Saxena Madhukar, Srivastava Neena, Banerjee Monisha
Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, Uttar Pradesh - 226007, India.
Department of Physiology, King George`s Medical University, Lucknow, Uttar Pradesh -226003, India.
Curr Diabetes Rev. 2018;14(3):307-319. doi: 10.2174/1573399813666170112145429.
Diabetes is the third widespread after heart disease and cancer. We have investigated genetic polymorphisms in cytokine genes viz. IL-4, IL-1Ra, IL-1β, IL-18, IL-6, TNF-α, IL-10 and ADIPOQ. The aim of study was to investigate the haplotypes, gene-gene interactions and their role in determining individual susceptibility to T2DM of family members with diabetic history.
Haplotype analysis of 2 SNPs each in IL-6 and adiponectin genes showing Pairwise Linkage disequilibrium (LD) was done by SHEsis software. Logistic regression was used to study various combinations of gene-gene interactions.
The TCGT* set of allele combination appeared to increase the disease risk upto 2 times while TATG* upto 51.4 times when four SNPs are taken together viz. IL-1β-511 C/T, IL-18-607 A/C, ADIPOQ1 +45 G/T and ADIPOQ2 +10211 T/G. Interaction of SNPs in eight genes showed one highly significant combination of alleles, TCGAGCTT* which increased the risk of T2DM upto 7.4 times while CAGAGCGT* allele combination increased the risk upto 4 times.
During pedigree analysis in six families with four SNPs, it was interesting to note that susceptible 'AC' genotype of IL-18-607 A/C was frequent in diabetic individuals in almost all families. Moreover, when checked for the presence of risk haplotypes it was observed that TCGT* and TATG* sets of allele combinations were present in most of the diabetic individuals. Individuals with certain abnormal biochemical parameters but not yet diagnosed for T2DM carried the risk genotype or haplotype. This suggested that individuals carrying risk genotypes/haplotypes might be susceptible to T2DM and develop the disease in the future.
糖尿病是仅次于心脏病和癌症的第三大常见疾病。我们研究了细胞因子基因中的遗传多态性，即白细胞介素-4（IL-4）、白细胞介素-1受体拮抗剂（IL-1Ra）、白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）和脂联素（ADIPOQ）。本研究的目的是调查单倍型、基因-基因相互作用及其在确定有糖尿病家族史的家庭成员患2型糖尿病个体易感性中的作用。
使用SHEsis软件对白细胞介素-6和脂联素基因中显示成对连锁不平衡（LD）的2个单核苷酸多态性（SNP）进行单倍型分析。采用逻辑回归研究基因-基因相互作用的各种组合。
当同时考虑4个SNP，即白细胞介素-1β-511 C/T、白细胞介素-18-607 A/C、脂联素1 +45 G/T和脂联素2 +10211 T/G时，等位基因组合TCGT使疾病风险增加高达2倍，而TATG使疾病风险增加高达51.4倍。8个基因中SNP的相互作用显示出一种高度显著的等位基因组合TCGAGCTT*，其使2型糖尿病风险增加高达7.4倍，而CAGAGCGT*等位基因组合使风险增加高达4倍。
在对6个家族的4个SNP进行系谱分析时，有趣的是，白细胞介素-18-607 A/C的易感“AC”基因型在几乎所有家族的糖尿病个体中都很常见。此外，在检查风险单倍型的存在时，观察到大多数糖尿病个体中存在等位基因组合TCGT和TATG。某些生化参数异常但尚未诊断为2型糖尿病的个体携带风险基因型或单倍型。这表明携带风险基因型/单倍型的个体可能易患2型糖尿病，并在未来发展为该疾病。
