Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
BACKGROUND
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.


METHODS
We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.


RESULTS
Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).


CONCLUSIONS
We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.
Hom
Geoffrey
G
Genentech, South San Francisco, CA 94080, USA.
Graham
Robert R
RR
Modrek
Barmak
B
Taylor
Kimberly E
KE
Ortmann
Ward
W
Garnier
Sophie
S
Lee
Annette T
AT
Chung
Sharon A
SA
Ferreira
Ricardo C
RC
Pant
P V Krishna
PV
Ballinger
Dennis G
DG
Kosoy
Roman
R
Demirci
F Yesim
FY
Kamboh
M Ilyas
MI
Kao
Amy H
AH
Tian
Chao
C
Gunnarsson
Iva
I
Bengtsson
Anders A
AA
Rantapää-Dahlqvist
Solbritt
S
Petri
Michelle
M
Manzi
Susan
S
Seldin
Michael F
MF
Rönnblom
Lars
L
Syvänen
Ann-Christine
AC
Criswell
Lindsey A
LA
Gregersen
Peter K
PK
Behrens
Timothy W
TW
D001402:B-Lymphocytes / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D009656:North America; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
D039481:CD11b Antigen; C509295:ITGAM protein, human; D019061:src-Family Kinases