Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE).
We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.
Han
Shizhong
S
Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Kim-Howard
Xana
X
Deshmukh
Harshal
H
Kamatani
Yoichiro
Y
Viswanathan
Parvathi
P
Guthridge
Joel M
JM
Thomas
Kenaz
K
Kaufman
Kenneth M
KM
Ojwang
Joshua
J
Rojas-Villarraga
Adriana
A
Baca
Vicente
V
Orozco
Lorena
L
Rhodes
Benjamin
B
Choi
Chan-Bum
CB
Gregersen
Peter K
PK
Merrill
Joan T
JT
James
Judith A
JA
Gaffney
Patrick M
PM
Moser
Kathy L
KL
Jacob
Chaim O
CO
Kimberly
Robert P
RP
Harley
John B
JB
Bae
Sang-Choel
SC
Anaya
Juan-Manuel
JM
Alarcón-Riquelme
Marta E
ME
Matsuda
Koichi
K
Vyse
Timothy J
TJ
Nath
Swapan K
SK
D000483:Alleles; D044466:Asian People / Q000235:genetics; D001499:Bayes Theorem; D039481:CD11b Antigen / Q000235:genetics*; D016022:Case-Control Studies; D003105:Colombia; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007564:Japan; D007723:Korea; D015810:Linkage Disequilibrium / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008800:Mexico; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D006113:United Kingdom; D044465:White People / Q000235:genetics
D039481:CD11b Antigen