Abstract：
To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.
摘要：
探讨混合巴西人群中HLA等位基因和单倍型与1型糖尿病（T1DAgeD）诊断年龄之间的潜在关系。这项全国性的研究是在巴西12个城市的公共诊所进行的。我们收集了1600名T1D患者的人口统计学和遗传数据。DNA样品用于确定基因组祖先（GA）并对DRB1，DQA1和DQB1进行HLA分型。我们探索了按T1DAgeD类别分组的患者的等位基因和单倍型频率和GA(<6年，≥6-<11年，≥11-<19年和≥19年），通过单变量和多变量分析以及主要成分分析。此外,我们考虑了自我报告的肤色种族,并确定了一级亲属中常见的T1D病史.DRB1~DQA1~DQB1单倍型的纯合性指数在T1DAgeD群体中表现出最高的变异,撒哈拉以南非洲和欧洲祖先的百分比在主成分分析（PCA）分析中显示出相反的趋势。关于等位基因和单倍型与T1DAgeD的关联，风险等位基因，如HLA-DQB1*03:02g，-DQA1*03:01g,-02:01g,DRB1*04:05g和-04:02g在具有早期疾病发作的T1D患者中更频繁地观察到杂合性或纯合性。相反，等位基因如DRB1*07:01g，-13:03g,DQB1*06:02g和DQA1*02:01在老年T1D患者中更为普遍。DR3/DR4.5组合与早期疾病发作显著相关。然而,性别,GA,熟悉的T1D病史和自我报告的肤色种族身份与T1D的发作没有显着关联。值得注意的是，非常常见的风险单倍型DRB1*03：01g~DQA1*05：01g~DQB1*02：01g没有区分T1DAgeD组。在混合的巴西人口中，高危单倍型DRB1*04:05~DQA1*03:01~DQB1*03:02在6岁以前诊断的个体中更为普遍.相比之下,保护等位基因DQA1*01:02g,DQB1*06:02g,DRB1*07：01g和DRB1*13：03g和单倍型DRB1*13：03g〜DQA1*05：01g〜DQB1*03：01g和DRB1*16：02g〜DQA1*01：02g〜DQB1*05：02g在成年期诊断的患者中更常见。值得注意的是,这些关联与性别等因素无关，经济地位,GA,熟悉的T1D历史和巴西的出生地区。这些等位基因和单倍型有助于我们对疾病发作异质性的理解，并且当检测到与众所周知的T1D基因组风险或保护因子相关时，可能对早期干预有影响。
