Genetically Predicted Cigarette Smoking in Relation to Risk of Polycystic Ovary Syndrome

Abstract

Background Evidence from observational studies has suggested a link between cigarette smoking and the risk of polycystic ovary syndrome (PCOS). However, it remains uncertain whether the observed relationship is causal or due to biases inherent in observational studies. Therefore, we adopted two-sample Mendelian randomization (MR) design to assess the potential causal association between smoking and the risk of PCOS. Methods Summary level data of PCOS was obtained from a genome-wide association study (GWAS) meta-analysis including 4,138 cases and 20,129 controls of European ancestry. Single-nucleotide polymorphisms (SNPs) associated with smoking initiation (n=360) were selected and used as genetic instrumental variables (IVs). MR analysis was performed using inverse-variance weighted (IVW) method, supplemented with the likelihood-based method, weighted median method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, and MR-Egger regression. Results Genetically predicted smoking initiation was associated with an increased risk of PCOS in the primary analysis (odds ratio (OR) =1.38, 95% confidence interval (CI) =1.12–1.69). MR-Egger regression did not detect the horizontal pleiotropy. Sensitivity analyses using alternative MR methods and restricted IVs produced similar results. Conclusion Our study provided evidence to support a potential causal association between smoking initiation and an increased risk of PCOS, providing a better understanding of the etiology and prevention of PCOS. Further studies are warranted to clarify the underlying biological mechanisms of smoking in the development of PCOS.

Causal relationships between modifiable risk factors and polycystic ovary syndrome: a comprehensive Mendelian randomization study

“…Furthermore, substantial evidence suggests that nicotine and smoking can reduce estrogen levels by inhibiting aromatase activity, thereby potentially affecting metabolic disturbances and hyperandrogenism in PCOS women ( 40 ). In contrast to previous MR analyses on smoking and PCOS ( 41 ), our study not only established a relationship between smoking initiation and PCOS but also revealed a close association between smoking per day and PCOS. Our research results aligned with most observational studies, providing causal evidence for the link between smoking and PCOS.…”

Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies

“…After exclusion of studies using overlapping or same outcome data, 29 articles based on non-overlapping populations were eligible for inclusion in one or more meta-analyses. The number of studies included in each outcome category was seven for circulatory system diseases, 4 , 5 , 6 , 7 , 8 , 9 , 10 six for digestive system diseases, 11 , 12 , 13 , 14 , 15 , 16 six for nervous system diseases, 17 , 18 , 19 , 20 , 21 three for musculoskeletal system outcomes, 22 , 23 , 24 two for endocrine and metabolic diseases, 25 , 26 two for eye diseases, 27 , 28 and four for neoplasms. 29 , 30 , 31 , 32 In addition to the included studies, 123 de novo MR analyses ( n =51 for smoking initiation, n = 72 for lifetime smoking) were conducted.…”

“…During the last few years, the potential causal association between smoking and risk of different diseases has been investigated using the Mendelian randomization (MR) approach. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 MR is a method that utilizes genetic variants associated with a difference in the exposure (e.g., smoking liability) as instrumental variable for the exposure to determine the causal role of the exposure in the development of disease. 33 The MR design mitigates confounding because genetic alleles are randomly allocated when passed from parents to offspring and therefore usually not related to other risk factors.…”

Lifestyle management in polycystic ovary syndrome – beyond diet and physical activity

“…Smoking is also associated with PCOS risk independent of BMI and age [ 142 ]. A Mendelian randomisation study supports these findings, demonstrating a 38% higher risk of PCOS development in genetically predicted smokers (based on single-nucleotide polymorphisms associated with smoking initiation) compared with those who never smoked [ 143 ]. In PCOS, smoking is associated with increased levels of T, DHEAS, TC, LDL-C and FINS [ 141 , 144 , 145 ].…”