McGrail Carolyn, Chiou Joshua, Elgamal Ruth, Luckett Amber M, Oram Richard A, Benaglio Paola, Gaulton Kyle J
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA.
University of Exeter College of Medicine and Health, Exeter, U.K.
Diabetes Care. 2025 Feb 1;48(2):202-211. doi: 10.2337/dc24-1251.
More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals.
We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS.
A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44).
In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.
超过10%的1型糖尿病（T1D）患者不具有高风险的HLA - DR3或 - DR4单倍型，这些患者具有不同的临床特征，如发病较晚和胰岛素依赖程度降低。我们旨在确定在不存在DR3/DR4的情况下T1D的遗传驱动因素，并改善对这些个体T1D风险的预测。
我们在12316个非DR3/DR4样本中进行了T1D关联和精细定位分析。接下来，我们进行了异质性测试，以检查无DR3/DR4单倍型个体与有DR3/DR4单倍型个体在T1D风险变异方面的差异。我们进一步评估了非DR3/DR4和DR3/DR4队列在基因调控元件和生物途径富集方面的全基因组差异。最后，我们开发了一种遗传风险评分（GRS）来预测无DR3/DR4个体的T1D，并与现有的T1D GRS进行比较。
在非DR3/DR4样本中总共鉴定出18个T1D风险变异。全基因组范围内，MHC及多个其他位点的风险变异对T1D的影响因DR3/DR4状态而异，并且非DR3/DR4 T1D有证据表明其多基因负担更大。与DR3/DR4相比，非DR3/DR4中与T1D相关的变异在参与抗原呈递、固有免疫和β细胞的调控元件和途径中更富集，而在T细胞中则减少。一种非DR3/DR4 GRS在区分非DR3/DR4 T1D与非糖尿病（曲线下面积0.867；P = 7.48×10 - 32）和2型糖尿病（0.907；P = 4.94×10 - 44）方面优于现有的风险评分GRS2。
总体而言，我们确定了T1D遗传风险因高风险HLA - DR3/DR4单倍型而异，这揭示了疾病机制，并能够在整个HLA背景下更准确地预测T1D。
