Dataset Information

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.

ABSTRACT: OBJECTIVE:Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin ?(M) (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. METHODS:The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. RESULTS:The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10(-5)). CONCLUSION:These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE.

SUBMITTER: Kim K

PROVIDER: S-EPMC3466387 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.

Kim Kwangwoo K Brown Elizabeth E EE Choi Chan-Bum CB Alarcón-Riquelme Marta E ME Kelly Jennifer A JA Glenn Stuart B SB Ojwang Joshua O JO Adler Adam A Lee Hye-Soon HS Boackle Susan A SA Criswell Lindsey A LA Alarcón Graciela S GS Edberg Jeffrey C JC Stevens Anne M AM Jacob Chaim O CO Gilkeson Gary S GS Kamen Diane L DL Tsao Betty P BP Anaya Juan-Manuel JM Guthridge Joel M JM Nath Swapan K SK Richardson Bruce B Sawalha Amr H AH Kang Young Mo YM Shim Seung Cheol SC Suh Chang-Hee CH Lee Soo-Kon SK Kim Chang-sik CS Merrill Joan T JT Petri Michelle M Ramsey-Goldman Rosalind R Vilá Luis M LM Niewold Timothy B TB Martin Javier J Pons-Estel Bernardo A BA Vyse Timothy J TJ Freedman Barry I BI Moser Kathy L KL Gaffney Patrick M PM Williams Adrienne A Comeau Mary M Reveille John D JD James Judith A JA Scofield R Hal RH Langefeld Carl D CD Kaufman Kenneth M KM Harley John B JB Kang Changwon C Kimberly Robert P RP Bae Sang-Cheol SC

Annals of the rheumatic diseases 20120420 11

<h4>Objective</h4>Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.<h4>Methods</h4>The authors e ...[more]

PMID: 22523428

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Project description:This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used. Confirmatory qPCR on SLE monocytes was performed. The entire 12p11 locus was investigated for genetic association using two additional GWAS. Expression of 150 genes at this locus was assessed. Based on this significance, qPCRs for DNM1L and KRAS were performed. Fifty genes were differentially expressed in at least two SLE GEO-datasets, with all probes directionally aligned. DDX11, an RNA helicase involved in genome stability, was downregulated in both GEO and Cordoba datasets. The most significant SNP, rs3741869 in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression. DDX11 was found repressed. The entire 12p11 locus showed three association peaks. Gene expression in GEO datasets identified DNM1L and KRAS, besides DDX11. Confirmatory qPCR validated DNM1L as an SLE susceptibility gene. DDX11, DNM1L and KRAS interact with each other and multiple known SLE genes including STAT1/STAT4 and major components of IFN-dependent gene expression, and are responsible for signal transduction of cytokines, hormones, and growth-factors, deregulation of which is involved in SLE-development. A genomic convergence approach with OASIS analysis of multiple GWAS and expression datasets identified DDX11 and DNM1L as novel SLE-genes, the expression of which is altered in monocytes from SLE patients. This study lays the foundation for understanding the pathogenic involvement of DDX11 and DNM1L in SLE by identifying them using a systems-biology approach, while the 12p11 locus harboring these genes was previously missed by four independent GWAS.

Dataset Information

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.

Publications

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.

Similar Datasets

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