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Race-specific association of an IRGM risk allele with cytokine expression in human subjects.

ABSTRACT: Immunity-related GTPase family M (IRGM), located on human chromosome 5q33.1, encodes a protein that promotes autophagy and suppresses the innate immune response. The minor allele of rs13361189 (-4299T>C), a single nucleotide polymorphism in the IRGM promoter, has been associated with several diseases, including Crohn's disease and tuberculosis. Although patterns of linkage disequilibrium and minor allele frequency for this polymorphism differ dramatically between subjects of European and African descent, studies of rs13361189 have predominantly been conducted in Europeans and the mechanism of association is poorly understood. We recruited a cohort of 68 individuals (30 White, 34 African American, 4 other race) with varying rs13361189 genotypes and assessed a panel of immune response measures including whole blood cytokine induction following ex vivo stimulation with Toll-like Receptor ligands. Minor allele carriers were found to have increased serum immunoglobulin M, C-reactive protein, and circulating CD8⁺ T cells. No differences in whole blood cytokines were observed between minor allele carriers and non-carriers in the overall study population; however, minor allele status was associated with increased induction of a subset of cytokines among African American subjects, and decreased induction among White subjects. These findings underline the importance of broad racial inclusion in genetic studies of immunity.

SUBMITTER: Ajayi T

PROVIDER: S-EPMC10412543 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Race-specific association of an IRGM risk allele with cytokine expression in human subjects.

Ajayi Teminioluwa T Rai Prashant P Shi Min M Gabor Kristin A KA Karmaus Peer W F PWF Meacham Julie M JM Katen Kevin K Madenspacher Jennifer H JH Schurman Shepherd H SH Fessler Michael B MB

Scientific reports 20230809 1

Immunity-related GTPase family M (IRGM), located on human chromosome 5q33.1, encodes a protein that promotes autophagy and suppresses the innate immune response. The minor allele of rs13361189 (-4299T>C), a single nucleotide polymorphism in the IRGM promoter, has been associated with several diseases, including Crohn's disease and tuberculosis. Although patterns of linkage disequilibrium and minor allele frequency for this polymorphism differ dramatically between subjects of European and African ...[more]

PMID: 37558924

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Project description:Crohn's disease (CD) is a chronic inflammatory gastrointestinal disorder. Genetic association studies have implicated dysregulated autophagy in CD. Among risk loci identified are a promoter single nucleotide polymorphism (SNP)( rs13361189 ) and two intragenic SNPs ( rs9637876 , rs10065172 ) in immunity-related GTPase family M ( IRGM) a gene that encodes a protein of the autophagy initiation complex. All three SNPs have been proposed to modify IRGM expression, but reports have been divergent and largely derived from cell lines. Here, analyzing RNA-Sequencing data of human tissues from the Genotype-Tissue Expression Project, we found that rs13361189 minor allele carriers had reduced IRGM expression in whole blood and terminal ileum, and upregulation in ileum of ZNF300P1, a locus adjacent to IRGM on chromosome 5q33.1 that encodes a long noncoding RNA. Whole blood and ileum from minor allele carriers had altered expression of multiple additional genes that have previously been linked to colitis and/or autophagy. Notable among these was an increase in ileum of LTF (lactoferrin), an established fecal inflammatory biomarker of CD, and in whole blood of TNF, a key cytokine in CD pathogenesis. Last, we confirmed that risk alleles at all three loci associated with increased risk for CD but not ulcerative colitis in a case-control study. Taken together, our findings suggest that genetically encoded IRGM deficiency may predispose to CD through dysregulation of inflammatory gene networks. Gene expression profiling of disease target tissues in genetically susceptible populations is a promising strategy for revealing new leads for the study of molecular pathogenesis and, potentially, for precision medicine. NEW & NOTEWORTHY Single nucleotide polymorphisms in immunity-related GTPase family M ( IRGM), a gene that encodes an autophagy initiation protein, have been linked epidemiologically to increased risk for Crohn's disease (CD). Here, we show for the first time that subjects with risk alleles at two such loci, rs13361189 and rs10065172 , have reduced IRGM expression in whole blood and terminal ileum, as well as dysregulated expression of a wide array of additional genes that regulate inflammation and autophagy.

Dataset Information

Race-specific association of an IRGM risk allele with cytokine expression in human subjects.

Publications

Race-specific association of an IRGM risk allele with cytokine expression in human subjects.

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