Increased Risk of Psoriasis due to combined effect of HLA-Cw6 and LCE3 risk alleles in Indian population

Abstract

HLA-Cw6 is one of the most associated alleles in psoriasis. Recently, Late Cornified Envelop 3 (LCE3) genes were identified as a susceptibility factor for psoriasis. Some population showed epistatic interaction of LCE3 risk variants with HLA-Cw6, while some population failed to show any association. We determined the associations of a 32.2 kb deletion comprising LCE3C-3B genes and three SNPs (rs1886734, rs4112788; rs7516108) at the LCE3 gene cluster among the psoriasis patients in India. All three SNPs at the LCE3 gene cluster failed to show any association. In contrary, for patients with HLA-Cw6 allele, all three SNPs and the LCE3C-3B deletion showed significant associations. While, all five LCE3 genes were upregulated in psoriatic skin, only LCE3A showed significant overexpression with homozygous risk genotype compared to the non-risk genotype. LCE3B also showed significant overexpression in patients with HLA-Cw6 allele. Moreover, LCE3A showed significantly higher expression in patients bearing homozygous risk genotype in presence of HLA-Cw6 allele but not in those having non-risk genotype, demonstrating the combined effect of HLA-Cw6 allele and risk associated genotype near LCE3A gene. Integration of genetic and gene expression data thus allowed us to identify the actual disease variants at the LCE3 cluster among the psoriasis patients in India.

Figure 1. Expression profiling of LCE3 genes.

(a–e) Expression pattern of five LCE3 genes in psoriatic and adjacent normal skin. All five LCE3 genes were significantly upregulated in psoriatic skin. (f–g) Variation in expression pattern from diseased tissue with respect to genotypes of LCE3 genes. Only LCE3A expression was significantly upregulated with risk genotype. (h–i) Expression pattern of LCE3 genes with respect to genotype and HLA-Cw6 status. Only LCE3A showed significant difference between homozygous non-risk and risk genotype in presence of HLA-Cw6. Error bars represents the Standard deviation.