Ibrahim Amir T, Hussain Ayman, Salih Mohamed A M, Ibrahim Omima Abdeen, Jamieson Sarra E, Ibrahim Muntaser E, Blackwell Jenefer M, Mohamed Hiba S
Central Laboratory, Ministry of Science and Technology, Khartoum, Sudan.
Institute of Endemic Disease, University of Khartoum, P. O. Box 102 Khartoum, Sudan.
J Diabetes Metab Disord. 2016 Mar 1;15:4. doi: 10.1186/s40200-016-0225-y. eCollection 2015.
Genetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected Sudanese population.
A total 240 T2D cases and 128 unrelated healthy control subjects were included in this study. Age, sex, weight and height were recorded, blood pressure and biochemical profiles of glucose and lipids were analysed. Single nucleotide polymorphism (SNP) genotyping was performed using the Sequenom MassARRAY® system. Fourteen SNPs were selected across 7 genes: CAPN10 (rs2975760 and rs5030952), PPARG (rs17036314 and rs1801282), IGF2BP2 (rs4402960 and rs1470579), CDKAL1 (rs9465871), HHEX (rs1111875), TCF7L2 (rs7903146, rs11196205 and rs12255372), and KCNJ11 (rs5215, rs1800467 and rs5219). Allelic and haplotype association analyses were performed under additive models in PLINK. P ≤ 0.007 (=0.05/7 genes) was the P-value required to achieve correction for multiple testing.
A significant genetic association between the SNPs rs7903146 (odds ratio 1.69, 95 % confidence interval 1.21-2.38, P = 0.002) and rs12255372 (odds ratio 1.70, 95 % confidence interval 1.20-2.41, P = 0.003) at TCF7L2 and T2D was found in Sudanese population. These associations were retained after adjusting for age, sex and BMI (e.g. rs7903146: odds ratio 1.70, P adj:age/sex/BMI = 0.005). The strongest haplotype association (odds ratio 2.24; P adj:age/sex/BMI = 0.0003) comprised the two point haplotype T_C across rs7903146 and rs11196205. Stepwise logistic regression demonstrated that SNP rs7903146 added significant main effects to rs11196205 or rs12255372, whereas the reverse was not true, indicating that the main effect for association with T2D in this population is most strongly tagged by SNP rs7903146. Adjusted analyses also provided support for protection from T2D associated with minor alleles at SNPs rs2975760 at CAPN10 (odds ratio 0.44, 95 % confidence interval 0.20-0.97, P adj:age/sex/BMI = 0.042) and rs1111876 at HHEX (odds ratio 0.60, 95 % confidence interval 0.39- 0.93, P adj:age/sex/BMI = 0.022).
Multiethnic associations between T2D and SNPs at TCF7L2, CAPN10 and HHEX extend to Sub-Saharan Africa, specifically Sudan.
2型糖尿病（T2D）的遗传易感性是多因素的。在大规模全基因组关联研究的跨种族荟萃分析中，越来越多的基因已被确定为T2D的危险因素。很少有研究在撒哈拉以南非洲人群中研究这些基因。本研究旨在寻找选定苏丹人群中T2D与多个顶级候选基因中的单核苷酸多态性（SNP）之间的关联。
本研究共纳入240例T2D患者和128名无血缘关系的健康对照者。记录年龄、性别、体重和身高，分析血压以及血糖和血脂的生化指标。使用Sequenom MassARRAY®系统进行单核苷酸多态性（SNP）基因分型。在7个基因中选择了14个SNP：钙蛋白酶10（CAPN10，rs2975760和rs5030952）、过氧化物酶体增殖物激活受体γ（PPARG，rs17036314和rs1801282）、胰岛素样生长因子2结合蛋白2（IGF2BP2，rs4402960和rs1470579）、周期蛋白依赖性激酶5调节亚基相关蛋白1样1（CDKAL1，rs9465871）、同源盒转录因子（HHEX，rs1111875）、转录因子7样2（TCF7L2，rs7903146、rs11196205和rs12255372）以及内向整流型钾通道蛋白11（KCNJ11，rs5215、rs1800467和rs5219）。在PLINK中采用加性模型进行等位基因和单倍型关联分析。P≤0.007（=0.05/7个基因）是进行多重检验校正所需的P值。
在苏丹人群中发现，TCF7L2基因的SNP rs7903146（比值比1.69，95%置信区间1.21 - 2.38，P = 0.002）和rs12255372（比值比1.70，95%置信区间1.20 - 2.41，P = 0.003）与T2D之间存在显著的遗传关联。在调整年龄、性别和体重指数后，这些关联仍然存在（例如rs7903146：比值比1.70，经年龄/性别/体重指数调整后的P值 = 0.005）。最强的单倍型关联（比值比2.24；经年龄/性别/体重指数调整后的P值 = 0.0003）包括rs7903146和rs11196205之间的两点单倍型T_C。逐步逻辑回归表明，SNP rs7903146对rs11196205或rs12255372有显著的主要影响，反之则不然，这表明该人群中与T2D关联的主要影响最强烈地由SNP rs7903146标记。校正分析还支持CAPN10基因的SNP rs2975760（比值比0.44，95%置信区间0.20 - 0.97，经年龄/性别/体重指数调整后的P值 = 0.042）和HHEX基因的rs1111876（比值比0.60，95%置信区间0.39 - 0.93，经年龄/性别/体重指数调整后的P值 = 0.022）的次要等位基因对T2D有保护作用。
T2D与TCF7L2、CAPN10和HHEX基因的SNP之间的多种族关联扩展到了撒哈拉以南非洲，特别是苏丹。
