Methodological paperThe genetic susceptibility profile of the South Indian women with polycystic ovary syndrome and the universality of the lack of association of type 2 diabetes genes
Introduction
Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women causing reproductive and metabolic dysfunctions and affecting 5–20% of the women in reproductive age, worldwide (Azziz et al., 2016). It is hallmarked by insulin resistance and hyperinsulinemia and a leading cause of anovulatory infertility. Associated with several co-morbidities like type 2 diabetes mellitus (T2DM), cardiovascular disease (CVDs) and endometrial cancers (Azziz et al., 2016; Legro et al., 1999), this syndrome exhibits phenotypic heterogeneity (Boomsma et al., 2006) and the underlying complex genetic etiology is still unclear. Although ~100candidate genes for PCOS susceptibility have been reported, the results of the association studies were largely inconsistent possibly due to the lack of uniformity in the diagnostic criteria, small sample size and ethnic heterogeneity (Dasgupta and Reddy, 2008; EI Hayek et al., 2016; Escobar-Morreale, 2018); relatively greater proportion of these studies failed to show association of the respective genes/variants with the disease than those that did (Dasgupta and Reddy, 2008). None of the significant variants observed were also shown to be causative to the disease. Further, most previous studies that explored genetic susceptibility to PCOS have included only a single gene and/or few polymorphisms in one of the pathways related to hyperandrogenism, insulin signaling and ovarian dysfunction. Given the complex nature of PCOS whose manifestation results from a large number of interacting genes and environmental factors, it is essential to explore a wide spectrum of genetic variants and environmental factors (Azziz et al., 2016; Dasgupta and Reddy, 2013; Lim et al., 2013) along with interactions among them. Although the recent large scale genome wide association studies (Chen et al., 2011; Day et al., 2015; Hayes et al., 2015; Lee et al., 2015; Shi et al., 2012) identified nearly 20 loci as being associated with this syndrome the subsequent attempts at validation of these loci again yielded inconsistent results (Fu et al., 2013; Jedrzejuk et al., 2015; Kim et al., 2014; Nazouri et al., 2015; Ranjzad et al., 2012; Saxena and Welt, 2013). Thus, altogether, a large number of putative genomic variants susceptible for PCOS were reported, yet no candidate gene has emerged as a convincing biomarker thus far.
As far as the Indian populations are concerned, there was complete paucity of knowledge on the status of association of the candidate genes with PCOS, the PCOS studies in India were mostly confined to the clinical dimensions till we initiated a project in 2007 aiming to identify genetic variants susceptible to PCOS in the Southern Indian women from Hyderabad and studied a number of genes through direct sequencing (Dasgupta et al., 2010, Dasgupta et al., 2012a, Dasgupta et al., 2012b, Dasgupta et al., 2012c, Dasgupta et al., 2012d, Dasgupta et al., 2015; Dasgupta and Reddy, 2013), followed by a couple of others (Gangopadhyay et al., 2016; Reddy et al., 2014; Shaikh et al., 2013, Shaikh et al., 2016; Siddamalla et al., 2018). On the other hand, given the phenotypic overlap and shared pathophysiology between PCOS and T2DM, a few attempts were also made recently to investigate the nature of association of T2DM genes with PCOS, which did not yield positive results (Barber et al., 2007; Ewens et al., 2011; Kim et al., 2012; Saxena and Welt, 2013; Xu et al., 2010).The results of our analysis of this PCOS cohort from Hyderabad for 15 SNPs from nine important genes, most significantly and consistently associated with T2DM (Reddy et al., 2016), were also confirmatory to the earlier studies among the non-Indian groups in not showing the association, suggesting probable universality of this pattern. Given the limited number of T2DM genes that we considered earlier pertains only to the diabetic component of PCOS and may not have direct implication to its reproductive component, which is key to the pathophysiology of PCOS, we had hypothesized that (1) there could be other T2DM genes that might play a more precise role in the manifestation of PCOS and/or (2) it may not be the diabetes genes per se but their interaction with the genes in the more crucial reproductive pathway that might trigger the manifestation of this syndrome. Therefore, it is imperative to explore the interactions between larger sets of genes in the metabolic/diabetic and reproductive pathways in order to identify the underlying genetic mechanisms for the manifestation of PCOS.
Indian populations are known to show high prevalence of T2DM (Kommoju and Reddy, 2011) and the prevalence rates are reported to be showing alarming increase with increasing urbanization and lifestyle changes in the recent decades. Hyderabad is considered as the diabetic capital of India and it would not be surprising if similar pattern of prevalence for PCOS is reported. The South Asian PCOS women were observed to have more severe reproductive and metabolic symptoms (Mehta et al., 2013) and also greater probability of developing T2DM when compared to others (Wijeyaratne et al., 2002). Further, the incidence of PCOS among Indian women and adolescents is reported to be escalating rapidly due to changing lifestyles (Anjali et al., 2017; Joshi et al., 2014) and the recent reports from the Indian infertility clinics suggest that ~ 60% of those coming to these clinics suffer from PCOS and the overall prevalence of PCOS is estimated at ~ 20% among the Indian women in reproductive age (Malathy Iyer, 2016). It is such an emerging health problem of national concern that the Indian Council of Medical Research (ICMR) has recently instituted a special clinic at the National Institute for Research in Reproductive Health (NIRRH), Mumbai, with an idea of evolving model PCOS clinics that can be replicated in public hospitals across the country. Further, Indian populations are known to show different patterns of genetic susceptibility to different complex genetic disorders (Aruna et al., 2011; Dasgupta et al., 2012d; Dhandapany et al., 2009; Pemberton et al., 2008; Uma jyothi and Reddy, 2015) as compared to the populations of other ethnic backgrounds. Yet the genetic studies pertaining to PCOS are too scanty among Indian populations (Dasgupta and Reddy, 2008; Kumuda and Reddy 2019, unpublished review) and, given the unique pattern of their genetic predisposition, it is necessary to undertake multi-centric studies to explore genetic susceptibility profile of the Indian PCOS women at large. It is also necessary to establish the role that the diabetes genes play in the manifestation of PCOS among the Indian women, in general, and particularly those from Hyderabad, to ascertain if the universality of the pattern of lack of association of T2DM genes with PCOS hitherto observed holds true.
Section snippets
Study design
The current study is a part of the major project entitled, “Identification of susceptibility genes associated with PCOS among Indian women” undertaken by the Molecular Anthropology Group of Biological Anthropology Unit, Indian Statistical Institute, Hyderabad, India, for which 250 primary PCOS cases and 299 controls were enrolled during 2008–2009.The patients were recruited from the gynecology clinic of the Osmania General Hospital and Anus Infertility Clinic from Hyderabad, India, as per the
Results
The Anthropometric, clinical and biochemical characteristics of the subjects and other background information were described elsewhere (Dasgupta and Reddy, 2013) and for the sake of brevity we are not reproducing the same here.
Discussion
There has been limited progress in the identification of genes susceptible to PCOS as compared to the other complex genetic diseases (Kosova and Urbanek, 2013).The major challenge in genetic studies on PCOS is to resolve phenotypic heterogeneity, while aiming at the primary cause of PCOS and its underlying molecular mechanisms. This study is the first of its kind among the Indian populations, designed to identify the genetic variants underlying susceptibility to PCOS in the South Indian women,
Conclusions
Given reasonably large cohort of our study with sufficient statistical power, the failure to detect any clear cut association of genetic variants with PCOS is somewhat intriguing and this could be plausibly because the effects of individual SNPs were too small (OR < 2) to reach highly significant levels of association with the disease. Given this, the absence of significant interactions, both pair wise as well as multiple SNP combinations, observed in this population is not surprising. However,
Authors' contributions
BMR conceived and designed the study, outsourced genotyping and supervised statistical analysis and drafting of the manuscript as principal investigator of the project; RP and AS prepared DNA samples for genotyping and IK reviewed literature, did statistical analysis in consultation with RP and prepared the first draft of the manuscript and made subsequent revisions of the manuscript based on the feedback from other authors. All authors read and approved the final manuscript.
Acknowledgements
BMR is thankful to the Director General, ICMR, for awarding him the Emeritus Medical Scientist (EMS) position and granting SRF position to Mrs. I. Kumuda to work in the EMS project under which the present study was carried out, to the Director(s) of the Indian Statistical Institute (ISI), Kolkata, for financial and logistics support at different stages of this project of which the present work is an extension, and Head, Department of Genetics and OU administration for logistic support during
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Sample collection, DNA isolation and genotyping of the 92 SNPs for this study accomplished when BMR was working as Professor of Indian Statistical Institute, and RP was an SRF associated with BMR as Ph.D student.