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PMID: 17982456 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.

Nature genetics ·Vol. 39 ·No. 12 ·2007-12-00 ·Pages 1477-82

Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Neale BM, Izmailova E, Roubenoff R, Parker AN, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, Weinblatt ME, Gabriel SB, Purcell S, Klareskog L, Gregersen PK, Shadick NA, Daly MJ, Altshuler D

Abstract

To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.

MeSH Terms

Alleles Arthritis, Rheumatoid/genetics Case-Control Studies Chromosomes, Human, Pair 6 Female Genetic Predisposition to Disease Genome, Human Humans Male Polymorphism, Single Nucleotide

Authors & Affiliations

38 authors, click to expand affiliations / ORCID

Plenge Robert M

Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. rplenge@partners.org

Cotsapas Chris

Davies Leela

Price Alkes L

de Bakker Paul I W

Maller Julian

Pe'er Itsik

Burtt Noel P

Blumenstiel Brendan

DeFelice Matt

Parkin Melissa

Barry Rachel

Winslow Wendy

Healy Claire

Graham Robert R

Neale Benjamin M

Izmailova Elena

Roubenoff Ronenn

Parker Alexander N

Glass Roberta

Karlson Elizabeth W

Maher Nancy

Hafler David A

Lee David M

Seldin Michael F

Remmers Elaine F

Lee Annette T

Padyukov Leonid

Alfredsson Lars

Coblyn Jonathan

Weinblatt Michael E

Gabriel Stacey B

Purcell Shaun

Klareskog Lars

Gregersen Peter K

Shadick Nancy A

Daly Mark J

Altshuler David

References (28)

28 references, click to expand

Epidemiology and genetics of rheumatoid arthritis.
Arthritis Res. 2002;4 Suppl 3:S265-72 PMID: 12110146
Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6758-63 PMID: 17412832
Multiple regions within 8q24 independently affect risk for prostate cancer.
Nat Genet. 2007 May;39(5):638-44 PMID: 17401364
Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles.
Arthritis Rheum. 2005 Dec;52(12):3813-8 PMID: 16320316
Clustering of disease features within 512 multicase rheumatoid arthritis families.
Arthritis Rheum. 2004 Mar;50(3):736-41 PMID: 15022313
The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein.
J Biol Chem. 1990 Sep 5;265(25):14705-8 PMID: 2118515
Efficiency and power in genetic association studies.
Nat Genet. 2005 Nov;37(11):1217-23 PMID: 16244653
Population structure, differential bias and genomic control in a large-scale, case-control association study.
Nat Genet. 2005 Nov;37(11):1243-6 PMID: 16228001
The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28.
Arthritis Res Ther. 2006;8(3):R57 PMID: 16542499
A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
Science. 2006 Dec 1;314(5804):1461-3 PMID: 17068223
The effects of human population structure on large genetic association studies.
Nat Genet. 2004 May;36(5):512-7 PMID: 15052271
Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.
Nat Genet. 2006 Sep;38(9):1055-9 PMID: 16936732
European population substructure: clustering of northern and southern populations.
PLoS Genet. 2006 Sep 15;2(9):e143 PMID: 17044734
Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.
Nat Genet. 2007 May;39(5):631-7 PMID: 17401366
The New York Cancer Project: rationale, organization, design, and baseline characteristics.
J Urban Health. 2004 Jun;81(2):301-10 PMID: 15136663
WHAP: haplotype-based association analysis.
Bioinformatics. 2007 Jan 15;23(2):255-6 PMID: 17118959
Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.
Nat Genet. 2007 May;39(5):645-9 PMID: 17401363
Assessing the impact of population stratification on genetic association studies.
Nat Genet. 2004 Apr;36(4):388-93 PMID: 15052270
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.
Am J Hum Genet. 2004 Aug;75(2):330-7 PMID: 15208781
Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases.
Ann Rheum Dis. 2003 Sep;62(9):835-41 PMID: 12922955
Genomic control for association studies.
Biometrics. 1999 Dec;55(4):997-1004 PMID: 11315092
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
Nature. 2007 Jun 7;447(7145):661-78 PMID: 17554300
Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.
Science. 2000 Sep 29;289(5488):2350-4 PMID: 11009421
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
A common genetic variant is associated with adult and childhood obesity.
Science. 2006 Apr 14;312(5771):279-83 PMID: 16614226
The bHLH factor Olig3 coordinates the specification of dorsal neurons in the spinal cord.
Genes Dev. 2005 Mar 15;19(6):733-43 PMID: 15769945
Principal components analysis corrects for stratification in genome-wide association studies.
Nat Genet. 2006 Aug;38(8):904-9 PMID: 16862161
Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.
Lancet. 1994 Oct 22;344(8930):1105-10 PMID: 7934491

Article Info

Journal

Nature genetics

Abbr.

Nat Genet

ISSN

1546-1718

DOI

10.1038/ng.2007.27

rplenge@partners.org

Published

2007-12-00

Epub

2007-00-04

Pages

1477-82

Language

English

Region

United States

NLM ID

9216904

PMCID

PMC2652744

Subset

Grants

NIAMS NIH HHS · R01 AR044422 · United States

NIAID NIH HHS · K08 AI055314-02 · United States

NIAID NIH HHS · K08 AI055314-01A1 · United States

NIAID NIH HHS · K08 AI055314-05 · United States

NIAMS NIH HHS · N01-AR-2-2263 · United States

NIAID NIH HHS · AI55314-3 · United States

NIAID NIH HHS · K08 AI055314 · United States

NIAID NIH HHS · K08 AI055314-04 · United States

NIAMS NIH HHS · R01-AR44422 · United States

NIAID NIH HHS · K08 AI055314-03 · United States

External Links

PubMed source DOI: 10.1038/ng.2007.27 PMC Full Text View journal details

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Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.

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