Human leukocyte antigen (HLA) system is the most polymorphic and gene dense region of human DNA that has shown many disease associations. It has been further divided into HLA classes I, II, and III. Polymorphism in HLA class II genes has been reported to play an important role in the pathogenesis of type 1 diabetes (T1D). It also showed association with T2D in different ethnic populations. However, a little is known about the relationship of HLA class I gene polymorphism and T2D. This study has evaluated the association of HLA-B (class I gene) variants with T2D in Pashtun ethnic population of Khyber Pakhtunkhwa. In the first phase of the study, whole exome sequencing (WES) of 2 pooled DNA samples was carried out, and DNA pools used were constructed from 100 diabetic cases and 100 control subjects. WES results identified a total of SNPs in HLA-B gene. In the next phase, first 5 out of reported SNPs were genotyped using MassARRAY® system in order to validate WES results and to confirm association of selected SNPs with T2D. Minor allele frequencies (MAFs) and selected SNPs×T2D association were determined using chi-square test and logistic regression analysis. The frequency of minor C allele was significantly higher in the T2D group as compared to control group (45.0% vs. 13.0%) () for rs2308655 in HLA-B gene. No significant difference in MAF distribution between cases and controls was observed for rs1051488, rs1131500, rs1050341, and rs1131285 (). Binary logistic regression analyses showed significant results for SNP rs2308655 (, , and ), while no considerable association was observed for the other 4 SNPs. However, when adjusted for these variants, the association of rs2308655 further strengthened significantly (, , and ), except for rs1131500, which has no additive effect. In conclusion, the finding of this study suggests rs2308655 variant in HLA-B gene as risk variant for T2D susceptibility in Pashtun population.

中文翻译：

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巴基斯坦开伯尔-普赫图赫瓦省普什图族人群 HLA-B 基因多态性与 2 型糖尿病的关联

人类白细胞抗原 (HLA) 系统是人类 DNA 中多态性和基因最密集的区域，已显示出许多疾病关联。它已进一步分为 HLA I、II 和 III 类。据报道，HLA II 类基因的多态性在 1 型糖尿病 (T1D) 的发病机制中起重要作用。它还显示与不同种族人群中的 T2D 相关。然而，关于HLA I类基因多态性与T2D的关系知之甚少。本研究评估了开伯尔-普赫图赫瓦省普什图族人群中 HLA-B（I 类基因）变异与 T2D 的关联。在研究的第一阶段，对 2 个合并的 DNA 样本进行了全外显子组测序 (WES)，使用的 DNA 库由 100 名糖尿病患者和 100 名对照受试者构建。WES 结果共确定了HLA-B 基因中的 S​​NP。在下一阶段，前 5 名报道的 SNP 使用 MassARRAY® 系统进行基因分型，以验证 WES 结果并确认所选 SNP 与 T2D 的关联。使用卡方检验和逻辑回归分析确定次要等位基因频率 (MAF) 和选定的 SNP × T2D 关联。与对照组相比，T2D 组中次要 C 等位基因的频率显着升高（45.0% 对 13.0%）（)用于 HLA-B 基因中的 rs2308655。对于 rs1051488、rs1131500、rs1050341 和 rs1131285，未观察到病例和对照之间的 MAF 分布有显着差异（）。二元逻辑回归分析显示 SNP rs2308655 (, ,和)，而其他 4 个 SNP 没有观察到明显的关联。然而，当针对这些变体进行调整时，rs2308655 的关联进一步显着增强（, ,和)，但 rs1131500 除外，它没有附加效应。总之，本研究的结果表明 HLA-B 基因中的 rs2308655 变异是普什图人群 T2D 易感性的风险变异。