Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait.
Department of Population Health, Dasman Diabetes Institute, Dasman, Kuwait.
Front Immunol. 2023 Aug 10;14:1238269. doi: 10.3389/fimmu.2023.1238269. eCollection 2023.
Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB103:01:01, DQA105:01:01, and DQB102:01:01, which conferred high risk, and DRB111:04:01, DQA105:05:01, and DQB103:01:01, which were protective. The DRB103:01:01~DQA105:01:01~DQB102:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB111:04-DQA105:05-DQB103:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.
1 型糖尿病（T1D）是一种复杂的自身免疫性疾病，在全球范围内发病率很高。遗传和环境因素的相互作用可能会在易感个体中引发 T1D。HLA 基因在 T1D 的发病机制中起重要作用，特定的单倍型与疾病风险增加相关。确定风险单倍型可以极大地提高遗传评分，有助于在难以分级的亚组中进行 T1D 的早期诊断。本研究采用下一代测序技术，通过招募科威特人群中的 95 名 1 型糖尿病患儿和 150 名对照，评估 HLA Ⅱ类等位基因、单倍型和氨基酸与 T1D 之间的关联。在 HLA-DRB1、HLA-DQA1 和 HLA-DQB1 基因座中鉴定到等位基因显著关联，包括 DRB103:01:01、DQA105:01:01 和 DQB102:01:01，它们赋予高风险，而 DRB111:04:01、DQA105:05:01 和 DQB103:01:01 则具有保护作用。DRB103:01:01~DQA105:01:01~DQB102:01:01 单倍型与发生 T1D 的风险最密切相关，而 DRB111:04-DQA105:05-DQB103:01 是唯一对 T1D 具有保护作用的单倍型。我们还在 HLA-DRB1、HLA-DQA1 和 HLA-DQB1 基因中鉴定到 66 个氨基酸位置与 T1D 显著相关，包括新的关联。这些结果验证并扩展了我们对科威特儿童中 HLA 基因与 T1D 之间关联的认识。鉴定出的风险等位基因、单倍型和氨基酸变异可能通过影响 HLA 结构和功能来影响疾病的发展，并可通过基于人群的筛查工作进行早期干预。
