Exploring The Clinical Risk Factors Of Polycystic Ovary Syndrome Based On Mendelian Randomization Study

BackgroundPolycystic Ovary Syndrome（PCOS）is a complex multisystemic disorder commonly seen in women of reproductive age and is characterized by hyperandrogenism and reproductive and metabolic dysfunction.The disease not only severely affects women’s fertility,but also puts them at increased risk for obesity,type 2 diabetes,glucose tolerance and insulin resistance,as well as cardiovascular disease in later life.Traditional observational epidemiological studies have shown an association between body mass index（BMI）,glycosylated hemoglobin A1c（Hb A1c）and its glycemic and erythrocytic pathways and PCOS,but their causal relationship is unclear.The Mendelian randomization（MR）approach overcomes the limitations inherent in observational studies by exploiting the principle of random assignment of alleles at conception,using data from the results of large-scale Genome-Wide Association Studies（GWAS）.Thus,improved causal inference can exclude confounding factors and determine the causal relationship between two complex diseases.In this study,the MR method was used to analyze the blood glucose of BMI,Hb A1c,and Hb A1c.The causal relationship between the erythrocyte pathway and PCOS.MethodThe present study used the blood glucose and erythrocyte pathway outcome data for BMI,Hb A1c,and Hb A1c obtained from the GWAS conducted by Biobank Japan（BBJ）,and was replicated using the Japan public health center-based prospective study（JPHC）and the Tohoku Medical Megabank Project（TMM）dataset（consisting of 173,430 individuals）were replicated with PCOS data from the GWAS in China,a cohort consisting of 4,386PCOS cases and 8,017 controls.Single Nucleotide Polymorphisms（SNPs）loci significantly associated with BMI and Hb A1c(P<5×10^-8)were selected as genetic instrumental variables.Finally,78 SNPs strongly associated with BMI and 31 SNPs strongly associated with Hb A1c were included as instrumental variables.Data were analyzed using the Inverse-Variance Weighted（IVW）method,with Odds Ratio（OR）as the main effect indicator and containing 95%Confidence Interval（CI）.Further sensitivity analyses included MR-Egger regression,weighted median estimation,and leave-one-out analysis.ResultsThe results of MR analysis were:there was a significant correlation between BMI and the risk of PCOS,IVW OR=2.208(95%CI:1.537-3.168,P=1.77×10^-5);reverse MR IVW OR=0.998（95%CI:0.998-1.009,P=0.77）,indicating that there is no clear causal relationship between PCOS and BMI.There is a clear causal relationship between Hb A1c and PCOS,IVW OR=1.377（95%CI=1.034-1.835,P=0.029）.In the subsequent analysis of different pathways affecting Hb A1c,the results showed that there is a causal relationship between the blood glucose pathway and PCOS:OR=1.390（95%CI:1.008-1.914,P=0.045）;there is a strong causal relationship between the red blood cell pathway and PCOS:OR=1.766（95%CI:1.059-2.951,P=0.029）.Further analysis of red blood cell related indicators,the results show that the mean corpuscular hemoglobin concentration（MCHC）and PCOS have a causal relationship:OR=0.728（95%CI:0.532-0.995,P=0.046）,MCHC is a protective factor for PCOS.Red blood cell count（Red Blood Cell,RBC）,mean corpuscular volume（MCV）and mean corpuscular hemoglobin（MCH）have no clear causal relationship with PCOS.Sensitivity analysis showed that after multiple tests,none of the genetic risk variant sites used in this study can be confirmed to be associated with PCOS alone.ConclusionThe results show that BMI and Hb A1c are causally related to PCOS.BMI and Hb A1c are risk factors for the onset of PCOS;on the contrary,PCOS is not a risk factor for BMI and Hb A1c;Hb A1c-related blood glucose and red blood cell pathways are causally related to PCOS,and the red blood cell pathway is more correlated;further analysis of the correlation between red blood cell-related RBC,MCV,MCH,MCHC and PCOS shows that only MCHC is related to PCOS and is a protective factor for PCOS.Other factors have no causal relationship with PCOS.This study provides further genetic support for the link between BMI,Hb A1c,MCHC and PCOS.However,further research is needed to explain the underlying mechanism of this association.