GGN repeat length and GGN/CAG haplotype variations in the androgen receptor gene and prostrate cancer risk in south Indian men

The ethnic variation in the GGN and CAG microsatellites of the androgen receptor (AR) gene suggests their role in the substantial racial difference in prostate cancer risk. Hence, we performed a casecontrol study to assess whether GGN repeats independently or in combination with CAG repeats were associated with prostate cancer risk in South Indian men. The repeat lengths of the AR gene determined by Gene scan analysis, revealed that men with GGN repeats £21 had no significant risk compared to those with >21 repeats (OR 0.91 at 95% CI-0.52–1.58). However, when CAG repeats of our earlier study was combined with the GGN repeat data, the cases exhibited significantly higher frequency of the haplotypes CAG £19/GGN £21 (OR-5.2 at 95% CI-2.17– 12.48, P 21(OR-6.9 at 95%CI-2.85–17.01, P < 0.001) compared to the controls. No significant association was observed between GGN repeats and prostate-specific antigen levels and the age at diagnosis. Although a trend of short GGN repeats length in high-grade was observed, it was not significant (P = 0.09). Overall, our data reveals that specific GGN/CAG haplotypes (CAG £19/GGN £21 and CAG £19/GGN > 21) of AR gene increase the risk of prostate cancer and thus could serve as susceptibility marker for prostate cancer in South Indian men

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits

The epigenetic paradigm in periodontitis pathogenesis

Epigenome refers to "epi" meaning outside the "genome." Epigenetics is the field of study of the epigenome. Epigenetic modifications include changes in the promoter CpG Islands, modifications of histone protein structure, posttranslational repression by micro-RNA which contributes to the alteration of gene expression. Epigenetics provides an understanding of the role of gene-environment interactions on disease phenotype especially in complex multifactorial diseases. Periodontitis is a chronic inflammatory disorder that affects the supporting structures of the tooth. The role of the genome (in terms of genetic polymorphisms) in periodontitis pathogenesis has been examined in numerous studies, and chronic periodontitis has been established as a polygenic disorder. The potential role of epigenetic modifications in the various facets of pathogenesis of periodontitis is discussed in this paper based on the available literature

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular diseases—an updated systematic review

Abstract Background Cardiovascular diseases (CVDs) are the leading cause of mortality in India. Residual risk exists in patients receiving optimal guideline-directed medical therapy. Possession of certain somatic mutations, at a variant allele frequency of ≥ 2% in peripheral blood, driving clonal expansion in the absence of cytopenias and dysplastic hematopoiesis is defined as clonal hematopoiesis of indeterminate potential (CHIP). Recently, it was found that carriers of CHIP had a higher risk to have coronary artery disease (CAD) and early-onset myocardial infarction. Association of CHIP with heart failure and valvular heart diseases is increasingly being considered. The common link that connects CHIP mutations and CVDs is inflammation leading to increased expression of cytokines and chemokines. We intended to do a systematic review about the association of CHIP mutations and CVD along with identifying specific CHIP mutations involved in increasing the risk of having CVDs. The main body of the abstract We performed an extensive literature search in PubMed and Google Scholar databases. Out of 302 articles, we narrowed it down to 10 studies based on our pre-specified criteria. The methodology adopted for the identification of CHIP mutations in the selected studies included – whole-exome sequencing (n = 3), whole-genome analysis (n = 1), transcriptome profiling analysis (n = 1), whole-genome analysis (n = 1), and single-cell RNA-sequencing (n = 1). We found that the available literature suggested an association between CHIP and CVD. The most commonly described CHIP mutations in patients with CVD are DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B. We further analyzed the commonly mutated CHIP genes using bioinformatics tools. Protein function and interaction analysis were performed using the g: Profiler and GeneMANIA online tools. The results revealed significant bio grid interactions for molecular functions, biological processes, and biological pathways. Interaction analysis showed significant physical and co-expression interactions. Short conclusion We conclude that there exists a significant association between CHIP mutations and CVD with DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B as the commonly implicated genes. The recognition of the link between CHIP and cardiovascular events will expand our understanding of residual risk and will open up new avenues of investigation and therapeutic modalities in the management of patients with CVD

GGN repeat length and GGN/CAG haplotype variations in the androgen receptor gene and prostate cancer risk in south Indian men

The ethnic variation in the GGN and CAG microsatellites of the Androgen Receptor (AR) gene suggests their role in the substantial racial difference in prostate cancer risk. Hence, we performed a case-control study to assess whether GGN repeats independently or in combination with CAG repeats were associated with prostate cancer risk in South Indian men. The repeat lengths of the AR gene determined by Gene scan analysis, revealed that men with GGN repeats &#8804;21 had no significant risk compared to those with &#62;21 repeats (OR 0.91 at 95% CI-0.52–1.58). However, when CAG repeats of our earlier study was combined with the GGN repeat data, the cases exhibited significantly higher frequency of the haplotypes CAG &#8804;19/GGN &#8804;21 (OR-5.2 at 95% CI-2.17–12.48, P &#60; 0.001) and CAG &#8804;19/GGN &#62; 21(OR-6.9 at 95%CI-2.85–17.01, P &#60; 0.001) compared to the controls. No significant association was observed between GGN repeats and prostate-specific antigen levels and the age at diagnosis. Although a trend of short GGN repeats length in high-grade was observed, it was not significant (P = 0.09). Overall, our data reveals that specific GGN/CAG haplotypes (CAG &#8804;19/GGN &#8804;21 and CAG &#8804;19/GGN &#62; 21) of AR gene increase the risk of prostate cancer and thus could serve as susceptibility marker for prostate cancer in South Indian men

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

The 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 &#60; 0.001). Men with &#8804; 19 CAG repeats had a significantly increased risk of cancer compared to those with &#62;19 CAG repeats (age-adjusted OR = 7.01; 95% CI = 3.52–13.94; P &#60; 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

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

<p>Despite the advances in <i>in vitro</i> 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 <i>ESR1</i> 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 <i>ESR1</i> (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.</p> <p><b>Abbreviations:</b> CI: confidence interval; COH: controlled ovarian hyperstimulation; DNA: deoxyribonucleic acid; ESR: estrogen receptors; FSH: follicle stimulating hormones; FSHR: FSH receptor; IVF: <i>in vitro</i> fertilization; PGR: progesterone receptors; SNP: single nucleotide polymorphism</p