Molecular Genetics Of Pelvic Organ Prolapse

Background and Objectives Prevalence of Pelvic organ prolapse(POP)was reported between 3%and 10%.It is the third leading cause of hysterectomy for women of all ages and the main reason for elderly women in America,seriously affecting their health and quality of life.The existing evidence shows that POP is a disease with family aggregation.Genetic and environmental factors have the same effect on POP.Old age,vaginal delivery,high BMI,physical labor are the environmental risk factors.It has been reported that collagen coding gene,metalloproteinase coding gene and hormone receptor coding gene are pop pathogenic genes.The purpose of this study is to sequence the whole genome of pop family and find out the candidate pathogenic genes.Methods From August 2016 to December 2019,POP patients in the OBGY Department of Beijing Union Medical College Hospital were recruited.The inclusion criteria were:Level ? or above POP without cervical extension,at least one natural lineal relative of the proband had POP,no Marfan syndrome/Ehlers Danlos syndrome,willing to participate in this trial.A total of 25 POP families were collected,11 of which were previously collected by our research group and 14 were newly collected.We collected the peripheral blood of proband and their related family members and extracted their DNA.The whole genome sequencing(WGS)was carried out by GeneSeeq Inc.We search for rare mutations by comparing the result of WGS with the existing databases,1000G,ESP 6500,ExAC and gnomAD.The pathogenicity of the mutation was analyzed by using the prediction tools of bioinformatics SIFT,Polyphen-2,MutationTaster,LRT,GERP++and CADD.For all previously reported POP candidate genes in the literature,we analyzed their frequency in patients and healthy controls.The statistical software is SPSS,and the detection method is Fisher exact test.Results According to the existing families in this research,POP is a disease with polygenic and partial autosomal dominant inheritance.COL6A1,COL6A6,LAMC3,LAMA5,COL7A1,FAT4,MMP9,MMP1,THBS1,FN1,ZFAT,ESR2 are the candidate gene of POP.Among them,LAMC3,MMP1,COL6A1,and MMP9 genes were verified in the diseased individuals except the proband in the family.OR values of MMP1 and COL14A1 were above 3,but there was no statistical difference.Conclusion POP is a disease with polygenetic inheritance and partial autosomal dominant inheritance.COL6A1,COL6A6,LAMC3,LAMA5,COL7A1,FAT4,MMP9,MMP1,THBS1,FN1,ZFAT and ESR2 are candidate disease-associated genes.LAMC3,MMP1,COL6Aland MMP9 genes are more likely to cause disease.