Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome

Abstract

Objective: Polycystic ovary syndrome (PCOS) is a multigenic disorder, and insulin resistance is one of its hallmark features. Polymorphisms in exon 17 of insulin receptor (INSR) gene are reported to be associated with PCOS. We investigated this association in Indian women and its putative relationship with PCOS associated traits, which has not been explored so far. Methods: In this case control study, the polymorphisms were investigated by direct sequencing in 180 women with PCOS and 144 age matched controls. Clinical, anthropometric, biochemical, and hormonal parameters were also estimated. Results: The silent C/T polymorphism at His1058 in exon 17 of INSR was found to be present in our study population. The polymorphic genotype (CTCTT) was significantly associated with PCOS in lean women (c 2 Z8.493, dfZ1, PZ0.004). It showed association with higher fasting insulin levels (PZ0.02), homeostasis model assessment of insulin resistance (PZ0.005), free androgen index (PZ0.03), and lower quantitative insulin sensitivity check index (PZ0.004) in lean PCOS women. No other novel or known polymorphism was identified in exon 17 in this cohort. Conclusions: The study shows significant association of C/T polymorphism at His1058 of INSR with PCOS in the lean rather than obese Indian women. Its association with indices of insulin resistance and hyperandrogenemia is also seen in the same group. The findings strengthen the concept that pathogenesis of PCOS is different in lean and obese women.

Influence of gene variants related to calcium homeostasis on biochemical parameters of women with polycystic ovary syndrome

“…Also, previous epidemiologic studies have also shown significant associations of ADIPOQ gene variants with insulin resistance [13] and obesity [14]. Furthermore, a significant association between INSR gene variants and insulin resistance has been observed [15].…”

Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome

“…Follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH) and total testosterone were measured by chemiluminescence immunoassay while serum insulin and sex hormone binding globulin (SHBG) levels were estimated by radioimmunoassay method as stated earlier [19]. Complete lipid profiling including triglycerides (TG), cholesterol, high-density lipoproteincholesterol (HDL-C), apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B) was performed by enzymatic and immunoturbidimetric methods on an automated biochemistry analyzer (Erba 200, Mannheim, Germany) using commercial kits (Randox laboratories Ltd., Llanberis, UK).…”

“…Complete lipid profiling including triglycerides (TG), cholesterol, high-density lipoproteincholesterol (HDL-C), apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B) was performed by enzymatic and immunoturbidimetric methods on an automated biochemistry analyzer (Erba 200, Mannheim, Germany) using commercial kits (Randox laboratories Ltd., Llanberis, UK). Indices of IR including homeostatic model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI); hyperandrogenic parameters such as free testosterone, bioavailable testosterone and free androgen index (FAI) were estimated as reported earlier [19]. Further, homeostatic model assessment of steady-state β-cell function (HOMA-B %) was calculated as [20 X Fasting insulin (μIU/ml)]/[fasting glucose (mmol/l)-3.5] [27] while LDL values were determined using LDL (mg/dl)=Cholesterol (mg/dl) -HDL-C (mg/dl) -[TG (mg/dl)/5] formula [10].…”

Past, Present and Future of Insulin Gene and Its Related Genes In Relation To Polycystic Ovary Syndrome

“…However, replication of this association has been highly variable. Two studies found increased frequency of His1058 T allele in PCOS patients from China and India [23,24]; whereas few other studies did not see a significant association in Korean and Turkish PCOS patients [25][26][27], although it should be noted that all these studies lacked power due to small sample sizes. To overcome this limitation, Ioannidis in 2010 combined the data from these studies for a meta-analysis of the His1058 C/T polymorphism in a total of 795 cases and 576 controls, and estimated the combined odds ratio (OR) of 1.28 (95% confidence interval (CI) 0.88-1.85), which suggests that His1058 variation is likely not a major contributor to the etiology of PCOS [28].…”