A Genome-wide Association Study Of Severe Acne In Han Chinese Population

Severe acne is a common chronic inflammatory skin disease and characterized by cysts, nodules and potential scarring, which generally distributed in the face, upper chest, and back. It’s a disease with long duration and can cause extensive damage to the skin. However, the treatment to the scarring usually has poor results. Severe acne is rarely life-threatening, but it can cause anxiety or depression, which further influence psychological health. Severe acne peaks in teenage years and have a seriously negative impact on the social, future employment, and marriage for teenagers.At present, most of the study of acne is limited to genes that are involved in androgen metabolism, immune response and inflammation processes. Moreover, the secretion and metabolism of androgen is also regulated by adrenal cortical hormone, and other metabolic or signaling pathways. Because severe acne is a polygenic disease resulting from the combined action of multiple genes, the strategies of candidate gene study has some limitations in that a variety of other metabolic pathways or signal transduction pathways are excluded. Indeed, identifying the causative susceptibility genes is an important prerequisite to early control the disease. In this paper, we performed three studies:genome-wide association study (GWAS), genotype-phenotype correlations study and gene pathway study, to identify susceptibility genes and related gene pathways of severe acne and to study their relationship with the clinical phenotypes.(1) We performed the genome-wide association study for severe acne that is to search the susceptibility genes in a Han Chinese population comprising2,916cases and4,716controls. We used a two-stage study strategy. In initial GWAS stage,1,056cases and1,056controls were genotyped using the Illumina HumanOmniZhongHua-8BeadChip which could detect900,015SNPs. In the replication stage, we genotyped the101SNPs in an independent cohort of1,860cases and3,660controls using Sequenom MassArray. The101SNPs included86SNPs with the most significant P value in the discovery stage and15SNPs with nominal association evidence located within or close to nine susceptibility genes. We combined the initial GWAS and replication stages together and identified two new susceptibility loci at11p11.2(DDB2, rs747650, Pcombined=4.41×10-9, OR=1.24and rs1060573, Pcombined=1.28×1O-8, OR=1.23) and1q24.2(SELL, rs7531806, Pcombined=1.20×10-8, OR=1.22) that are involved in androgen metabolism, inflammation processes and scar formation in severe acne. These results point to new genetic susceptibility factors and suggest several new biological pathways related to severe acne.(2) Two novel susceptibility loci1q24.2(SELL)和11p11.2(DDB2) for severe acne have been identified in our GWAS of a Han Chinese population. We further investigated their relationships with clinical phenotypes, including onset age, atrophic scarring, hypertrophic scarring and family history, as well as investigated correlations between the four clinical phenotypes. This study will lay a foundation for further study of pathogenesis of severe acne. We used the Chi square test to compare the allele frequency of3SNPs (rs7531806, rs747650, rs1060573) among different clinical phenotypes. Spearman’s Correlation Coefficient (rs) is calculated to measure the relationship between different clinical phenotypes. Significant association was found for the11p11.2(DDB2) with disease family history (P<0.05). Hypertrophic scarring was positively correlated with atrophic scarring (rs=0.315). The study suggested that susceptibility loci11p11.2(DDB2) is associated with disease family history of severe acne and not correlated with the other phenotypes of severe acne, while there are also correlations between these different phenotypes. These results not only shed more light on the role of llpll.2(DDB2) in the pathogenesis of severe acne, but also deepen our understanding of the relationship between disease-related clinical phenotypes.(3) In this study, we applied genome-wide pathway analysis to GWAS data of severe acne (900,015variants,1,056cases and1,056controls) and expected to discover gene pathways associated with the severe acne. We applied two customized of pathway-based analysis methods, VEGAS and Top-SNP, to the GWAS data in order to evaluate enrichment of pathways for their contribution to severe acne. Pathways used in this study are retrieved from two databases including KEGG and BioCarta. Fifteen significant pathways are identified by the two pathway analysis methods using a FDR of P<0.05. Of these, at least five pathways participate in immune response and inflammation processes (lectin Induced complement pathway, cells and molecules involved in local acute inflammatory response, cell adhesion molecules, IL3signaling pathway, cytokines and inflammatory response). The finding is consistent with previous understanding of pathogenesis of the disease:severe acne is a disease closely related to inflammatory reaction. Moreover, other pathways that are less known for their association with severe acne were identified in this study, such as tyrosine metabolism and calcium signaling. Our study not only provided more insight into biological signaling pathways associated with severe acne and promote understanding of the pathogenesis, but also provided some potential new targets for prediction and therapy of severe acne. These findings will also facilitate future follow-up and functional studies for severe acne.