Decoding type 2 diabetes mellitus genetic risk variants in Pakistani Pashtun ethnic population using the nascent whole exome sequencing and MassARRAY genotyping: A case-control association study

• Published in: PloS one Vol. 18; no. 1; p. e0281070
• Main Authors: Jan, Asif, Zakiullah, Ali, Sajid, Muhammad, Basir, Arshad, Amina, Shah, Yasar, Bahadur, Haji, Khan, Hamayun, Khuda, Fazli, Akbar, Rani, Ijaz, Kiran
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.01.2023; Public Library of Science (PLoS)
• Subjects: Age; Analysis; Bioinformatics; Biology and Life Sciences; Care and treatment; Case-Control Studies; Developing countries; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diagnosis; Ethnicity; Ethylenediaminetetraacetic acid; Exome Sequencing; Gender; Genetic aspects; Genetic Predisposition to Disease; Genetic susceptibility; Genetic testing; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Genotyping; Health risks; Hepatocyte nuclear factor 4; Humans; Insulin resistance; LDCs; Medicine and Health Sciences; Methods; Minority & ethnic groups; Pakistan; Patients; People and Places; Polymorphism, Single Nucleotide; Population studies; Research and Analysis Methods; Risk analysis; Risk factors; Single-nucleotide polymorphism; Statistical analysis; Statistical tests; Type 2 diabetes; Pakistan; Peshawar Pakistan; China; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0281070

Genome-wide association studies have greatly increased the number of T2DM associated risk variants but most of them have focused on populations of European origin. There is scarcity of such studies in developing countries including Pakistan. High prevalence of T2DM in Pakistani population prompted us to design this study. We have devised a two stage (the discovery stage and validation stage) case-control study in Pashtun ethnic population in which 500 T2DM cases and controls each have been recruited to investigate T2DM genetic risk variants. In discovery stage Whole Exome Sequencing (WES) was used to identify and suggest T2DM pathogenic SNPs, based on SIFT and Polyphen scores; whereas in validation stage the selected variants were confirmed for T2DM association using MassARRAY genotyping and appropriate statistical tests. Results of the study showed the target positive association of rs1801282/ PPARG (OR = 1.24, 95%Cl = 1.20–1.46, P = 0.010), rs745975/ HNF4A (OR = 1.30, 95%Cl = 1.06–1.38, P = 0.004), rs806052/ GLIS3 (OR = 1.32, 95%Cl = 1.07–1.66, P = 0.016), rs8192552/ MTNR1B (OR = 1.53, 95%Cl = 0.56–1.95, P = 0.012) and rs1805097/ IRS-2 (OR = 1.27, 95%Cl = 1.36–1.92, P = 0.045), with T2DM; whereas rs6415788/GLIS3, rs61788900/ NOTCH2 , rs61788901/ NOTCH2 and rs11810554/ NOTCH2 (P>0.05) showed no significant association. Identification of genetic risk factors/variants can be used in defining high risk subjects assessment, and disease prevention.