@article{7f92a83930b74b8ab60748b70e005ad1,
title = "REL, encoding a member of the NF-B family of transcription factors, is a newly defined risk locus for rheumatoid arthritis",
abstract = "We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 × 10 10). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 × 10 14) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 × 10 11) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 × 10 9) and BLK (rs2736340; OR = 1.19; P = 5.69 × 10 9). c-Rel is an NF-B family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ.",
author = "Gregersen, {Peter K.} and Amos, {Chistopher I.} and Lee, {Annette T.} and Yue Lu and Remmers, {Elaine F.} and Kastner, {Daniel L.} and Seldin, {Michael F.} and Criswell, {Lindsey A.} and Plenge, {Robert M.} and Holers, {V. Michael} and Mikuls, {Ted R.} and Tuulikki Sokka and Moreland, {Larry W.} and Bridges, {S. Louis} and Gang Xie and Begovich, {Ann B.} and Siminovitch, {Katherine A.}",
note = "Funding Information: US samples. For our GWA analysis, we included GWA data on 868 North American rheumatoid arthritis cases samples reported previously8. We refer to these samples as {\textquoteleft}NARAC I{\textquoteright}. All cases included in the current analysis are positive for antibodies to CCP (CCP+). Details of sample collections used to compile the NARAC II dataset (n = 952) for final analysis on the Illumina HapMap370 chip are described below. (1) Rheumatoid arthritis probands in NARAC collection of affected sibling pair families in whom siblings did not meet criteria for rheumatoid arthritis (n = 17), as well as probands of NARAC trio families (n = 158). Collection criteria have been previously published8. No affected members of these families were included in our previously published GWAS8. Only CCP+ subjects were studied in the current analysis. (2) The Veterans Affairs Rheumatoid Arthritis Registry (VARA). VARA subjects, all meeting classification criteria for rheumatoid arthritis, are currently being enrolled from six VA centers (Dallas, Denver, Jackson, Omaha, Salt Lake City and Washington, DC). VARA is a longitudinal observational study that was started by T. Mikuls at the Omaha VA Medical Center. As of May 1, 2008, over 1,100 subjects have been enrolled. Of the 332 cases included in this analysis, 301 were documented to be CCP+ (n = 332). (3) The Studies of Etiologies of Rheumatoid Arthritis (SERA) cohort. This cohort study, funded by the US National Institutes of Health (R01 AR051394), is co-directed by M. Holers and J. Norris at the University of Colorado Denver. SERA is a multicenter prospective cohort study designed to investigate genetic and epidemiologic associations with rheumatoid arthritis–related autoimmunity during the preclinical period of rheumatoid arthritis development. For the SERA study, probands with rheumatoid arthritis are recruited by rheumatologists from clinics at the University of Colorado Denver School of Medicine (UCDSOM), Cedars-Sinai Medical Center, Los Angeles, California, the Rheumatoid Arthritis Investigation Network (RAIN) centered in Omaha, Nebraska, North Shore-Long Island Jewish Health System/Feinstein Institute for Medical Research, and the Benaroya Research Institute at Virginia Mason, Seattle, Washington. Additionally, probands are recruited through community outreach efforts and advertisements posted in the Arthritis Foundation News-letter. Once a proband with rheumatoid arthritis has expressed interest in the study and consents to release of medical information, their medical charts are reviewed by a SERA rheumatologist to ensure a diagnosis of rheumatoid arthritis. Probands are considered to have rheumatoid arthritis if they meet four of seven of the American College of Rheumatology (ACR) 1987 Revised Classification Criteria for rheumatoid arthritis or if they have been determined to have rheumatoid arthritis by a clinical evaluation by a board-certified rheumatologist. Only CCP+ cases were studied in the current analysis (n = 160). (4) Multiple Autoimmune Disease Genetics Consortium (MADGC). The MADGC collection of multiplex families includes individuals with rheumatoid arthritis who meet 1987 ACR criteria for disease. The details of the MADGC collection have been previously published24. Only CCP+ cases were studied in the current analysis (n = 105). (5) UCSF Rheumatoid Arthritis Genetics Project. Participants in the UCSF Rheumatoid Arthritis Genetics Project collection were recruited from UCSF Arthritis Clinics and private rheumatology practices in northern California as well as by nation-wide outreach according to a protocol approved by the University of California, San Francisco institutional review board. All cases fulfilled 1987 ACR criteria for rheumatoid arthritis and are of self-reported European origin, including grandparental countries of origin. Only CCP+ cases were studied in the current analysis (n = 86). (6) Early Rheumatoid Arthritis Treatment Evaluation Registry (ERATER). This study in Nashville, Tennessee comprised 452 cases with rheumatoid Funding Information: This work was supported by grants from the US National Institutes of Health NO1-AR-2-2263 (P.K.G.), RO1 AR44422 (P.K.G.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation. The work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by grants from the Canadian Institutes for Health Research (MOP79321) and Ontario Research Fund (RE01061) and a Canada Research Chair to K.A.S.",
year = "2009",
month = jul,
doi = "10.1038/ng.395",
language = "English (US)",
volume = "41",
pages = "820--823",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",
}