Association Study Of Genetic Variants In Androgen-Regulated Genes And Risk Of Severe Acne In Han Population From Southwest China

Objective To explore whether genetic variants of the CYP21A2, CYP19A1, CYP11B1and CYP11B2, the four key genes involved in the synthesis and metabolism of androgen, are associated with severe acne in Yunnan province.Methods In this study, we genotyped31SNPs of the CYP21A2(rs6464, rs6467, rs6474, rs6465), CYP19A1(rs4646, rs10046, rs700519, rs8023263, rs2899473, rs12594287, rs2414096, rs727479, rs767199, rs11636667, rs749292, rs730154, rs28757111, rs2470152, rs41399553, rs1902584, rs1004984, rs28757078), and CYP11B1/CYP11B2(rs6387, rs6410, rs4539, rs1799998, Intron2W/C, rs4736312, rs7818826, rs4534, rs5280) genes using SNaPshot assay in1200individuals including569severe acne patients and631controls in Han Chinese from Yunnan, China to explore the association of the four candidate genes with severe acne and established the linkage disequilibrium blocks and haplotype structures in analyses stratified by gender.Results1. For single-marker, we found that rs6474(p.Arg103Lys)(all cases vs. controls, P=0.001) and rs6465(all cases vs. controls,P=0.025) of the CYP21A2gene were associated with severe acne. Significant associations were observed between male patients and controls for the CYP21A2(rs6474,P=0.002; rs6465, P=0.012), CYP19A2genes (rs8023263, P=0.037; rs2470152, P=0.007) and CYP11B1/CYP11B2genes[rs4534(p.Arg43Gln)(P=0.027), rs5280(c.-64T>C)(P=0.023)], but no significant associations were found between female patients and controls in all the four candidate genes.2. Haplotype analysis showed:for the CYP21A2gene, major haplotype AGG was associated significantly with the decrease of the risk of male severe acne(OR=0.697,95%CI=0.531-0.913,P=0.009). Inversely, haplotype AGA was associated significantly with the increase of the risk of male severe acne (OR=1.822,95%CI=1.245-2.665, P=0.002) and haplotype AGA also showed a risk effect on whole patients but the P values were marginally significant(OR=1.350,95%CI=1.017-1.792, P=0.044). The positive haplotypes of CYP21A2for male severe patients remain significant after Bonferroni correction, but note that this positive associations for whole severe acne disappeared after Bonferroni correction. However, for CYP19A1, we could not find any significant heterogeneity under overall haplotype test and single haplotype test in analyses including all subjects or in analyses stratified by gender(P>0.05). CYP11B1/CYP11B2gene haplotype analysis showed that haplotype CACCA (P=0.040) and haplotype AGCTA (P=0.016) were signifiacntly associatied with whole severe acne patients, note that this positive associations disappeared after Bonferroni correction. Howerv, in analyses stratified by gender of haplotype for CYP11B1/CYP11B2, all the haplotypes showed no significant association for male and female case and control.3. Strong linkage disequilibrium(LD) were observed in gene variants of the two gene, CYP11B1and CYP11B2, which could confer the genetic susceptibility to severe acne via the mechanisms in the LD with the causative variant(s) in both gene.Conclusion1. SNP rs6474(p.Arg103Lys) and rs6465of the CYP21A2gene were associated with severe acne patients.2. Six SNPs of CYP21A2[rs6474(p.Arg103Lys), rs6465], CYP19A1(rs8023263, rs2470152) and CYP11B1/CYP11B2[rs4534(p.Arg43Gln), rs5280(c.-64T>C)] were significantly associated with male severe acne patients.3. The CYP21A2gene was the most significant associated with male severe acne, haplotype AGG of the CYP21A2gene was a protective factor for male against severe acne whereas haplotype ATA of the CYP21A2gene was a risk factor for male in development of severe acne.4. The gene variant(s) in CYP11B2are in strong linkage disequilibrium (LD) with variants in CYP11B1, thus variant(s) in the CYP11B2can confer the genetic susceptibility to severe acne via the mechanisms in the LD with the causative variant(s) in CYP11B1or the undiscovered causative variant(s) in CYP11B2itself.