Distribution of CYP2C8 and CYP2C9 amino acid substitution alleles in South Indian diabetes patients: A genotypic and computational protein phenotype study

Abstract

The CYP2C8 and CYP2C9 are two major isoforms of the cytochrome P450 enzyme family, which is involved in drug response, detoxification, and disease development. This study describes the differential distribution of amino acid substitution variants of CYP2C8 (*2-I269F & *3-R139K) and CYP2C9 (*2-C144R & *3-L359A) genes in 234 type 2 diabetes mellitus (T2DM) patients and 218 healthy controls from Andhra Pradesh, South India. Single locus genotype analysis has revealed that homozygous recessive genotypes of 2C8*2-TT (P ≤ .03), 2C9*2-TT (P ≤ .02), and heterozygous 2C9*3-AC (P ≤ .006) are seen to be increasingly present in the case group, indicating a significant level of their association with diabetes in Andhra population. The statistical significance of these recessive genotypes has persisted even under their corresponding allelic forms (P ≤ .01). Genotype association results were further examined by computational protein structure and stability analysis to assess the deleteriousness of the amino acid changes. The mutant CYP 2C8 and 2C9 (both *2 and *3) proteins showed structural drifts at both amino acid residue (range 0.43Å-0.77Å), and polypeptide chain levels (range 0.68Å-1.81Å) compared to their wild-type counterparts. Furthermore, the free energy value differences (range -0.915 to -1.38 Kcal/mol) between mutant and native protein structures suggests the deleterious and destabilizing potential of amino acid substitution polymorphisms of CYP genes. The present study confirms the variable distribution of CYP2C8 (*2 and *3) and CYP2C9 (*2 and *3) allelic polymorphisms among South Indian diabetic populations and further warrants the serious attention of CYP gene family, as a putative locus for disease risk assessment and therapy.

The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad

“…In fact, there were no other genetic studies of type 2 diabetes in the population of Hyderabad when the corresponding author of this manuscript initiated a project in the year 2009 at the Indian Statistical Institute (ISI), Hyderabad, and 15 SNPs belonging to nine genes that were known to be involved in blood-glucose homeostasis—TCF7L2 [ 19 ], insulin secretion and action-IGF2BP2 and SLC30A8 [ 20 ], insulin signaling pathway and adipocyte differentiation—IRS1, CAPN10 and PPARG [ 21 ] and pancreatic beta cell development-CDKAL1, CDKN2A/B and HHEX [ 22 ] were genotyped. Further studies of T2DM in Hyderabad were too scanty and focused only on a couple of genes/SNPs [ 23 – 25 ]. Overall, the results among the Indian populations were found to be largely inconsistent with exception to a few SNPs—rs7903146 and rs12255372 of TCF7L2, rs2970847 of PGC-1α, rs9939609 of FTO, rs1801282 of PPARG, rs4402960 of IGF2BP2 and rs5219 of KCNJ11 [ 9 – 11 , 19 , 26 – 32 ] that showed a relatively greater degree of consistency in their association with T2DM.…”

Genotyping and clinical characteristics screening of children with intellectual disability in Western India

“…The reported findings demonstrated that ID is involved diversified phenotypic characteristics rather than described with single feature [30]. A genotyping study for celiac disease on Saudi Arabian population was evident potential susceptible locus using bio-statistical analysis [31] and another study on South Indian diabetic patients was signified the result by correlating genotypic and computational approach [32]. Our approach to the current study was based on the necessity to understand the genotype-phenotype consequences and computational protein phenotype predictions in intellectually disabled children of Western Indian population.…”

“…Intellectual Disability (ID) is a prominent characteristic in most of the neurodevelopmental disorders affecting health, teaching and community services in growing nations. A meta-analysis of international studies reported the prevalence of intellectual disability between 1% and 3% of the worldwide population [1]; the world health organization characterized this clinical condition by Intelligence Quotient (IQ) score of less than 70; mild (55-70), moderate (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54), severe (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) and profound (<20) [2]. The environmental factors such as maternal alcohol abuse during pregnancy, infections, birth complications and extreme malnutrition are major causes of ID.…”

Identification of key genes involved in type 2 diabetic islet dysfunction: a bioinformatics study

“…A study showed that combined therapy with insulin and aspartame in diabetic rats induced CYP2E1 in the brain, which could have toxicological effects [31]. Another study in India indicated the variable distribution of CYP2C8 and CYP2C9 allelic polymorphisms in people with diabetes [32]. Study showed that ER stress is involved in molecular process of type 2 diabetes.…”