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Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis

dc.contributor.authorLammert, Craig
dc.contributor.authorMcKinnon, Elizabeth J.
dc.contributor.authorChalasani, Naga
dc.contributor.authorPhillips, Elizabeth J.
dc.date.accessioned2020-04-17T19:35:44Z
dc.date.available2020-04-17T19:35:44Z
dc.date.issued2019-06-18
dc.identifier.citationLammert C, McKinnon EJ, Chalasani N, Phillips EJ. Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis. Clinical and Translational Gastroenterology. 2019 Jun;10(6):e00032. DOI: 10.14309/ctg.0000000000000032.en_US
dc.identifier.issn2155-384X
dc.identifier.urihttp://hdl.handle.net/1803/9932
dc.description.abstractAbstract INTRODUCTION: HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist. METHODS: We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01. RESULTS: DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P= 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P= 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles. DISCUSSION: Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.en_US
dc.description.sponsorshipThis publication was made possible with support provided to C.L. from Grant Numbers, KL2TR001106, and UL1TR001108 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. Also in part, with support from the Indiana Clinical and Translational Sciences Institute funded, in part by Award Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award.en_US
dc.language.isoen_USen_US
dc.publisherClinical and Translational Gastroenterologyen_US
dc.rightsOpen Access This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.
dc.subjectPRIMARY SCLEROSING CHOLANGITISen_US
dc.subjectPRIMARY BILIARY-CIRRHOSISen_US
dc.subjectNORTH-AMERICAN PATIENTSen_US
dc.subjectRISKen_US
dc.subjectEPIDEMIOLOGYen_US
dc.subjectASSOCIATIONen_US
dc.subjectPREVALENCEen_US
dc.subjectDIAGNOSISen_US
dc.subjectVARIANTSen_US
dc.subjectDISEASEen_US
dc.titleNovel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitisen_US
dc.typeArticleen_US
dc.identifier.doi10.14309/ctg.0000000000000032


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