Transmission Of Polycystic Ovary Syndrome Susceptibility SNPs And Their Association With The Phenotype Changes In Offspring Born To PCOS Mothers

Background:Polycystic ovary syndrome(PCOS)is thought to be the most prevalent endocrinopathy in women of reproductive age,with a prevalence of 5%to 18%.The heterogeneity of PCOS is significant.The clinical characteristics include hyperandrogenism,obsity,infertility,and abnormal glucose and lipid metabolism etc.The pathogenesis of PCOS is still unknown.It is thought to be the result of the interaction of genetic and environmental factors.Previous studied found that offspring of women with PCOS had a higher rate of neonatal intensive care units and increased risk of manifesting PCOS-like phenotypes in adulthood.Family studies have also shown that abnormal metabolic traits occurred more often in the family members of PCOS patients.Single nucleotide polymorphism(single nucleotide polymorphism,SNP)is the most common type of human genetic variations.Genome-wide association studies(GWAS)in Han Chinese women has identified 18 genetic loci associated with PCOS.However,the frequency of SNPs located in these loci and their association with the phenotypic changes in PCOS-offspring has not been verified.Identifying the contribution of these candidate genes in phenotypic inheritance is helpful to explore the etiological mechanism of PCOS.Objective:The aim of this study is to analyze the frequency of PCOS susceptibility SNPs and their association with the phenotypic changes in offspring born to PCOS mothers.Methods:The study involved 172 children born to women with PCOS and 529 children born to those without as control according to age matching.All offspring were conceived from assisted reproductive technologies(ART).The age of offspring ranged form 1 to 8 years old.A morning fasting blood sample was obtained for DNA extracting and hormones examining.The genomic DNA was extracted from either total blood samples or umbilical cord blood(offspring younger than 2 years old).The samples were sequenced by Sanger sequenom,Taq Man-MGB probe assay and Sequenom MassARRAAY.In addition,growth and development index(height,weight,BMI)as well as endocrine and metabolic parameters(LH,E2,T,DHEAS,AMH,FT3,FT4,FBG,FINS,CHOL,LDL-C,HDL-C,etc.)of the offspring were measured at the same time.The frequency of alleles and clinical phenotypes were compared between offspring born to women with and without PCOS.Results:In male offspring,the fasting insulin(FINS)(P=0.032),homeostasis model assessment of insulin resistance(HOMA-IR)(P=0.032)and the homeostasis model assessment of pancreatic beta cell function(HOMA-β)(P=0.034)levels were higher in offspring of PCOS mothers compared to controls.In female offspring,PCOS offspring had a significantly higher AMH levels(P=0.001)compared to daughters from control mothers.Comparing neonatal outcomes and growth profiles between the groups revealed that there were no statistically significant differences.Allele and genotype frequencies for male offspring showed the significant results between groups included:rs 10818854 in the DENND1A gene(Pallele=0.021,Pgenotype=0.024);rs2268361(Pallele=0.013)and rs2349415(Pallele=0.047,Pgenotype=0.014)in FSHR gene;and rs2059807 in INSR gene(Pallele=0.028).In female offspring,there are significant difference of allele and genotype frequency between groups in rs2479106 in the DENND1A gene(Pallele=0.046,Pgenotype=0.036).The geno-pheno-type analysis was performed in offspring born to women with and without PCOS for the phenotypes that showed differences between groups.In male offspring of PCOS mothers,subjects with a A allele at rs10818854 had higher FINS(P=0.037)and HOMA-β(P=0.008)levels.Results remained difference after adjustment for maternal age and BMI,paternal BMI,and the offspring’s age(Padjust=0.046,Padjust=0.01,respectively).Male offspring with a T allele at rs2349415 in the gene FSHR had higher FINS(P=0.023),HOMA-IR(P=0.030)and HOMA-β levels(P=0.013)than those in the homozygous CC group.Only HOMA-β remained different after adjustment for maternal age and BMI,paternal BMI,and the offspring’s age(Padjust=0.03).The same increased trend in FINS,HOMA-IR and HOMA-βlevels could be found in the CC and TC group in rs2268361 compared to the TT group(P=0.029,P=0.030,P=0.046,respectively).Results were still significant after adjustment for maternal age and BMI,paternal BMI,and the offspring’s age(Padjust=0.002,Padjust=0.003,Padjust=0.005,respectively).In female offspring,no differences in AMH levels were found between different genotypes.Conclusion:Offspring born to PCOS mothers have a higher risk of displaying PCOS-like phenotypes than those born to non-PCOS mothers.We observed disturbances in carbohydrate metabolism in male offspring and elevated AMH levels in female offspring.In addition,male offspring of women with PCOS who inherited genetic variants were more susceptible to develop the metabolic abnormality in their later life.