| Background Psoriasis is an inflammatory skin disease involving multiple factors,such as immune,genetic and infection factors.At present,the genetic pathogenesis of psoriasis is not completely clear.With the continuous development of genetic research methods,through linkage analysis,genome-wide association analysis,second-generation sequencing and other methods,more than 80 disease susceptibility genes have been found,which explains part of the genetic mechanism of psoriasis.The human leukocyte antigen?HLA?system is the most complex and polymorphic system known to the human body,it contains a large family of genes encoding major human histocompatibility complex?MHC?proteins.These genes are located on chromosome 6p21 and are classified as I,II and III.Genes in the MHC region are characterized by high polymorphism,haplotype inheritance and extensive linkage imbalance,which has become one of the hot spots for geneticists.HLA is associated with many human diseases,such as cancer,autoimmune diseases and infectious diseases.In recent years,more and more evidence has shown that HLA is significantly correlated with psoriasis,especially the class I genes of HLA.HLA-C*06:02 has been proved to be the strongest susceptibility gene in many species and different subtypes of psoriasis.Although many studies have been conducted on the genetic of HLA region and psoriasis,no study has been conducted on the genetic variation characteristics of the subtype of family history.Object?1?To find the genetic variations of the patients with and without family history of psoriasis vulgaris?PsV?by conducting deep sequence in the HLA region.?2?To compare the heritability difference in patients with and without family history.?3?Look for the distinguish locus between subtypes with and without family history as a genetic marker to identify the two subtypes.Methods?1?Carry out deep sequence in the HLA region among 8,350 Chinese Han psoriasis vulgaris patients and 9,906 healthy controls by using Illumina sequencing platform,and collate genotyping data.?2?psoriasis patients were divided into two groups,with family history group and without family history group.Plink software was used to analyze in the two groups.Qualitative control was conducted on the genotyping data of the two groups,and stepwise regression analysis was conducted after correcting age,gender,region.The significant genetic risk loci were identified according to the Bonferroni corrected standard.?3?GCTA software was used to calculate the heritability of the two groups with and without family history,and to compare the difference in the genetic effect of the HLA region that acted on the two subtypes.?4?directly compare family history and non-family history patients,find the difference loci between them as genetic distingush marker.Results The sequencing data of the HLA region were preliminarily sorted out,including alleles,amino acids and single nucleotide polymorphism.As a result,there were a total of 26,775 mutation sites.According to the Bonferroni correction standard,the P value of significance was 0.05/26,775=1.87×10-6.In the family history versus healthy control group,the most significant locus was HLA-C*06:02(P=1.00 x10-352,OR=12.49,95%CI=11.07-14.09).Based on HLA-C*06:02,we conducted stepwise conditional regression analysis and found multiple loci of significant,allele HLA-C*07:04(P=6.87×10-13,OR=3.56,95%CI=2.51-5.03),rs28732166(P=4.62×10-15,OR=2.21,95%CI=1.81-2.70)on gene C2,rs9394133(P=2.97×10-9,OR=1.31,95%CI=1.20-1.43)on gene HLA-DPB2,HLA-A amino acid 9(P=6.00×10-7,OR=0.77,95%CI=0.70-0.86),so there were 5 independent signals related to family history subtypes.In the non-family history versus healthy control group,the most significant locus was HLA-C*06:02(P=1.00 x10-687,OR=13.20,95%CI=12.20-14.27).Stepwise regression analysis found that HLA-C*07:04(P=1.40×10-33,OR=4.05,95%CI=3.23-5.08),HLA-B amino acid 67(P=1.13 x10-45,OR=2.07,95%CI=1.87-2.29),HLA-B amino acid 32(P=4.71x10-20,OR=0.70,95%CI=0.64-0.75),gene GABBR1(P=1.42x10-19,OR=1.70,95%CI=1.52-1.91),rs3129917 on gene C6orf10(P=6.57x10-16,OR=1.47,95%CI=1.34-1.62)and rs9394133 on HLA-DPB2(P=1.23x10-12,OR=1.23,95%CI=1.16-1.30),a total of 7 independent signals that were related to non-family history subtype.Using GCTA to calculate heritability,the result of family history subtype was 12.1%?95%CI=9.7-14.5,SE=0.012?,and the non-family history subtype was15.8%?95%CI=13.8-17.8,SE=0.010?.According to the results,the heritability of HLA region that acted on family history group maybe lower than non-family history group.According to the above analysis results,the genetic variations in the HLA region with and without family history is not completely the same,and there is a difference in the heritability between the two subtypes.Direct comparison analysis in family history and non-family history groups showed that,the most significant site is HLA-B amino acid 325(P=3.57 x 10-8,OR=0.79,95%CI=0.72-0.86).However,this amino acid is not a functional pocket or domain,the possible reason maybe,based on the statistic power size in our study,and the quality control conditions,MAF>0.01,hwe>10-4 and call-rate>0.95,rare and low frequency casual distinguishing marker is difficult to detect,this amino acid may be linked to the target variant.Conclusions Deep sequence of HLA region was carried out in Chinese Han PsV patients,independent signals were found in subtypes that with and without family history respectively.The heritability of the HLA region that acted on the non-family history group maybe greater than family history group,and further analysis found that the HLA-B amino acid 325 was the distinguish locus between family history and non-family history group.This is the first exploration of the genetic characteristics in the MHC region as related to family history in Chinese Han patients,which can better explain the genetic pathogenesis of disease subtypes,the distinguish locus between family history and non-family history group can be used as genetic marker to predict the disease genetic predisposition in next generation.These results provide research basis for the development of precision medicine and promote the development of individualized medicine. |
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