region, although expected to occur at the same frequency, are not widely reported. METHOD We evaluated a 9-year old Omani boy for idiopathic intellectual disability using genetic methods, including multiplex ligation-dependent probe amplification (MLPA), for detection of microdeletions (P064-B3). RESULTS MLPA analysis revealed that the boy has a rare microduplication of the WBSCR. Prominent clinical features include global developmental delay with pronounced speech delay, dysmorphic facies, and autistic features. CONCLUSION Microduplications, in general, are reported at a lesser frequency, perhaps owing to their milder phenotype. Complete genetic assessment in children with idiopathic intellectual disability would help in identifying rare conditions such as duplication of the WBSCR.

Polymorphic Regions in Fc Gamma Receptor and Tumor Necrosis Factor-α Genes and Susceptibility to Chronic Periodontitis in a Cohort From South India

BACKGROUND Polymorphisms in the immunoglobulin G Fc receptor II (FcGR) and tumor necrosis factor-α (TNFA) genes are known to influence pathogenesis and severity of several inflammatory conditions. Association of FcGR and TNFA gene polymorphisms with chronic periodontitis (CP) susceptibility has been found to be diverse among different ethnic populations. Objectives of the present study are to determine association of functional single nucleotide polymorphisms (SNPs) in FcGR and TNF-α genes with CP susceptibility in a cohort from South India. METHODS Polymorphisms of: 1) FCGR2A 131His/Arg (rs1801274); 2) FCGR2B 232Ile/Thr (rs1050501); 3) TNFA -1031T/C (rs1799964); and 4) TNFA -863C/A (rs1800630) were analyzed among patients with healthy gingiva (n = 176) and patients with CP (n = 177). Genotyping was performed using allele-specific real-time polymerase chain reaction assay. Association between CP and SNPs was examined by multivariable logistic regression analysis with adjustment for: 1) age; 2) sex; and 3) oral hygiene index (OHI). Epistatic interaction between FcGR polymorphisms and interleukin 1B (IL1B) +3954C/T (rs1143634) was assessed using multifactorial dimensionality reduction analysis. RESULTS Among four SNPs analyzed, only FCGR2A 131His/Arg showed significant association with CP in a dominant model (odds ratio: 1.6; 95% confidence interval: 1.028 to 2.530). This significance disappeared after correcting for multiple comparisons using Bonferroni analysis, or after adjusting for age, sex, and OHI. A significant redundant interaction between IL1B +3954 C/T and FCGR2A 131His/Arg was observed. CONCLUSION Study results suggest the variant form of the SNP in FCGR2A 131His/Arg, FCGR2B 232Ile/Thr, TNFA -1031T/C, and TNFA -863C/A are not associated with CP susceptibility in the selected cohort from South India.

Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies

To the Editor: Conotruncal heart anomalies (CTA) are structural malformations involving the outflow tract. While the exact incidence of CTA in India is not known, it remains the most common type of structural birth defect with a major impact on pediatric morbidity and mortality. While most CTA are sporadic, a few are associated with genetic syndromes; the 22q11 deletion syndrome (22q11.2DS) being the predominate one. The CTA related to the 22q11.2DS are usually associated with a common 3 Mb or 1.5 Mb proximally deleted region, both of which include the TBX1 gene. However, mutations of the TBX1 gene have also been reported in patients who do not have the 22q11.2 deletion but present with CTA. The TBX1 gene encodes a transcription factor of the T-box family and mouse models have demonstrated that TBX1 haploinsufficiency cause cardiac outflow tract lesions. In a casecontrol study involving 96 cases of CTA and 100 control subjects, ranging in age from newborns to 18 y, fluorescence in situ hybridization (FISH) was performed on the cases to rule out the 22q11.2 μ-deletion. Further, screening for mutations or sequence variants in four exons of the Tbox region, which showed 98 % homology to mouse TBX1, was performed using Sanger sequencing. One out of the 96 cases with CTA (1 %) was found to have the 22q11.2 μ-deletion. However, no pathogenic mutations or sequence variants of TBX1 were detected in the patients and healthy controls. While this is in agreement with the report by Conti et al. [1], it is also in contrast with a few studies that have documented either mutations or polymorphisms in TBX1 associated with isolated CTA [2–5]. Our results, though negative, provide corroborative evidence that TBX1 mutations may not be associated with CTA in the selected pediatric population.

Association of estrogen, progesterone and follicle stimulating hormone receptor polymorphisms with in vitro fertilization outcomes

ABSTRACT Despite the advances in in vitro fertilization (IVF), the implantation success rate for infertile women remains approximately only 15%. In this study, we sought to determine whether implantation failure after repeated IVF treatments is influenced by the presence of common variants in estrogen α, progesterone and follicle stimulating hormone receptor genes. The study population included three groups of women: group 1 were 50 women who had the transfer of ≥3 high-quality embryos during the IVF procedure without ever having had a clinical pregnancy; group 2 were 50 women who achieved a clinical pregnancy after ≤3 high-quality embryos transfers and group 3 were 50 control subjects who achieved a clinical pregnancy without any fertility therapy that resulted in a one live-born infant. Genotype analysis was performed using polymerase chain reaction and Sanger sequencing for rs6165, rs6166, rs2234693, rs9340799. While progesterone receptor single nucleotide polymorphism (SNP) was genotyped based on the amplicon size, the repeats for the ESR1 TA-repeat polymorphism were calculated based on the fragment length. A higher frequency of the heterozygote AG genotype was observed in the infertile groups when compared to controls. Significantly, an allele combination of T of rs2234693, A of rs9340799; S of ESR1 (TA), A of rs6166, G of rs6165 and del of PROGINS had a higher frequency in women who had a successful IVF outcome compared to women who had an unsuccessful IVF outcome, indicating a possible protective combined genotype that could reduce a negative outcome during IVF. This study has demonstrated that combining several candidate genes is needed to assess which may play a role in fertility. Abbreviations: CI: confidence interval; COH: controlled ovarian hyperstimulation; DNA: deoxyribonucleic acid; ESR: estrogen receptors; FSH: follicle stimulating hormones; FSHR: FSH receptor; IVF: in vitro fertilization; PGR: progesterone receptors; SNP: single nucleotide polymorphism

Genetic Polymorphisms in miR-146a, miR-196a2 and miR-125a Genes and its Association in Prostate Cancer

The increase in incidence of prostate cancer in the Indian Population stresses the need to identify genetic markers for susceptibility and prognosis. Recent studies show that microRNAs play an important role in tumorigenesis by altering proliferation, differentiation and cell death. Gene polymorphisms not only in promoter region but also within miRNA gene have been shown to affect expression. The present study was aimed to analyze the role of miR-146a, miR-196a2 and miR-125a gene polymorphisms in prostate cancer. Genotyping of three SNPs rs73318382, rs57095329, rs2910164 in miRNA146a, rs11614913 in miR-196a2 and rs41275794, rs12976445, rs10404453 and rs1297533 in miR-125a was performed in 100 cases and 100 controls. Statistical analysis revealed the heterozygous AG genotype of the rs57095329 was significantly decreased in the cases when compared to the controls (OR-0.45, CI -0.24 to 0.85, p value-0.02) indicating an inverse association of this genotype with prostate cancer. Further the heterozygous CT of miR-196a2 (rs11614913) (OR-1.88, CI-1.06 to 3.35, p-0.02) and homozygous CC of miR-125a (rs12976445) (OR-2.55, CI -1.15 to 4.65, p-0.03) showed increased risk for prostate cancer. Combined analysis of all the genotypes revealed that the haplotype combination AGGCGTGG (OR = 0.09 at CI 95% (0.01–0.65) showed an inverse association with prostate cancer. Stratified analysis based on the age and tumor grade revealed no significant association.

Genomic imbalance in subjects with idiopathic intellectual disability detected by multiplex ligation-dependent probe amplification

Intellectual disability (ID) is a complex disorder with heterogeneous aetiology. The prevalence rate is about 2–3% worldwide. The cause of ID in at least half of the affected population is unclear and is reported as idiopathic ID. In addition to chromosomal abnormalities (Rio et al. 2002) and single gene mutations (Curry et al. 1997), segmental aneusomy caused by genomic rearrangements that may occur throughout the genome is implicated as a significant aetiological factor. Of late, the chromosomal subtelomeric regions have gained significance in the evaluation of ID owing to their proximity to telomeric repeat sequences which increases their probability of being involved in a deleterious rearrangement, causing ID (Raynham et al. 1996). These rearrangements are often undetectable by conventional karyotyping and call for sensitive, targeted approaches such as fluorescent in situ hybridization (FISH). In recent times, multiplex ligationdependent probe amplification (MLPA) has emerged as a robust and powerful method for the simultaneous detection of imbalances in multiple regions of the genome (Schouten et al. 2002). In India, ID constitutes 11% of genetic referrals, forming one of the top four genetic disorders in the country (Verma 2000). Considering this, we previously investigated subtelomeric rearrangements by FISH and chromosomal abnormalities by conventional cytogenetics (Mohan et al. 2016) in subjects with ID. In the present study, we extend the evaluation of children with idiopathic ID, with the objective of investigating interstitial genomic rearrangements using MLPA in a subset of the aforementioned study population. In addition, we compare the detection of subtelomeric rearrangements in seven children using MLPA owing to its merits, such as rapidity, cost-effectiveness and scope for simultaneous analysis of multiple samples.