From the, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
J Intern Med. 2021 May;289(5):662-674. doi: 10.1111/joim.13187. Epub 2020 Nov 11.
Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution.
We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression.
We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue.
Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.
1 型糖尿病（T1D）是一种影响早年个体的自身免疫性疾病。尽管先前的研究已经确定了影响 T1D 诊断年龄的遗传位点，但这些研究并未以高分辨率研究基因组。
我们对来自芬兰（芬兰糖尿病肾病研究）、英国（英国遗传资源调查糖尿病）和撒丁岛的队列进行了全基因组荟萃分析，以研究诊断年龄与单核苷酸多态性（SNP）的关联。通过全基因组关联分析（GWAS），我们将 T1D 诊断年龄与基因表达联系起来。
我们确定了两个与 T1D 诊断年龄相关的染色体区域：6 号染色体 HLA 区域的多个独立变体和 17 号染色体 q12 上的一个位点。我们使用来自两个全血数据集、淋巴细胞系、脾脏、胰腺和小肠组织的转录组预测模型进行了基因水平的关联测试。在非 HLA 基因中，全血中 PNMT 表达降低，以及多个组织中 IKZF3 和 ZPBP2 表达升高、ORMDL3 和 GSDMB 转录水平降低，与 T1D 诊断年龄较低相关（FDR = 0.05）。这些基因位于与 T1D、其他自身免疫性疾病和儿童哮喘相关的 17q12 上。此外，先前未涉及 T1D 的基因 PHF20L1 在淋巴细胞、胰腺和脾脏中的表达较高与较低的诊断年龄相关。总的来说，非 HLA 关联在各种血细胞、血管组织和胎胸腺组织中富含开放染色质。
17q12 上的多个基因和 8 号染色体上的 PHF20L1 与 T1D 诊断年龄相关，只有进一步的研究才能阐明这些基因在免疫和 T1D 发病中的作用。
