| Objective To investigate whether there is genetic correlation between clinical endophenotype and chronic prostatitis,to further search for key genes affecting the expression level of clinical endophenotype,and to provide new ideas for the diagnosis,treatment and prevention of chronic prostatitis in clinical practice.Method Part I: genetic correlation between 29 clinical endomorphic phenotypes and chronic prostatitis was calculated based on linkage imbalance score.Part II:using SNP sites as instrumental variables,Mendelian randomization was used to investigate whether there is a causal relationship between clinical endomorphic phenotypes and chronic prostatitis.Part III: using the exon chip scanning association study method,to find the important SNP sites or genes that affect the change of Complement C3 and C4.Result First,there was a significant genetic correlation between multiple clinical endophenotypes and chronic prostatitis.Second,a causal relationship was found between complement C4 and chronic prostatitis.Third,two snps and TNXB that may affect complement C3 and C4 levels was found.Conclusion There is a significant genetic correlation between clinical endophenotype and chronic prostatitis,and the study found a causal relationship between complement C4 and chronic prostatitis,and found an important SNP and key genes affecting the level of complement C4,providing a new diagnosis and treatment idea and prevention strategy for the clinical practice of chronic prostatitis.Part I: Based on Gwas Data,the Correlation Analysis Between Chronic Prostatitis and 29 Clinical Intermediate Phenotypic Data Was StudiedObjective Chronic prostatitis（CP）is a very common and highly heterogeneous complex disease,which the biological mechanism involved is very complex.At present,there is no exact single etiology that can explain the pathogenesis of CP.Genome Wide Association Study（GWAS）,as a genome-wide,high-density systems biology approach,has been used to evaluate the genetic diversity of Single Nucleotide Polymorphism.It has overcome the defect that traditional hypothesis-driven research can not carry out global research,and has found a large number of genes related to diseases and complex traits,which has brought a fundamental change to the understanding of the genetic factors of many complex diseases or traits.Genome-wide association was used to calculate the genetic pleiotropy of CP and associated intermediate phenotypes,as well as the presence of important genetic correlation loci and key genes.Methods Nucleic acid was extracted from 1699 cases of CP patients in the study group and 1999 cases of healthy control group,respectively.Illumina Human Omni Zhonghua-8 chip was used to genotyping the DNA samples of case group.Illumina Human Omni 1-Quad chip was used for genotyping of DNA samples from the control group,and Plink 1.07 software was used for genome-wide association analysis of the data.The content levels of 29 clinical biochemical indexes（intermediate phenotypes）in serum of the included control group were determined.Python software was used to calculate the linkage disequilibrium relationship between 29 clinical biochemical indicators including qualified SNP sites and their nearby SNP sites,and the LD regression coefficient between CP and 29 clinical biochemical indicators was calculated.Result the calculation of genetic correlation between CP and 29 lipid metabolism-related intermediate phenotypes found that chronic prostatitis was significantly related to 18 clinical endophenotypes such as BMI（rg=0.4224,P <0.05）complement C4（rg=0.3245,P < 0.05）,and HDL（rg=-0.3331,P < 0.05）.Conclusion there was a significant genetic correlation between chronic prostatitis and 18 intermediate phenotypes,such as body mass index（BMI）,Ig G,ferritin,complement C4,testosterone and triglyceride,suggesting that there was genetic correlation between these intermediate phenotypes and CP.It can be used as the key research target to conduct the next step of causality research.Part II: Mendelian Randomized Study of Causality Between Genetically Related Intermedial Phenotypes and the Risk of Chronic ProstatitisObjective In the era of GWAS high-throughput genomic technology,it is easy to obtain a large number of phenotypic genetic data.Therefore,further mining of GWAS data of CP disease and exploring the molecular genetic mechanism of CP are expected to bring new breakthroughs in the study of the etiology and clinical typing of CP.A large number of studies have shown an important relationship between CP and lipid metabolism（intermediate phenotype）in vivo.Intermediate phenotypes refer to the internal phenotypes that can be found through biochemical tests or physical examinations,which are closer to the biological basis of the disease and less affected by external factors than the exogenous phenotypes of the disease.Therefore,it has significant advantages to study the etiology and pathogenesis of CP disease through intermediate phenotypes.Can the verified strong positive sites related to intermediate endophenotype be used as tool variables to explore the causal relationship between intermediate endophenotype and CP?Methods The SNP loci data were derived from the genotyping results in Part I.Statistical methods:（1）screen the common associated SNP sites between clinical biochemical indexes and CP;（2）use R language program to calculate the causal relationship between clinical biochemical indexes and CP,including:Mendelian randomization-egger regression（MR Egger）,Inverse variance weighted（IVW）,Weighted median estimator（WME）,Wald ratio,Simple mode,Weighted mode.Result the SNP sites shared between 15 biochemical indexes and CP were used as tool variables.The inverse variance weighted method used in the five calculation methods showed that there was a causal relationship between complement C4 and chronic prostatitis（C4,B value = 0.4411447,SE value =0.2135727,P value = 0.03887114,P < 0.05,statistically significant）.Conclusion There is a causal relationship between clinical biochemical index complement C4 and chronic prostatitis.C4 may be a causal factor in the occurrence and development of chronic prostatitis.Part Ⅲ: Study On The Exon Gene Chips Scanning Association Of Complement C3 And C4Objective Complement is important for the survival of organisms.Although,our previous genome wide association study（GWAS）on C3 and C4 levels had identified many significant loci,a large amount of information on the heredity of low and rare frequency was ignored.In this chapter,the whole exon chip was used to scan the genetic variation related to Complement C3 and C4.Methods Based on the Fangchenggang Area Male Health and Examination Survey（FAMHES）,1544 healthy volunteers were selected randomly to conduct the exome gene chips.After rigorous quality control,1505（97.5%）individuals and 237,346 variants were left with a call rate >95% and Hardy-Weinberg Equilibrium（HWE）>1×10-6.Associations were conducted in single-variant and gene-based analysis with EMMAX and EMMAXTV,respectively.Result After filtration,two new variants for C4 were apparent（rs4151648: MAF=0.02261,P=4.24×10-20;rs3129953: MAF=0.0448,P=8.47×10-13）.However,for C3,we did not find a positive genetic signal(Ptop=4.69×10-6).When it came to the gene-based analysis,two genes were revealed to be significant for C4(C2: P=1.0×10-7,TNXB: P=1.0×10-7)in chromosome 6.Even so,no positive result was present for C3.After conditional analysis,TNXB(Pcondition=1.2×10-6,2.0×10-7)was confirmed to be significant again,but the analysis of the C2 gene failed（Pcondition=0.75,0.65）.In addition,further haplotype and expression analysis suggested mutation of rs3129953 could be easier than rs4151648 in influencing the expression of C4,whose levels increased along with the mutation of these two newly identified loci and increasing age.Conclusion Our results indicated that two new loci（rs4151648 and rs3129953）and the TNXB gene might be potential genetic factors influencing C4 levels,which would contribute to understand related diseases of prostatitis further. |
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