Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 배상철 | - |
dc.date.accessioned | 2019-12-08T15:15:26Z | - |
dc.date.available | 2019-12-08T15:15:26Z | - |
dc.date.issued | 2018-07 | - |
dc.identifier.citation | HUMAN MOLECULAR GENETICS, v. 27, no. 13, page. 2392-2404 | en_US |
dc.identifier.issn | 0964-6906 | - |
dc.identifier.issn | 1460-2083 | - |
dc.identifier.uri | https://academic.oup.com/hmg/article/27/13/2392/4975620 | - |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/119477 | - |
dc.description.abstract | Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1. | en_US |
dc.description.sponsorship | We are grateful for support from US Department of Veteran Affairs and Defense (BX001834, PR094002) and the National Institutes of Health (NIH) (R01AI024717, R01AI063274, R01AI082714, R01AI083194, U01AI130830, R01AR043274, R01AR043727, R01AR043814, R01AR051545, R01AR056360, R01AR057172, R01AR058959, R01AR060366, R01AR063124, R01AR065626, R01AR62277, R01AI024717, R01DK107502, GM103456, GM104938, HG006828, HG008666, K24AI078004, K24AR02318, K24AR002138, MD007909, P01AR49084, P30AR053483, P30AR055385, P30GM103510, P30AR070549, P30GM110766, P60AR053308, P60AR062755, P60AR064464, P60AR066464, R01AR44804, R01AR043727, R01AR069572, R01AR064820, R01NS099068, R21AI070304, R21HG008186 S10RR027015, TR000077, U01AI101934, U01HG006828, U01HG008666, U19AI082714, U54GM104938, UL1RR029882, UL1TR000004, UL1TR001417, ULTR000062, UL1TR000150, UL1TR000154, 1U54TR001353, 2U54MD007587, 4T32GM063483, 5T32GM105526). Support for the project was also provided by the Cincinnati Children's Research Foundation Endowed Scholar Award, Lupus Research Alliance "Novel Approaches" Award, Kirkland Scholar Award, National Basic Research Program of China (973 program) (2014CB541901), National Natural Science Foundation of China (No. 81230072; 81421001), grants from the State Key Laboratory of Oncogenes and Related Genes (No. 91-14-05), Key Research Program of the Chinese Academy of Sciences (KJZD-EW-L01-3), the Program of the Shanghai Commission of Science and Technology (No. 12JC1406000; No. 12431900703), the Proyecto de Excelencia of the Junta de Andalucia (CTS2548), Arthritis Foundation, Alliance for Lupus Research "Target Identification in Lupus" grant, funds from the Spaulding Paolozzi Autoimmunity Center of Excellence, the Richard M Silver MD Endowment for Inflammation Research, the SmartState Center of Economic Excellence in Inflammation and Fibrosis research, and the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI13C2124). | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | OXFORD UNIV PRESS | en_US |
dc.subject | GENOME-WIDE ASSOCIATION | en_US |
dc.subject | GENETIC SUSCEPTIBILITY LOCI | en_US |
dc.subject | RHEUMATOID-ARTHRITIS | en_US |
dc.subject | FAMILIAL AGGREGATION | en_US |
dc.subject | AUTOIMMUNE-DISEASES | en_US |
dc.subject | IFN-ALPHA | en_US |
dc.subject | ERYTHEMATOSUS | en_US |
dc.subject | STAT4 | en_US |
dc.subject | POPULATION | en_US |
dc.subject | ADMIXTURE | en_US |
dc.title | A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus | en_US |
dc.type | Article | en_US |
dc.relation.no | 13 | - |
dc.relation.volume | 27 | - |
dc.identifier.doi | 10.1093/hmg/ddy140 | - |
dc.relation.page | 2392-2404 | - |
dc.relation.journal | HUMAN MOLECULAR GENETICS | - |
dc.contributor.googleauthor | Patel, Zubin H. | - |
dc.contributor.googleauthor | Lu, Xiaoming | - |
dc.contributor.googleauthor | Miller, Daniel | - |
dc.contributor.googleauthor | Forney, Carmy R. | - |
dc.contributor.googleauthor | Lee, Joshua | - |
dc.contributor.googleauthor | Lynch, Arthur | - |
dc.contributor.googleauthor | Schroeder, Connor | - |
dc.contributor.googleauthor | Parks, Lois | - |
dc.contributor.googleauthor | Magnusen, Albert F. | - |
dc.contributor.googleauthor | Bae, Sang-Cheol | - |
dc.relation.code | 2018001445 | - |
dc.sector.campus | S | - |
dc.sector.daehak | COLLEGE OF MEDICINE[S] | - |
dc.sector.department | DEPARTMENT OF MEDICINE | - |
dc.identifier.pid | scbae | - |
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