Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus.
نویسندگان
چکیده
OBJECTIVE Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene-gene interactions in a number of known lupus susceptibility loci. METHODS Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. RESULTS We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10(-5) [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10(-45)). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively). CONCLUSION We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
منابع مشابه
Codon 72 Polymorphism of p53 Gene and Hematologic Manifestations in Patients with Systemic Lupus Erythematosus
Background: Systemic lupus erythematosus is a systemic autoimmune disorder with unclear etiology. The importance of some genes in the development of systemic lupus erythematosus has been implicated. The gene polymorphism in codon 72 has attracted a lot of attention and its role in the occurrence or progression of many cancers and autoimmune diseases especially systemic lupus erythematosus has ...
متن کاملGene–Gene and Gene-Sex Epistatic Interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in Systemic Lupus Erythematosus
Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene-gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six sing...
متن کاملEffects of Major Epigenetic Factors on Systemic Lupus Erythematosus
The pathogenesis of systemic lupus erythematosus (SLE) is influenced by both genetic factors and epigenetic modifications; the latter is a result of exposure to various environmental factors. Epigenetic modifications affect gene expression and alter cellular functions without modifying the genomic sequences. CpG-DNA methylation, histone modifications, and miRNAs are the main epigenetic factors ...
متن کاملThe major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes.
The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the locati...
متن کاملGenetic Modifiers of Systemic Lupus Erythematosus in FcγRIIB−/− Mice
FcgammaRIIB is a potent lupus susceptibility gene as demonstrated by the observation that mice deficient in this molecule develop spontaneous antinuclear antibodies (ANA) and fatal glomerulonephritis when on the C57BL/6 background. To determine the mechanisms underlying the epistasis displayed by this gene we have constructed hybrids between FcgammaRIIB(-/-) and the systemic lupus erythematosus...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Arthritis and rheumatism
دوره 64 2 شماره
صفحات -
تاریخ انتشار 2012