Rao Durga Koteswara, Murthy Dwaraknath K, Shaik Nazia Sultana, Banaganapalli Babajan, Konda Kumaraswami, Rao Hanmantha P, Ganti Eswar, Ahmed Awan Zuhair, A El-Harouni Ashraf, Elango Ramu, Ali Khan Imran, Shaik Noor Ahmad
Department of Genetics, Osmania University, Hyderabad, India.
Department of Biotechnology, KL University, Vaddeswaram, Andhra Pradesh, India.
Clin Exp Pharmacol Physiol. 2017 Dec;44(12):1171-1179. doi: 10.1111/1440-1681.12810. Epub 2017 Sep 20.
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 2C82-TT (P ≤ .03), 2C92-TT (P ≤ .02), and heterozygous 2C93-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.
细胞色素P450酶家族的两种主要亚型CYP2C8和CYP2C9参与药物反应、解毒和疾病发展过程。本研究描述了来自印度南部安得拉邦的234例2型糖尿病（T2DM）患者和218例健康对照中CYP2C8（2-I269F和3-R139K）及CYP2C9（2-C144R和3-L359A）基因氨基酸替代变体的差异分布。单基因座基因型分析显示，病例组中2C82-TT（P≤0.03）、2C92-TT（P≤0.02）的纯合隐性基因型以及2C9*3-AC杂合基因型（P≤0.006）的出现频率逐渐增加，表明它们在安得拉人群中与糖尿病存在显著关联。即使在其相应等位基因形式下，这些隐性基因型的统计学意义依然存在（P≤0.01）。通过计算蛋白质结构和稳定性分析进一步检验基因型关联结果，以评估氨基酸变化的有害性。与野生型对应蛋白相比，突变型CYP 2C8和2C9（2和3）蛋白在氨基酸残基水平（范围为0.43Å - 0.77Å）和多肽链水平（范围为0.68Å - 1.81Å）均显示出结构漂移。此外，突变型与天然蛋白结构之间的自由能值差异（范围为 - 0.915至 - 1.38千卡/摩尔）表明CYP基因氨基酸替代多态性具有有害性和破坏稳定性的潜力。本研究证实了CYP2C8（2和3）及CYP2C9（2和3）等位基因多态性在南印度糖尿病患者群体中的可变分布，并进一步强调了CYP基因家族作为疾病风险评估和治疗的假定位点值得高度关注。
