MHC, LCE And IL12B Have Epistatic Effects On Risk For Psoriasis In Chinese Population

Background Psoriasis is a common inflammatory cutaneous disorder characterized by red scaly patches. The prevalevence of psoriasis is about 0.123% in Chinese Han population. So far there have heen about 4 million psoriasis patients in China. Clinically, psoriasis vulgaris is the most common, accounting for the total number of patients over 90%. The exact pathogenesis of psoriasis remains unclear. It is agreed generally that the psoriasis is a complex disease which arises from genetic and environmental factors. The predisposing genes can be grouped into two parts: HLA-associated and lacking HLA associations genes. As genome wide association (GWA) studies have produced a large amount of data, further study on gene-gene interaction and multi-marker association would be important for elucidating the biological and biochemical pathways that underline disease.Objective We evaluated the associations of single nucleotide polymorphisms (SNP) in MHC region with psoriasis, and determined the epistasis and combined effects of MHC locus and IL12B, LCE on risk for psoriasis.Method We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. According the combined effects, we finally compared the clinical difference between the carriers of the risk alleles and non-carriers psoriasis patients.Result①Extremely high significance of association was detected between rs1265181 and psoriasis (P combined <10E-300, OR =16.52, 95%CI: 15.28-18.44).②For rs4085613_A, the most significant association evidence was observed under recessive model, the homozygous and heterozygous odds ratio (ORhom / ORhet) estimates of this SNP supported this recessive model. Additive model is the best fit for the association of rs3213094_A, the ORhom / ORhet estimates further suggested the additive effects of this SNP. Similarly, the dominant association model was fit for rs1265181_G, where GG and CG show similar risk effects.③We observed significant interactions between MHC and LCE (p=0.0379) and between MHC and IL12B (p=0.0287) in the discovery sample. Interaction between MHC and LCE was significant in the replication sample (p=0.0091) while interaction between MHC and IL12B just show marginal significance (p=0.066). Analysis of combined sample showed pronounced evidence for both MHC by LCE (p=0.0016) and MHC by IL12B (0.0036) interaction after adjusting for potential study sample effect.④We further analyzed the combined effect of MHC, LCE and IL12B on the risk for psoriasis. the risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. The risk effects decreased in individuals with risk allele in one gene and protective allele in another, as compared with those with risk alleles in both genes.⑤We compared the clinical features between the carriers of the risk alleles and non-carriers psoriasis patients, and observed obvious clinical difference between the two group.Conclusion This study had confirmed a significant association between MHC region and psoriasis. More important, we provided evidence for interactions between MHC and LCE and between MHC and IL12B in determining the risk of psoriasis in Chinese population and estimated the combined effects of these genes. Besides, we suggested that MHC might be the main effect gene on the risk for psoriasis. We also found that carriers of the risk alleles have obvious clinical difference with non-carriers.