Contents lists available at ScienceDirect Meta Gene journal homepage: www.elsevier.com/locate/mgene Insulin gene VNTR class III allele is a risk factor for insulin resistance in Kashmiri women with polycystic ovary syndrome Shayaq Ul Abeer Rasool a , Sairish Ashraf b , Mudasar Nabi b , Fouzia Rashid c , Shariq R. Masoodi d , Khalid M. Fazili a , Shajrul Amin b, ⁎ a Department of Biotechnology, University of Kashmir, Srinagar, India b Department of Biochemistry, University of Kashmir, Srinagar, India c Clinical Biochemistry, University of Kashmir, Srinagar, India d Sheri Kashmir Institute of Medical Sciences, Srinagar, India ARTICLE INFO Keywords: Polycystic ovary syndrome Insulin resistance INS VNTR Obesity ABSTRACT Purpose: PCOS is a complex heterogeneous multifactorial endocrine disorder characterized by anovulation, hyperandrogenism and polycystic ovaries. PCOS afects 5–10% women of reproductive age is also suggested to increase the risk of insulin resistance, cardiovascular disorders and T2DM. The aim of this study was to assess the possible association of INS VNTR polymorphism with PCOS and their phenotype-genotype interactions in Kashmiri women with PCOS. Methods: A total of 349 subjects including 249 cases and 100 age-matched healthy controls were recruited in the study. DNA was extracted from peripheral venous blood from all subjects and association analysis was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype-pheno- type correlation analysis was performed to evaluate the association of INS VNTR polymorphism with phenotypic features. Results: Allele frequency (OR = 0.86, C.I. 0.48–1.54, P = .61) and genotype distribution (P = .79, χ 2 =0.46) showed no signifcant association between INS VNTR and PCOS. The dominant (OR=1.21, χ 2 = 0.026, P = .871), recessive (OR = 0.83, χ 2 =0.35, P = .549) and heterozygote vs. homozygote (OR = 1.25, χ 2 =0.45, P = .50) genotype model analysis further supported this fnding. Genotype-phenotype correlation analysis showed class III allele carrier (I/III + III/III genotype) was signifcantly associated with increased weight (P = .044), BMI (P = .021) insulin (F) (P = .049) and HOMA IR (P = .02) in recessive model in PCOS women. Conclusions: INS VNTR polymorphism does not increase the risk of PCOS. However, INS VNTR class III allele is associated with elevated BMI and HOMA IR, suggesting its role in the pathogenesis of insulin resistance and obesity in Kashmiri women with PCOS. 1. Introduction Polycystic ovary syndrome is the most widespread endocrine-me- tabolic disorder afecting 5–10% of women of reproductive age worldwide (Escobar-Morreale, 2018; Azziz et al., 2004; Knochenhauer et al., 1998; Lauritsen et al., 2012). It is a heterogeneous and multi- faceted syndrome manifested as a collection of symptoms including hirsutism, acne, alopecia, acanthosis, obesity, and infertility but is commonly characterized by hyperandrogenism (clinical and/ bio- chemical), anovulation and polycystic ovaries (Schmidt et al., 2016; Azziz et al., 2016; Amsterdam, 2012; Bouchard and Fauser, 2014; Goodman et al., 2015; Azziz et al., 2009). The PCOS related complications present across lifespan starting from reproductive and dermatological concerns to metabolic and psychological complications like diabetes, metabolic syndrome, cardiovascular disorders, en- dometrial carcinoma depression, and reduced quality of life as age progresses (Amsterdam, 2012; Sir-Petermann et al., 2016; Bhattacharya and Jha, 2010; Anagnostis et al., 2018). The etiology of PCOS is multifactorial: multigenic, intrauterine, epigenetic and environmental interactions are suggested in the patho- genesis of PCOS (Hoeger, 2014; Diamanti-Kandarakis et al., 2012; Azziz, 2016; Goodarzi et al., 2011). Genetic variants like single nu- cleotide polymorphisms (SNP) are extensively investigated as potential precursors for various complex disorders including PCOS (Chen et al., https://doi.org/10.1016/j.mgene.2019.100597 Received 3 April 2019; Received in revised form 17 May 2019; Accepted 26 June 2019 ⁎ Corresponding author at: Department of Biochemistry, University of Kashmir, Srinagar 190006, India. E-mail address: shajrulamin@uok.edu.in (S. Amin). Meta Gene 21 (2019) 100597 Available online 27 June 2019 2214-5400/ © 2019 Elsevier B.V. All rights reserved. T