Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104, USA. SLEGEN@wfubmc.edu
Harley
John B
JB
Alarcón-Riquelme
Marta E
ME
Criswell
Lindsey A
LA
Jacob
Chaim O
CO
Kimberly
Robert P
RP
Moser
Kathy L
KL
Tsao
Betty P
BP
Vyse
Timothy J
TJ
Langefeld
Carl D
CD
Nath
Swapan K
SK
Guthridge
Joel M
JM
Cobb
Beth L
BL
Mirel
Daniel B
DB
Marion
Miranda C
MC
Williams
Adrienne H
AH
Divers
Jasmin
J
Wang
Wei
W
Frank
Summer G
SG
Namjou
Bahram
B
Gabriel
Stacey B
SB
Lee
Annette T
AT
Gregersen
Peter K
PK
Behrens
Timothy W
TW
Taylor
Kimberly E
KE
Fernando
Michelle
M
Zidovetzki
Raphael
R
Gaffney
Patrick M
PM
Edberg
Jeffrey C
JC
Rioux
John D
JD
Ojwang
Joshua O
JO
James
Judith A
JA
Merrill
Joan T
JT
Gilkeson
Gary S
GS
Seldin
Michael F
MF
Yin
Hong
H
Baechler
Emily C
EC
Li
Quan-Zhen
QZ
Wakeland
Edward K
EK
Bruner
Gail R
GR
Kaufman
Kenneth M
KM
Kelly
Jennifer A
JA
D000483:Alleles; D019540:Area Under Curve; D039481:CD11b Antigen / Q000235:genetics*; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D002880:Chromosomes, Human, Pair 11; D002885:Chromosomes, Human, Pair 16; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D016001:Confidence Intervals; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012372:ROC Curve; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics; D044465:White People
D039481:CD11b Antigen; D005819:Genetic Markers; D006680:HLA Antigens; C431713:IRF5 protein, human; C509295:ITGAM protein, human; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C508327:PXK protein, human; D017346:Protein Serine-Threonine Kinases; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22