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Clin Exp Pharmacol Physiol. 2017 Dec;44(12):1171-1179. doi: 10.1111/1440-1681.12810. Epub 2017 Sep 20.

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

Author information

1
Department of Genetics, Osmania University, Hyderabad, India.
2
Department of Biotechnology, KL University, Vaddeswaram, Andhra Pradesh, India.
3
Department of Genetic Medicine, Faculty of Medicine & Princess Al-Jawahara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Saudi Arabia.
4
Department of General Medicine, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences, Chinoutpalli, Vijayawada, Andhra Pradesh, India.
5
Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Saudi Arabia.
6
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.

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.

KEYWORDS:

CYP2C8; CYP2C9; South India; T2DM

PMID:
28686288
DOI:
10.1111/1440-1681.12810
[Indexed for MEDLINE]

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