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Fc? receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.

ABSTRACT: To investigate whether the Fc? receptor IIIa-66L/R/H (Fc?RIIIa-66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by Fc?RIIIa-66L/R/H and Fc?RIIIa-176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis.Fc?RIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG-binding assays. Using Pyrosequencing methodology, FCGR3A single-nucleotide polymorphism and CNV genotypes were determined in a cohort of 1,728 SLE patients and 2,404 healthy controls.The Fc?RIIIa-66L/R/H (rs10127939) polymorphism influenced ligand binding capacity in the presence of the Fc?RIIIa-176V (rs396991) allele. There was a trend toward an association of the low-binding Fc?RIIIa-176F allele with lupus nephritis among African Americans (P = 0.0609) but not among European Americans (P > 0.10). Nephritis among African American patients with SLE was associated with Fc?RIIIa low-binding haplotypes containing the 66L/R/H and 176F variants (P = 0.03) and with low-binding genotype combinations (P = 0.002). No association was observed among European American patients with SLE. The distribution of FCGR3A CNV was not significantly different among controls and SLE patients with or without nephritis.Fc?RIIIa-66L/R/H influences ligand binding. The low-binding haplotypes formed by 66L/R/H and 176F confer enhanced risk of lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or lupus nephritis in either African Americans or European Americans.

SUBMITTER: Dong C

PROVIDER: S-EPMC4069204 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Fcγ receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.

Dong Chaoling C Ptacek Travis S TS Redden David T DT Zhang Kui K Brown Elizabeth E EE Edberg Jeffrey C JC McGwin Gerald G Alarcón Graciela S GS Ramsey-Goldman Rosalind R Reveille John D JD Vilá Luis M LM Petri Michelle M Qin Aijian A Wu Jianming J Kimberly Robert P RP

Arthritis & rheumatology (Hoboken, N.J.) 20140501 5

<h4>Objective</h4>To investigate whether the Fcγ receptor IIIa-66L/R/H (FcγRIIIa-66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66L/R/H and FcγRIIIa-176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis.<h4>Methods</h4>FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG-binding assays. Using Pyrose ...[more]

PMID: 24782186

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Project description:Systemic Lupus Erythematosus (SLE) is a chronic, multisystem, inflammatory autoimmune disease that disproportionately affects women. Trends in SLE prevalence and clinical course differ by ancestry, with those of African American ancestry presenting with more active, severe and rapidly progressive disease than European Americans. Previous research established altered epigenetic signatures in SLE patients compared to controls. However, the contribution of aberrant DNA methylation (DNAm) to the risk of SLE by ancestry and differences among patients with SLE-associated Lupus Nephritis (LN) has not been well described. We evaluated the DNA methylomes of 87 individuals including 41 SLE patients, with and without LN, and 46 controls enrolled in an ancestry diverse, well-characterized cohort study of established SLE (41 SLE patients [20 SLE-LN+, 21 SLE-LN-] and 46 sex-, race- and age-matched controls; 55% African American, 45% European American). Participants were genotyped using the Infinium Global Diversity Array (GDA), and genetic ancestry was estimated using principal components. Genome-wide DNA methylation was initially measured using the Illumina MethylationEPIC 850K Beadchip array followed by methylation-specific qPCR to validate the methylation status at putative loci. Differentially Methylated Positions (DMP) were identified using a case-control approach adjusted for ancestry. We identified a total of 51 DMPs in CpGs among SLE patients compared to controls. Genes proximal to these CpGs were highly enriched for involvement in type I interferon signaling. DMPs among European American SLE patients with LN were similar to African American SLE patients with and without LN. Our findings were validated using an orthogonal, methyl-specific PCR for three SLE-associated DMPs near or proximal to MX1, USP18, and IFITM1. Our study confirms previous reports that DMPs in CpGs associated with SLE are enriched in type I interferon genes. However, we show that European American SLE patients with LN have similar DNAm patterns to African American SLE patients irrespective of LN, suggesting that aberrant DNAm alters activity of type I interferon pathway leading to more severe disease independent of ancestry.

Dataset Information

Fc? receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.

Publications

Fcγ receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.

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