Dataset Information

The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study.

ABSTRACT: The association between polycystic ovary syndrome (PCOS) and endometrial cancer remains unclear. We aimed to investigate the causal association between genetically predicted PCOS and endometrial cancer risk in two ethnic groups through a two-sample Mendelian randomization (MR) approach. Our study includes 13 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for PCOS in Europeans, and another 13 SNPs are used as IVs for PCOS in Asians. Outcome data were obtained from the largest published meta-GWAS of European ancestry to date, as well as from the BioBank Japan Project of Asian ancestry. Our study demonstrates that genetically predicted PCOS is not causally associated with the risk of overall endometrial cancer in either Europeans or Asians (odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.85-1.01, p = 0.09 and OR = 0.98, 95% CI 0.84-1.13, p = 0.75, respectively). Subgroup analyses according to histotype further illustrate that PCOS might not be associated with the risk of either endometrioid endometrial cancer or non-endometrioid endometrial cancer in European ancestry. No pleiotropy is found in our study, and a sensitivity analysis shows similar results. Our results indicate that genetically predicted PCOS might not be associated with the risk of endometrial cancer.

SUBMITTER: Chen H

PROVIDER: S-EPMC8602912 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study.

Chen Hanxiao H Zhang Yaoyao Y Li Shangwei S Tao Yuanzhi Y Gao Rui R Xu Wenming W Yang Yihong Y Cheng Kemin K Wang Yan Y Qin Lang L

Frontiers in endocrinology 20211105

The association between polycystic ovary syndrome (PCOS) and endometrial cancer remains unclear. We aimed to investigate the causal association between genetically predicted PCOS and endometrial cancer risk in two ethnic groups through a two-sample Mendelian randomization (MR) approach. Our study includes 13 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for PCOS in Europeans, and another 13 SNPs are used as IVs for PCOS in Asians. Outcome data were obtained from the larg ...[more]

PMID: 34803918

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Project description:BackgroundPolycystic ovary syndrome (PCOS) is a multifaceted endocrine and metabolic syndrome with complex origins and pathogenesis that has not yet been fully elucidated. Recently, the interconnection between gut microbiota and metabolic diseases has gained prominence in research, generating new insights into the correlation between PCOS and gut microbiota composition. However, the causal link between PCOS and gut microbiota remains relatively unexplored, indicating a crucial gap in current research.MethodsWe conducted a two-sample Mendelian randomization analysis using summary statistics obtained from the MiBioGen Consortium's extensive genome-wide association studies (GWAS) meta-analysis, focusing on the gut microbiota. Summary statistics for PCOS were acquired from the FinnGen Consortium R7 release data. Various statistical approaches, including inverse variance weighted, MR-Egger, maximum likelihood, weighted model, and weighted median, have been employed to investigate the causal association between the gut microbiota and PCOS. Additionally, we performed a reverse causal analysis. Cochran's Q statistic was used to assess the heterogeneity of the instrumental variables. Regarding the relationships between PCOS and specific genera within the gut microbiota, a significance level of P < 0.05 was observed, but only when q ≥ 0.1.ResultsOur analysis revealed that specific microbial genera, namely Bilophila (P = 4.62 × 10-3), Blautia (P = 0.02), and Holdemania (P = 0.04), displayed a protective effect against PCOS. Conversely, the presence of the Lachnospiraceae family of bacteria was associated with a detrimental effect on PCOS (P = 0.04). Furthermore, reverse Mendelian randomization analysis confirmed the significant influence of Lachnospiraceae on PCOS. No significant variations in instrumental variables or evidence of horizontal pleiotropy were observed.ConclusionsThe results revealed a definitive causal link between PCOS and the presence of Bilophila, Blautia, Holdemania, and Lachnospiraceae in the gut microbiota. This discovery could provide pivotal insights, leading to novel preventive and therapeutic approaches for PCOS.

Project description:BackgroundPolycystic ovary syndrome (PCOS) is defined by oligo/anovulation, hyperandrogenism, and polycystic ovaries with uncertain pathogenesis. The proteome represents a substantial source of therapeutic targets, and their coding genes may elucidate the mechanisms underlying PCOS. However, reports on the profiles of the human plasma protein-coding genes and PCOS are limited. Here, we aimed to investigate novel biomarkers or drug targets for PCOS by integrating genetics and the human plasma proteome.MethodsOur study acquired the protein quantitative trait loci from DECODE Genetics, offering 4,907 proteins in 35,559 individuals while obtaining PCOS summary statistics by accessing the FinnGen biobank (1,639 cases and 218,970 controls) and the genome-wide association study catalog (797 cases and 140,558 controls). Herein, we sequentially used two-sample Mendelian randomization (MR) analyses and colocalization to verify the causal link between candidate proteins, their coding genes, and PCOS. Further PCOS data download was conducted by accessing the Gene Expression Omnibus and Zenodo platforms. Gene expression level analysis, pathway enrichment analysis, immune cell infiltration, and transcription factor prediction were performed, aiming at detecting specific cell types with enriched expression and exploring potential optimized treatments for PCOS.ResultsMR analysis revealed 243 protein-coding genes with a causal relationship to PCOS risk, of which 12 were prioritized with the most significant evidence. Through colocalization analysis, three key genes, CUB domain-containing protein 1 (CDCP1), glutaredoxin 2 (GLRX2), and kirre-like nephrin family adhesion molecule 2 (KIRREL2), were identified. Subsequently, the three genes were strongly related to immune function and metabolism in terms of biological significance. In single-cell analysis, the expression levels of genes in ovarian theca cells were explored.ConclusionOverall, three protein-coding genes (CDCP1, GLRX2, and KIRREL2) may be related to a higher PCOS risk, suggesting that they may be entry points for exploration of PCOS pathogenesis and treatment, warranting further clinical investigations.

Dataset Information

The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study.

Publications

The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study.

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