{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:46:48Z","timestamp":1793083608875,"version":"4.5.0"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Polymorphisms of\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      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\u2013DR\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      1 key. Risk alleles were shared among different causes of ATIN and\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      genotypes associated with kidney injury and immune therapy response.\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two genome-wide significant loci, rs35087390 of\n                      <jats:italic toggle=\"yes\">HLA-DQA1<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =3.01\u00d710\n                      <jats:sup>\u221239<\/jats:sup>\n                      ) on 6p21.32 and rs2417771 of\n                      <jats:italic toggle=\"yes\">PLEKHA5<\/jats:italic>\n                      on 12p12.3 (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =2.14\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ), emerged from the analysis.\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      imputation using two reference panels suggested that\n                      <jats:italic toggle=\"yes\">HLA-DRB1*14<\/jats:italic>\n                      mainly drives the HLA risk association\n                      <jats:italic toggle=\"yes\">. HLA-DRB1<\/jats:italic>\n                      residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">HLA<\/jats:italic>\n                      risk genotype was associated with disease severity and response rate to immunosuppressive therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.0000000000000091","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T10:01:55Z","timestamp":1675764115000},"page":"895-908","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":6,"title":["Genome-Wide Association Study in Acute Tubulointerstitial Nephritis"],"prefix":"10.1681","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-707X","authenticated-orcid":false,"given":"Xu-Jie","family":"Zhou","sequence":"first","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Su","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5508-0664","authenticated-orcid":false,"given":"Jingyuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong-Hong","family":"Xie","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"WeGene, Shenzhen Zaozhidao Technology Co., Ltd., Shenzhen, China"},{"name":"Human Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, China"},{"name":"Shenzhen WeGene Clinical Laboratory, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"WeGene, Shenzhen Zaozhidao Technology Co., Ltd., Shenzhen, China"},{"name":"Human Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, China"},{"name":"Shenzhen WeGene Clinical Laboratory, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jia","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui","family":"Li","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Juan","family":"Yu","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapan K.","family":"Nath","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam C.","family":"Tsoi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan"},{"name":"Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan"},{"name":"Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine C.","family":"Berthier","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Liu","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huji","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China"},{"name":"Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China"},{"name":"School of Clinical Medicine, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-Ming","family":"Hao","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 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