STUDY 0F CLINICAL CHARACTERISTICS AND ASSOCIATION OF A CDKAL1 GENE POLYMORPHISM (RS10946398) WITH DIABETES MELLITUS TYPE 2 T2DM IN CASES PRESENTED AT THE DIABETIC CENTRE ISLAMABAD

Abstract

Diabetes Mellitus type 2 is a prevalent disease that afflicts more than 415 million people and a leading cause of morbidity and moratility worldwide. It is influenced by both the genetic and non -genetic factors. Among non-genetic risk factors age, BMI, lack of physical activity, obesity, hypertension, and many other factors contribute to its prevalence.CDK5 Regulatory subunit association protein 1 (CDKAL) is a protein encoding gene which encodes a tRNA modifying enzyme which is involved in the proper protein translation and in the regulation of insulin production, encoded by CDKAL1 gene variations in the CDKAL1 gene sequence leading to the misreading of Lys codon in proinsulin, which results in the decreased production of glucose stimulated pro-insulin. In present study a total of 100 types 2 patients were enrolled through THE DIABETES CENTRE Islamabad. Following the study the possible demographic and clinical risk factors were documented and genotyped to study gene association. Various sequence of CDKAL1 are polymorphisms such as r s4712523, rs10946398, rs7754840, and rs7756992,rs9465871 reported to be associated with T2DM of these variants the SNP rs10946398 is reported to have an impact on risk of type 2 diabetes in different population including European , Japanese, Chinese and Indian population. Research have shown that this SNP rs10946398 overturns the regulation of CDKAL1 expression, results in decreased insulin production however there is no reported case from our population. Blood samples collected from the patients after informed consent. DNA was extracted and the primers were designed to perform the TETRA-ARMS PCR. In our study we genotyped 17 T2DM patients and 10 controls for rs10946398 CDKAL1 using tetra ARMS PCR. Data analysis of clinical and demographic characteristics revealed that among diabetes patients most of the cases were males with age higher than 35y.80% of the Patients had cholesterol more than 150mg/dl , 94% had HBA1C more than 6 , 76.6% had higher triglyceride levels more than 150mg/dl. After TETRA ARMS PCR Analysis the AA allele was found to be 8 in cases and 6 in control AC was 7 in cases and 3 in control however minor allele (C) was found in homozygous form in 2 cases and 1 control. As number of cases genotyped for r s 10946398 polymorphism was not sufficient therefore showed a non- significant association between (p=0.25) with risk of type 2 diabetes. Therefore the findings of the C allele for DM in our population could not be ruled out. Hence study do not support CDKAL1 gene polymorphism rs10946398 in Pakistani population. However this was a small scale study further large studies are required to xiv Abstract find the exact probability of the variant in a population and its role in disease onset and its progression and pathogenesis.