Redondo Maria J, Cuthbertson David, Steck Andrea K, Herold Kevan C, Oram Richard, Atkinson Mark, Brusko Todd M, Parikh Hemang M, Krischer Jeffrey P, Onengut-Gumuscu Suna, Rich Stephen S, Sosenko Jay M
Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Health Informatics Institute, University of South Florida, Tampa, FL, USA.
Diabetologia. 2025 Mar;68(3):588-601. doi: 10.1007/s00125-024-06338-7. Epub 2024 Dec 13.
AIMS/HYPOTHESIS: Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB104-DQA103-DQB10302 (HLA-DR4-DQ8) and/or HLA-DRB10301-DQA10501-DQB10201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.
We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant.
IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, p<0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, p<0.001).
CONCLUSIONS/INTERPRETATION: Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.
目的/假设：许多关于1型糖尿病发病机制的研究聚焦于具有高风险HLA单倍型的个体。我们检验了这样一个假设，即在胰岛自身抗体阳性个体中，与具有这些高风险HLA单倍型的个体相比，缺乏HLA - DRB104 - DQA103 - DQB10302（HLA - DR4 - DQ8）和/或HLA - DRB10301 - DQA10501 - DQB10201（HLA - DR3 - DQ2）与表型差异相关。
我们将1型糖尿病患者的自身抗体阳性亲属根据是否同时具有HLA - DR4 - DQ8和HLA - DR3 - DQ2（DR3/DR4；n = 1263）、具有HLA - DR4 - DQ8但不具有HLA - DR3 - DQ2（DR4/非DR3；n = 2340）、具有HLA - DR3 - DQ2但不具有HLA - DR4 - DQ8（DR3/非DR4；n = 1607）以及既不具有HLA - DR3 - DQ2也不具有HLA - DR4 - DQ8（DRX/DRX；n = 1294）分为四组。组间比较包括人口统计学特征、代谢指标以及入组时针对GAD65的自身抗体（GADA%）、IA - 2（IA - 2A%）或胰岛素（IAA%）的患病率。p值<0.01被认为具有统计学意义。
DRX/DRX组的IA - 2A%（20.9%）低于DR4/非DR3组（38.5%，p<0.001）和DR3/DR4组（44.8%，p<0.001），但与DR3/非DR4组（20.0%）相似。相反，DRX/DRX组（43.4%）、DR4/非DR3组（41.1%）和DR3/DR4组（41.0%）的IAA%相似，但DR3/非DR4组的IAA%较低（30.1%，p<0.001）。与DR3/DR4组相比，DRX/DRX组的参与者年龄更大，白人参与者患病率更低，超重/肥胖患病率更高，且保留的C肽水平更高（通过较低的Index60衡量）（所有比较，p<0.005）；与DR4/非DR3组相比，白人或非西班牙裔参与者患病率更低，Index60更低；与DR3/非DR4组相比，年龄更小，西班牙裔参与者患病率更高，Index60更低（所有比较，p<0.005）。在进展为临床1型糖尿病的1292名参与者中，DR3/非DR4组的GADA%更高，IA - 2A%和IAA%更低，与其他组相比（所有比较，p<0.01），且DR3/DR4组诊断时年龄最小（所有比较，p<0.001）。
结论/解读：与DR3/DR4和DR4/非DR3个体相比，缺乏两种高风险HLA单倍型（DRX/DRX）或具有HLA - DR3 - DQ2但缺乏HLA - DR4 - DQ8（DR3/非DR4）的自身抗体阳性个体具有表型差异，提示1型糖尿病存在病因异质性。
