ITGAM – Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with a strong genetic component. Genome-wide association studies first identified the integrin alpha M gene (ITGAM) at 16p11.2 as a susceptibility locus for SLE in European cohorts (rs1143679; P = 1.7×10⁻¹⁷; OR = 1.78) and replicated in African-Americans (overall meta‐analysis P = 6.9×10⁻²²) (PMID:18204448).

The association of the nonsynonymous variant rs1143679 (p.Arg77His) has been confirmed across multiple independent samples, including U.S., Swedish, UK, Colombian, and Mexican cohorts (n > 10,000 total), with a combined meta-analysis OR = 1.83 (95% CI 1.69–1.98; P = 7.1×10⁻⁵⁰) (PMID:19129174).

Subphenotype analyses demonstrate that the risk allele A at rs1143679 predisposes to lupus nephritis (OR 2.15; P = 4.69×10⁻²²), discoid rash (OR 2.03; P = 1.77×10⁻¹⁴), and immunological manifestations (OR 1.86; P = 3.49×10⁻²²) in European-derived SLE patients (PMID:19939855).

Resequencing of ITGAM in 73 SLE cases identified two rare, case-specific variants, c.2821T>G (p.Phe941Val) and c.3433G>A (p.Gly1145Ser), both of which significantly impair CR3-mediated phagocytosis in vitro (61% and 26% reduction; P = 0.006 and P = 0.0232) (PMID:24886912). The common p.Arg77His variant also reduces iC3b‐mediated phagocytosis by 31% and adhesion to ICAM‐1 by 24% in human monocytes (P < 0.03) (PMID:22586164).

In vivo studies show that knock‐in mice expressing the 77His allele have normal leukocyte recruitment but display impaired dendritic cell–mediated antigen-specific T cell proliferation (P < 0.01), and genetic deletion of Itgam accelerates lupus nephritis in combination with other risk alleles (PMID:31673770; PMID:35634296).

Moreover, pharmacologic activation of CD11b using the agonist ONT01 suppresses suPAR production, reduces type I interferon and cytokine levels, and protects against glomerulonephritis in murine lupus nephritis models, supporting a therapeutic avenue targeting Mac‐1 activation (PMID:39211173).

References

• Nature genetics • 2008 • A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. PMID:18204448
• Human molecular genetics • 2009 • 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). PMID:19129174
• Annals of the rheumatic diseases • 2012 • The rs1143679 (R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes. PMID:22586164
• Arthritis and rheumatism • 2013 • Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils. PMID:23918739
• Mammalian genome • 2019 • Mice expressing the variant rs1143679 allele of ITGAM (CD11b) show impaired DC-mediated T cell proliferation. PMID:31673770
• bioRxiv • 2024 • CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis. PMID:39211173

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