High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups.
OBJECTIVE
Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility.


METHODS
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.


RESULTS
We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4.


CONCLUSIONS
Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.
Namjou
Bahram
B
Oklahoma Medical Research Foundation, Oklahoma City, USA.
Sestak
Andrea L
AL
Armstrong
Don L
DL
Zidovetzki
Raphael
R
Kelly
Jennifer A
JA
Jacob
Noam
N
Ciobanu
Voicu
V
Kaufman
Kenneth M
KM
Ojwang
Joshua O
JO
Ziegler
Julie
J
Quismorio
Francesco P
FP
Reiff
Andreas
A
Myones
Barry L
BL
Guthridge
Joel M
JM
Nath
Swapan K
SK
Bruner
Gail R
GR
Mehrian-Shai
Ruth
R
Silverman
Earl
E
Klein-Gitelman
Marisa
M
McCurdy
Deborah
D
Wagner-Weiner
Linda
L
Nocton
James J
JJ
Putterman
Chaim
C
Bae
Sang-Cheol
SC
Kim
Yun Jung
YJ
Petri
Michelle
M
Reveille
John D
JD
Vyse
Timothy J
TJ
Gilkeson
Gary S
GS
Kamen
Diane L
DL
Alarcón-Riquelme
Marta E
ME
Gaffney
Patrick M
PM
Moser
Kathy L
KL
Merrill
Joan T
JT
Scofield
R Hal
RH
James
Judith A
JA
Langefeld
Carl D
CD
Harley
John B
JB
Jacob
Chaim O
CO