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Abstract：
Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR β 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN.
Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design.
We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations.
Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy.
We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.
Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design.
We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations.
Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy.
We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.
摘要：
背景：急性肾小管间质性肾炎（ATIN）是一种罕见的免疫相关疾病，约占无法解释的急性肾损伤（AKI）病例的10％。由于样本量小和候选基因设计，先前对促成其发病机理的遗传因素之间关系的阐明受到了阻碍。
方法：我们进行了第一个两阶段全基因组关联研究（GWAS）和荟萃分析，涉及544例肾脏活检定义的ATIN和2,346例中国血统的对照。我们进行了统计精细映射分析，提供了重要变体的功能注释，估计的基于单核苷酸多态性(SNP)的遗传力，并检查基因型和亚表型的相关性。
结果：两个全基因组显著位点，6p21.32上HLA-DQA1的rs35087390（P=3.01×10-39）和12p12.3上PLEKHA5的rs2417771（P=2.14×10-8），从分析中得出。使用两个参考面板的HLA归因表明HLA-DRB1*14主要驱动HLA风险关联。属于口袋P10的HLA-DRB1残基60是关键氨基酸位置。有和没有HLA基因座的基于SNP的遗传力估计分别为20.43％和10.35％。不同的临床子表型（药物相关或肾小管间质性肾炎和葡萄膜炎综合征）似乎具有相同的风险等位基因。但HLA风险基因型与疾病严重程度和免疫抑制治疗的应答率相关。
结论：我们确定了两个与ATIN易感性相关的候选基因组区域。研究结果表明，遗传赋予的免疫失调风险与ATIN的发病机理有关。
方法：我们进行了第一个两阶段全基因组关联研究（GWAS）和荟萃分析，涉及544例肾脏活检定义的ATIN和2,346例中国血统的对照。我们进行了统计精细映射分析，提供了重要变体的功能注释，估计的基于单核苷酸多态性(SNP)的遗传力，并检查基因型和亚表型的相关性。
结果：两个全基因组显著位点，6p21.32上HLA-DQA1的rs35087390（P=3.01×10-39）和12p12.3上PLEKHA5的rs2417771（P=2.14×10-8），从分析中得出。使用两个参考面板的HLA归因表明HLA-DRB1*14主要驱动HLA风险关联。属于口袋P10的HLA-DRB1残基60是关键氨基酸位置。有和没有HLA基因座的基于SNP的遗传力估计分别为20.43％和10.35％。不同的临床子表型（药物相关或肾小管间质性肾炎和葡萄膜炎综合征）似乎具有相同的风险等位基因。但HLA风险基因型与疾病严重程度和免疫抑制治疗的应答率相关。
结论：我们确定了两个与ATIN易感性相关的候选基因组区域。研究结果表明，遗传赋予的免疫失调风险与ATIN的发病机理有关。
