@article{7e803af916c44ffeb5f1e7b136a51d5e,
title = "A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus",
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.",
author = "Patel, {Zubin H.} and Xiaoming Lu and Daniel Miller and Forney, {Carmy R.} and Joshua Lee and Arthur Lynch and Connor Schroeder and Lois Parks and Magnusen, {Albert F.} and Xiaoting Chen and Mario Pujato and Avery Maddox and Zoller, {Erin E.} and Bahram Namjou and Brunner, {Hermine I.} and Michael Henrickson and Huggins, {Jennifer L.} and Williams, {Adrienne H.} and Ziegler, {Julie T.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Glenn, {Stuart B.} and Adam Adler and Nan Shen and Nath, {Swapan K.} and Stevens, {Anne M.} and Freedman, {Barry I.} and Pons-Estel, {Bernardo A.} and Tsao, {Betty P.} and Jacob, {Chaim O.} and Kamen, {Diane L.} and Brown, {Elizabeth E.} and Gilkeson, {Gary S.} and Alarc{\'o}n, {Graciela S.} and Javier Martin and Reveille, {John D.} and Anaya, {Juan Manuel} and James, {Judith A.} and Sivils, {Kathy L.} and Criswell, {Lindsey A.} and Vil{\'a}, {Luis M.} and Michelle Petri and Scofield, {R. Hal} and Kimberly, {Robert P.} and Edberg, {Jeffrey C.} and Rosalind Ramsey-Goldman and Bang, {So Young} and Lee, {Hye Soon} and Bae, {Sang Cheol} and Boackle, {Susan A.}",
note = "Funding Information: We thank Dr Artem Barski for his invaluable help and guidance in the development and analysis of the HMGA1 ChIP experiments. Mass spectrometry data were collected in the UC Proteomics Laboratory on the 5600 + TripleT of system funded in part through an NIH shared instrumentation grant (S10 RR027015–01; KD Greis-PI). Funding Information: 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{\textquoteright}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 Andaluc{\'i}a (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). Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2018",
month = jul,
day = "1",
doi = "10.1093/hmg/ddy140",
language = "English (US)",
volume = "27",
pages = "2392--2404",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "13",
}
