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IRS1 Genetic Variants Associated with Glucose Control and Insulin Resistance in Type 2 Diabetes Mellitus Patients from Bosnia And Herzegovina

| Diabetes
Authors:
*Lejla Mahmutovic,1 Tamer Bego,2 Maria Sterner,3 Emma Ahlqvist,3 Zelija Velija Asimi,4 Besim Prnjavorac,5 Nour Hamad,1 Adlija Causevic,2 Leif Groop,3 Sabina Semiz1,2
Disclosure:

Dr Semiz, Dr Bego, Dr Causevic, Dr Asimi, and Dr Prnjavorac were involved in the patient recruitment, sample collection, and data acquisition. Dr Sterner, Dr Gremsperger, and Dr  Ahlqvist were involved in the genotyping analysis and data acquisition. Dr Mahmutovic and Dr Hamad were responsible for the statistical analysis and have made substantial contributions to the data interpretation. Dr Mahmutovic was involved in the writing of the initial draft of the manuscript. Dr Groop, Dr Ahlqvist, and Dr Causevic reviewed and revised the manuscript. Dr Semiz conceived and designed the study, co-ordinated and supervised the study, provided financial support, interpreted the data, and revised the manuscript. All authors read and approved the final manuscript. The authors have declared no conflicts of interest.

Acknowledgements:

The authors would like to thank medical doctors and paramedical staff from the Clinic of Endocrinology at the Clinical Center University of Sarajevo and General Hospital Tesanj for the recruitment of study subjects. They also acknowledge the invaluable contribution of the individuals who participated in this study. The authors thank Dr Fadila Serdarevic for her kind help with the statistical analysis. This study was supported by grants from the Council of Ministers of Bosnia and Herzegovina/Ministry of Civil Affairs of Bosnia and Herzegovina and the Federal Ministry of Education and Science of Bosnia and Herzegovina awarded to Dr Semiz.

Citation
EMJ Diabet. ;6[1]:44-45. Abstract Review No. AR6.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

INTRODUCTION

Previous studies have reported conflicting results regarding the association of IRS1 gene variation with Type 2 diabetes mellitus (T2DM) and insulin resistance in different ethnic groups.1-4 Here, we examined the association of single nucleotide polymorphisms rs7578326, rs2943641, and rs4675095 in the IRS1 gene with T2DM and related traits in a population from Bosnia and Herzegovina, which is among the European countries with the highest T2DM prevalence (12.3%).

MATERIALS AND METHODS

Our study involved 390 T2DM patients and 252 unrelated, nondiabetic control subjects. Biochemical parameters, including but not limited to, fasting glucose (FG), fasting insulin (FI), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), HbA1c, and lipid levels were measured in all participants. Genotyping analysis was performed by the Sequenom MassARRAY® iPLEX® platform (Agena Bioscience, Inc., San Diego, California, USA) in co-operation with Lund University Diabetes Centre, Lund University, Malmö, Sweden. In addition, we also performed a sensitivity analysis to identify the potential effects of IRS1 genetic variation on T2DM development and T2DM-related traits in a subgroup of untreated T2DM patients.

RESULTS

Our results demonstrated that after adjustment for BMI, age, and sex, rs7578326 and rs4675095 variants were positively associated with FG levels. The risk A allele of rs7578326 was also associated with higher HbA1c (B=0.034; 95% confidence interval [CI]: 0.003–0.065; pdom=0.035) and HOMA-IR levels (B=0.316; 95% CI: 0.026–0.607; prec=0.033) in non-treated T2DM patients. This is in line with a recent study showing that the rs7578326 risk A allele is associated with higher HOMA-IR and FI levels.5 Importantly, rs2943641 T allele carriers had lower HbA1c levels in non-treated T2DM patients (B=0.034; 95% CI: 0.006–0.062; prec=0.017), confirming recent results of a study performed in >12,000 American Hispanic or Latino participants, which found that risk C allele was associated with HbA1c, FI, HOMA-IR, TG, and high-density lipoprotein levels.6 Furthermore, risk C allele was associated with HOMA-IR (B=0.353; 95% CI: 0.095–0.611; prec=0.008), FI (B=0.350; 95% CI: 0.022–0.487; prec=0.033), and HbA1c levels (B=0.032; 95% CI: 0.002–0.065; pdom=0.040) in non-treated T2DM patients. In addition, our results demonstrated an association of the risk rs7578326/rs2943641 haplotype with FG levels and HOMA-IR, thus confirming the observed effects of rs7578326 and rs2943641 risk alleles individually on FG levels and IR. Interestingly, the effects of the IRS1 haplotype in the Bosnia and Herzegovina population on increased very low-density lipoprotein levels and waist circumference were also observed in control subjects. This is consistent with an adverse metabolic profile, including dyslipidaemia, which was recently reported to be associated with IRS1 genetic variation.5,6

CONCLUSION

We reported that IRS1 gene variants were significantly associated with insulin resistance markers, glucose, and HbA1c levels. Interestingly, rs7578326 and rs2943641 IRS1 variants located near to each other on the IRS1 gene showed relatively similar effects on HOMA-IR, glucose, and insulin levels, which was confirmed by haplotype analysis including these two single nucleotide polymorphisms. On the other hand, the rs4675095 variant was significantly associated with glucose levels in controls and lipid levels in diabetic patients. Thus, our findings confirmed that mutations in IRS1 gene would interfere with the function of the IRS1 protein encoded by this gene.

References
Soyal SM et al. Associations of haplotypes upstream of IRS1 with insulin resistance, Type 2 diabetes, dyslipidemia, preclinical atherosclerosis, and skeletal muscle LOC646736 mRNA levels. J Diabetes Res. 2015;2015:405371. Samani NJ et al.; WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357(5):443-53. Rung J et al. Genetic variant near IRS1 is associated with Type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet. 2009;41(10):1110-5. Kilpeläinen TO et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat Genet. 2011;43(8):753-60. Zheng JS et al. Modulation by dietary fat and carbohydrate of IRS1 association with Type 2 diabetes traits in two populations of different ancestries. Diabetes Care. 2013;36(9):2621-7. Qi Q et al. Genetic variation near IRS1 is associated with adiposity and a favorable metabolic profile in U.S. Hispanics/Latinos. Obesity. 2016;24(11):2407-13.