HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes

Abstract

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, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 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, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (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, A*11:01:01 (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. Graphical abstract

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

“…This model was associated with type 2 diabetes (T2D; chromosome 16:p13.3 ´ chromosome 14:q31.3; p-value = 0.001344; The MS intrachromosomal model for chromosome 6:p21.32 mapped to the HLA region (chromosome 6:p21.3), which is well characterized in the literature for its dynamic role encoding cell-surface proteins responsible for regulation of the immune system (Dendrou et al, 2018). MS, as well as numerous other conditions including Alzheimer's disease (AD), type 1 diabetes, and rheumatic heart disease, have been linked to the HLA region (Auckland et al, 2020;Jiang et Lu et al, 2017;Patsopoulos et al, 2013). This highlights the strong genetic effect that combinations of alleles in the HLA region have on disease susceptibility and protection.…”

History of pediatric type 1 diabetes in China

“…In addition to HLA II , HLA I have been proved to play a role in the susceptibility to T1DM at different ages of onset. The haplotypes A33‐DR3 and A33‐DR9 were susceptible genotypes in Han population 17 …”

“…The haplotypes A33-DR3 and A33-DR9 were susceptible genotypes in Han population. 17 Besides HLA genes, a study from Shanghai analyzed the genetic correlations and differences between the key factors in the innate immune.…”

The impact of family history of type 2 diabetes on clinical heterogeneity in idiopathic type 1 diabetes

“…32 The HLA DR-DQ haplotypes were constructed using the PHASE program. 33 According to previous studies in Chinese T1D patients, 31,[34][35][36] DR3, DR4 and DR9 were recognized as susceptible haplotypes, and others were recognized as DRX. The detailed HLA DRB1-DQA1-DQB1 in DR3, DR4 and DR9 haplotypes are listed in Table S1.…”