Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases

doi:10.1016/j.autrev.2011.07.007

Autoimmunity Reviews

Volume 11, Issue 4, February 2012, Pages 276-280

https://doi.org/10.1016/j.autrev.2011.07.007 Get rights and content

Abstract

Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case–control association between rs1143679 and ADs (N = 18,457) including primary Sjögren's syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (p_meta = 0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.

Introduction

Genetic susceptibility of multiple autoimmune diseases (ADs) often shares underlying commonalities [1]. The hypothesis that clinically distinct ADs may be controlled by a common set of susceptibility genes was put forward [1], and there is a growing understanding that susceptibility to the ADs is due to complex interactions between multiple genes and environmental factors. Some of these underlying predisposing factors may be shared among many ADs.

Recently, applying a trans-ethnic mapping approach, we identified and replicated an association between a variant at exon-3 (rs1143679) of Integrin-α-M (ITGAM, also known as CD11b) and systemic lupus erythematosus (SLE) susceptibility in individuals with Caucasian, African, and Hispanic ancestry [2], [3]. Our subsequent comprehensive imputation-based association analysis of the ITGAM-ITGAX region also demonstrated that this missense variant, which changes this amino acid from an arginine to histidine (R77H), explained SLE-association with ITGAM [4].

ITGAM encodes the α-chain subunit of the heterodimeric Integrin-α_Mβ₂, a cell surface receptor expressed primarily on monocytes and neutrophils. It plays an important role in activation, adherence, and migration of leukocytes through stimulated endothelium, and also in the phagocytosis of complement coated particles and neutrophil apoptosis [5]. Using a computer model, we also speculated that substitution of the residue 77 at this coding variant (R77H) may alter the conformation of the αI domain of α_Mβ₂ which might affect the binding capacity of various ligands (i.e., ICAM1), implicated in susceptibility to various inflammatory ADs.

Several recent reports have examined the relationship between rs1143679 and non-SLE ADs, in particular RA [6], [7] and SSc [8], [9]. Although association was not found with RA, SSc association results were contradictory. The goal of this study was to further study the role of the ITGAM variant R77H (rs1143679), in general autoimmunity. Since rs1143679 is robustly associated with SLE we hypothesize that this association could be replicated in other ADs including primary Sjögren's syndrome (pSS), systemic scleroderma (SSc), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), celiac disease (CED), and type 1 diabetes (T1D).

Section snippets

Study populations

We used de-identified DNA samples from 2050 cases from seven ADs (pSS, SSc, MS, RA, JIA, CED, T1D) and 2879 controls from ethnically matched populations (Table 1). All subjects were enrolled into their respective studies after obtaining their written informed consent and following protocols approved by the appropriate institutional review boards. All patients with ADs met the international classification criteria for their respective disease [10], [11], [12], [13], [14].

The entire Colombian

Results

Cases and controls for all populations were in HWE (p ≥ 0.01) for rs1143679. Disease allele (A) frequencies were consistent across populations, with the highest and lowest MAF estimated to be 10.1% and 15.9% in European-American and Argentine controls, respectively. Overall F_ST = 0.003 for control from all populations were not stratified at this variant, i.e. allele frequencies were not different between controls.

Summary of allelic associations and relevant information are given in Table 1. In our

Discussion

The genetic risk factors for ADs might well consist of two forms: those common to many ADs and those specific to a given disorder [21], [22]. Combinations of common and disease-specific alleles at HLA and non-HLA genes, in interaction with epigenetic and environmental factors over time may determine the final clinical autoimmune phenotype [1]. Since the ITGAM SNP rs1143679 has been consistently associated SLE across multiple, diverse populations, it is important to assess its relation with

Take-home messages

•
An association between a variant at exon-3 (rs1143679) of Integrin-α-M (ITGAM) and SLE susceptibility has been described in multiple ethnic populations.
•
ITGAM encodes the α-chain subunit of the heterodimeric Integrin-αMβ2, a cell surface receptor that expresses primarily on monocytes and neutrophils. It plays an important role in different processes of leukocytes.
•
Although genetic susceptibility of autoimmune diseases often shares underlying commonalities, R77H (rs1143679) polymorphism of ITGAM

Acknowledgments

We wish to thank the patients and their families for their cooperation. We are thankful to Dr. Jorge Oksenberg, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA, for providing the genotype data for MS. This study was made possible by funding from NIH (R01AI063622, R01AR060366, R21AI094377, P20RR15577, P30RR031152, U19AI082714, P30AR053483, K23AR50177, R01DE015223, P01AI083194, P01AR049084, N01AR62277, R01DE018209, R37AI024717, R01AR042460, P20RR020143),

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ReviewEvaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases

Abstract

Introduction

Section snippets

Study populations

Results

Discussion

Take-home messages

Acknowledgments

Blood

Gastroenterology

Am J Hum Genet

Autoimmun Rev

Autoimmun Rev

Clin Immunol Immunopathol

Kidney Int

Eur J Intern Med

Autoimmun Rev

Autoimmun Rev

Is there a common genetic basis for autoimmune diseases?

Clin Dev Immunol

A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus

Nat Genet

Admixture in Hispanic Americans: its impact on ITGAM association and implications for admixture mapping in SLE

Genes Immun.

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)

Hum Mol Genet

No evidence for association of the systemic lupus erythematosus-associated ITGAM variant, R77H, with rheumatoid arthritis in the Caucasian population

Rheumatology (Oxford)

Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factors

Arthritis Rheum

Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic sclerosis: results from 2 large European Caucasian cohorts

J Rheumatol

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum

Review
Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases