Evaluation of TRAF6 in a large multiancestral lupus cohort.
OBJECTIVE
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.


METHODS
Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.


RESULTS
Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5)  and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2)  = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model.


CONCLUSIONS
Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Bahram
B
Namjou
Chan-Bum
CB
Choi
Isaac T W
IT
Harley
Marta E
ME
Alarcón-Riquelme
Jennifer A
JA
Kelly
Stuart B
SB
Glenn
Joshua O
JO
Ojwang
Adam
A
Adler
Kwangwoo
K
Kim
Caroline J
CJ
Gallant
Susan A
SA
Boackle
Lindsey A
LA
Criswell
Robert P
RP
Kimberly
Elizabeth E
EE
Brown
Jeffrey
J
Edberg
Graciela S
GS
Alarcón
Anne M
AM
Stevens
Chaim O
CO
Jacob
Gary S
GS
Gilkeson
Diane L
DL
Kamen
Betty P
BP
Tsao
Juan-Manuel
JM
Anaya
Eun-Mi
EM
Kim
So-Yeon
SY
Park
Yoon-Kyoung
YK
Sung
Joel M
JM
Guthridge
Joan T
JT
Merrill
Michelle
M
Petri
Rosalind
R
Ramsey-Goldman
Luis M
LM
Vilá
Timothy B
TB
Niewold
Javier
J
Martin
Bernardo A
BA
Pons-Estel
Timothy J
TJ
Vyse
Barry I
BI
Freedman
Kathy L
KL
Moser
Patrick M
PM
Gaffney
Adrienne H
AH
Williams
Mary E
ME
Comeau
John D
JD
Reveille
Changwon
C
Kang
Judith A
JA
James
R Hal
RH
Scofield
Carl D
CD
Langefeld
Kenneth M
KM
Kaufman
John B
JB
Harley
Sang-Cheol
SC
Bae
D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics*
D048029:TNF Receptor-Associated Factor 6