Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus.
ABSTRACT We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants affecting susceptibility to SLE.
Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate.
Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han [rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal.
Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.
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ABSTRACT: The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.Autoimmune diseases. 01/2014; 2014:203435.
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ABSTRACT: Genome-wide association studies have identified more than 50 robust loci associated with systemic lupus erythematosus (SLE) susceptibility, and follow-up studies help reveal candidate causative genetic variants and their biological relevance contributing to the development of SLE. Epigenetic modulation is emerging as an important mechanism for understanding how the implicated genes interact with environmental factors. We review recent progress toward identifying causative variants of SLE-associated loci and epigenetic impact on lupus, especially genetic-epigenetic interactions that modulate expression levels of SLE susceptibility genes.Current Opinion in Rheumatology 07/2014; · 5.07 Impact Factor
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ABSTRACT: In recent years, genome-wide association studies have led to an expansion in the identification of regions containing confirmed genetic risk variants within complex human diseases, such as systemic lupus erythematosus (SLE). Many of the strongest SLE genetic associations can be divided into groups based on their potential roles in different processes implicated in lupus pathogenesis, including ubiquitination, DNA degradation, innate immunity, cellular immunity, lymphocyte development, and antigen presentation. Recent advances have also shown several genetic associations with SLE subphenotypes and subcriteria. Many areas for further exploration remain to move lupus genetic studies toward clinically informative end points.Rheumatic Disease Clinics of North America 01/2014; · 1.74 Impact Factor