HLA Ⅰ类基因与 DR-DQ 一起调节中国需要胰岛素的 1 型糖尿病患者的疾病风险和发病年龄。
HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes.
机构信息
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.
出版信息
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.
METHODS
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.
RESULTS
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。
方法
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。
结果
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。
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