The Association Study On Polymorphisms Of Mitochondrial DNA With Polycystic Ovary Syndrome In A Chinese Population

Objective Polycystic ovary syndrome（PCOS）is a common endocrine disorder with an estimated prevalence of 5-20%in global reproductive-age women and was characterized by chronic anovulation,hyperandrogenemia and polycystic ovaries.However,there is no clear-cut explanation of PCOS pathogenesis up to now.Mitochondrial DNA（mtDNA）polymorphisms have been reported to be associated with multiple diseases,such as type 2 diabetes,neurodegenerative diseases,and various tumors.Here we aim to investigate the relationship between mtDNA D-loop region polymorphisms,mtDNA haplotype and PCOS,as well as the correlation of D-loop polymorphisms and clinical characteristics of PCOS in a Chinese population.And compare the difference in mtDNA copy number between the PCOS group and the control group.Methods Between 2015 and 2018,a total of 421 women with PCOS and 409 women who had only male-factor or tubal-factor infertility were recruited from Reproductive Center of the First Affiliated Hospital of Anhui Medical University.The D-loop region of peripheral blood samples were amplified and sequenced,and polymorphisms were identified by comparison with the revised Cambridge Reference Sequence（r CRS）.Then we divided the mtDNA polymorphisms of every subject into a haplogroup.In the statistical analysis,categorical variables such as nucleotide variations and PCOS were preliminarily evaluated by univariate logistic regression to analyze the association between nucleotide variations and PCOS.In the subsequent multivariate regression analysis,BMI and age were used as correction factors to further confirm results.Benjamini-Hochberge False Discovery Rate（BH FDR）was applied to correct the P value in multiple test by using the R software.Compare the difference in the frequency of D-loop polymorphism and haplogroup distribution between PCOS patients and controls,and analyze the relationship between D-loop polymorphism and clinical characteristics of PCOS.Then,we randomly selected 168 PCOS patients and 83controls from all 830 subjects.The mtDNA copy number of PCOS and control patients was measured using droplet digital polymerase chain reaction（dd PCR）.The Mann-Whitney U test was used to compare the difference in mtDNA copy number between PCOS patients and the controls.Results The polymorphisms G207A(P_BH=0.045,OR=0.320),16036GGins(P_BH=0.023,OR=0.080)and 16049Gins(P_BH<0.001,OR=0.051)were associated with decreased risk of PCOS.No variants were associated with PCOS,and within the PCOS group,no statistical significance was found between D-loop polymorphisms and clinical characteristics（overweight/obesity,LH:FSH>2,hyperandrogenemia,and insulin resistance）.mtDNA haplogroup analysis suggested that haplotype A15（P=0.009,OR=0.055）was significantly associated with decreased risk of PCOS.Compared with controls,the mtDNA copy number of PCOS patients was significantly higher（P<0.001）.Conclusions mtDNA D-loop polymorphisms G207A,16036GGins,and 16049Gins may be the protective factors for PCOS.Mitochondrial haplotype A15 appears to confer resistance to PCOS in Chinese women.Increased mtDNA copy number may be a compensatory effect in the early stage of PCOS.