Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.
OBJECTIVE
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.


METHODS
We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.


RESULTS
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064).


CONCLUSIONS
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA. kaufman.kenneth@cchmc.org
Kenneth M
KM
Kaufman
Jian
J
Zhao
Jennifer A
JA
Kelly
Travis
T
Hughes
Adam
A
Adler
Elena
E
Sanchez
Joshua O
JO
Ojwang
Carl D
CD
Langefeld
Julie T
JT
Ziegler
Adrienne H
AH
Williams
Mary E
ME
Comeau
Miranda C
MC
Marion
Stuart B
SB
Glenn
Rita M
RM
Cantor
Jennifer M
JM
Grossman
Bevra H
BH
Hahn
Yeong Wook
YW
Song
Chack-Yung
CY
Yu
Judith A
JA
James
Joel M
JM
Guthridge
Elizabeth E
EE
Brown
Graciela S
GS
Alarcón
Robert P
RP
Kimberly
Jeffrey C
JC
Edberg
Rosalind
R
Ramsey-Goldman
Michelle A
MA
Petri
John D
JD
Reveille
Luis M
LM
Vilá
Juan-Manuel
JM
Anaya
Susan A
SA
Boackle
Anne M
AM
Stevens
Barry I
BI
Freedman
Lindsey A
LA
Criswell
Bernardo A
BA
Pons Estel
Joo-Hyun
JH
Lee
Ji-Seon
JS
Lee
Deh-Ming
DM
Chang
R Hal A
RH
Scofield
Gary S
GS
Gilkeson
Joan T
JT
Merrill
Timothy B
TB
Niewold
Timothy James
TJ
Vyse
Sang-Cheol
SC
Bae
Marta E
ME
Alarcón-Riquelme
Chaim O
CO
Jacob
Kathy
K
Moser Sivils
Patrick M
PM
Gaffney
John B
JB
Harley
Amr H
AH
Sawalha
Betty P
BP
Tsao
D001483:Base Sequence; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors
D051783:Methyl-CpG-Binding Protein 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases