Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Endocrinology of the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Diabetologia. 2021 Sep;64(9):2026-2036. doi: 10.1007/s00125-021-05476-6. Epub 2021 May 22.
AIMS/HYPOTHESIS: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes.
A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing.
The susceptible DR3 (β = -0.09, p = 0.0009) and DR4-DQ8 (β = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C15:02:01 was negatively associated with onset age (β = -0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years.
CONCLUSIONS/INTERPRETATION: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.
目的/假设：本研究旨在研究 HLA Ⅰ类基因在不同发病年龄的 1 型糖尿病易感性中的作用，此外还研究了 HLA Ⅱ类基因的既定作用。
共纳入 361 例 1 型糖尿病患者（192 例发病年龄<18 岁，169 例发病年龄≥18 岁）和 500 名来自中国的健康对照者，采用下一代测序技术对 HLA-A、-B、-C、-DQA1、-DQB1 和-DRB1 基因进行基因分型。
易感 DR3（β=-0.09，p=0.0009）和 DR4-DQ8（β=-0.13，p=0.0059）单倍型与发病年龄呈负相关，而保护性 DR11（β=0.21，p=0.0314）和 DR12（β=0.27，p<0.0001）单倍型与发病年龄呈正相关。在与 DR-DQ 单倍型进行连锁不平衡调整后，A11:01:01 与发病年龄呈正相关（β=0.06，p=0.0370），而易感 C15:02:01 与发病年龄呈负相关（β=-0.21，p=0.0050）。β的单位为双平方根（四次方根），表示与每一个 HLA 单倍型/等位基因相关的发病年龄变化的年数。此外，B46:01:01 具有保护作用（OR 0.41，0.46；pc[校正多重比较]=0.0044，0.0040），而 A24:02:01（OR 2.71，2.25；pc=0.0003，0.0002）和 B54:01:01（OR 3.96，3.79；pc=0.0018，0.0004）在<18 岁组和≥18 岁组中与健康对照组相比具有易感性。在 DR4-DQ4 背景下，与<18 岁患者相比，发病年龄≥18 岁的患者中 A11:01:01（61.29% vs 28.26%，pc=0.0144）增加，而易感 A*24:02:01（19.35% vs 47.83%，pc=0.0403）减少。
结论/解释：除了 DR-DQ 单倍型外，还发现了新的 HLA Ⅰ类等位基因在不同发病年龄的 1 型糖尿病易感性中发挥作用，这可以提高对疾病异质性的认识，并对未来研究的设计具有意义。
