Evaluation of imputation-based association in and around the integrin- -M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE)

Abstract

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.

Complement Receptor 3 Influences Toll-like Receptor 7/8-Dependent Inflammation

“…The locus that encodes ITGAM on chromosome 16 provided a strong association with susceptibility to SLE in separate genome-wide association studies (25,26) and replication studies of multiple populations (27) reaching an odds ratio of 1.78 (1.56 -2.03). The missense SNP, rs1143679, results in an amino acid change from arginine to histidine at position 77 (R77H) in the extracellular I/A ligand-binding domain of CD11b.…”

Association of ITGAM polymorphism with systemic lupus erythematosus: a meta‐analysis

“…1,3,5,[14][15][16][17][18][19] Two studies were excluded as the number of allele could not be extracted. 18,19 Thus, seven studies met the inclusion criteria.…”

“…4 Although studies have suggested that ITGAM allele may confer susceptibility to SLE, investigations performed in different ethnic groups yielded apparently inconclusive results regarding the disease susceptibility conferred by specific polymorphism. Han et al 5 demonstrated that rs1143679, which converts Arginine 77 to Histidine explains the association of rs9937837 or rs11574637 with SLE and best explains the ITGAM-SLE association. The study by Yang et al 3 found that logistic regression analysis on Thai samples indicates that rs1143679 remains significant when controlling the effect of rs9888739 or rs1143678.…”

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

“…193 A study of ITGAM in 661 Korean and 176 Japanese patients with SLE found that rs1143679 was monomorphic, in contrast to the results of previous Caucasian studies. 194 PXK. PXK encodes the phox homology domain containing serine/threonine kinase that binds to and modulates Na-and K-ATPase activity, and has five splice isoforms that are widely expressed in human tissues.…”