Discussion
In the present MR study, we systematically assessed the causal associations of a broad range of lifestyle factors with the risk of OC by histologic subtypes. We found genetically determined years of education to be inversely associated with overall OC, and subtypes of LMSOC, HGSOC, IMOC, LGSOC, and EOC. The associations of education with risk of all OC, HGSOC, IMOC, and LMSOC were independent of BMI. Genetic liability to higher coffee or tea consumption was positively associated with the risk of EOC, which may partly mediated by BMI. Our results further showed that increased dietary fat intake was positively associated with HGSOC, but inversely and independently associated with EOC. Genetic predisposition to a higher BMI was associated with an increased risk of LMSOC, LMMOC, and EOC. Although little clear evidence supports the role of smoking initiation in ovarian carcinogenesis, elevated lifetime smoking index was positively associated with overall OC, HGSOC, and EOC. In contrast, there was limited evidence for causal associations of physical activities, alcohol drinking, sleep duration, and insomnia with any type of OC.
Education level is a concerned social determinant and has been proposed as a modifiable risk factor for a number of diseases. An understanding of the causal links from education level to health outcomes may help disease prevention. A recent observational study reported that the incidence of borderline ovarian tumors decreased in women with a high educational level [4]. Our study found that genetically predicted higher education level was causally and independently associated with lower risks of many OC subtypes, further suggesting the protective effect of educational attainment on OC development. Possible pathways may link education level to OC prevention. Firstly, modifiable risk factors have been reported largely mediates the educational effects on diseases. Moreover, high level of education is more likely to drive positive health-related behaviors and thus reduce the risk of OC. [38]. The associations between education and OC subtypes were attenuated in the multivariable MR analysis with adjustment for genetically predicted BMI and lifetime smoking index liability, which may suggest that BMI and lifetime smoking index partly mediate the associations.
Studies have not demonstrated either an overall protective or detrimental effect on OC development in coffee or tea drinkers. In previous observational analyses, the RR estimates of coffee or tea consumption were significantly heterogeneous, with individual studies suggesting positive [5], [6], [39]–[41], null [8], [42]–[45], and inverse [7], [45]–[48] associations with OC risk. Inconsistencies observed in the literature may be due to the interference of confounders, lack of compatibility of categorical definitions, and differences in definitions for baseline groups. Our study is the first to use MR analyses to explore the relationship between coffee or tea consumption with OC histotypes. In the subtype analyses, we found evidence for a positive association between endometrioid OC risk and genetically predicted coffee intake levels. Similarly, a suggestive increased risk was only observed in the endometrioid subtype in the tea consumption analyses. The etiology of endometrioid OC resulting from coffee or tea consumption warrants to be established. The major endometriosis mechanism in OC is estrogen-dependent, endometriosis acts as a precursor for OC, which is easily developed in the low-progesterone and high-estrogen conditions [49]. The intake of caffeine and caffeine-containing beverages has been positively associated with estrone and sex hormone-binding globulin concentrations and inversely with bioavailable testosterone [50], [51]. These hormonal changes may influence hormone-dependent diseases. Therefore, caffeine intake has been associated with the risk of endometriosis and has been hypothesized to exert its effects through the alteration of endogenous hormone levels [52]. Our findings of an increased risk for endometrioid carcinoma in coffee or tea drinkers are consistent with the hormonally mediated hypothesis.
The current knowledge on the association between dietary fat intake and OC was inconclusive. Pooled analyses of observational studies have reported positive [9] or null [53] association between fat intake and overall OC risk, however, there were limited data for the OC subtypes. Although we found no indication of a causal effect of relative fat intake on overall OC risk, a persistent borderline association was observed between fat intake and HGSC, which was corroborated with the findings that serous ovarian cancer was more susceptible to dietary fat consumption than other subtypes [53]. Due to the pathological specificity of endometrioid OC and the composition of dietary fat, our result of an inverse association between relative fat intake and this subtype may get support from a prospective study that higher intake of omega-3 may be protective for OC overall and endometrioid tumors in particular [54]. Further MR analyses for the effects of dietary fat components on OC subtypes are needed.
BMI has been associated with OC in observational studies [14], [55]. However, the effect of BMI increase on the etiology of histological subtypes of OC remains controversial [56] [57]. In our analyses with updated GWAS studies including 583 BMI SNPs and 25,509 OC cases, which may afford the analysis greater instrument strength and greater statistical power to detect effects, we observed positive associations of genetically predicted BMI with LMSOC, LMMOC, and EOC, which complemented the findings from previous observational studies [14]. A high BMI has been linked to benign ovarian tumors, the evidence from epidemiological, histopathological, and molecular studies suggests that borderline tumors may develop from benign tumors [58], [59]. This theory of progression for borderline tumors is supported by our finding that low malignant potential tumors were associated with BMI, but not high-grade cancers.
The association between physical activity and OC risk remains less clear. It has been hypothesized from previous meta-analysis of observational studies that physical activity may protect against the development of OC [12], [60], [61], whereas positive or null associations were found from time to time [11], [13], [62]. Across studies, the findings are inconclusive especially when considering histologic type [13], [63], indicating that this issue needs to be resolved. We identified no causal relationship for overall acceleration average, self-reported MVPA, and VPA, with overall OC by MR analyses, which supported the findings from three large prospective studies including up to 96,216 participants showing that MVPA, VPA, or overall physical activity were not independently associated with reduced risk of OC [10], [11], [62]. In this study, we further showed that physical activities do not affect the risk of OC subtypes, which contributed to the knowledge regarding the evaluation of lifestyle behaviors on OC histotypes incidence.
Studies of the association of smoking with the risk of OC have not been entirely consistent. [17], [64], [65]. One reason for the variation in these results may be the different methods employed to assess and analyze these measures of smoking exposure. Here we improve our study by using two sets of instruments for smoking [28]. Our analyses by OC histological subtypes demonstrated limited associations between smoking initiation and OC subtypes. However, we found that the lifetime smoking index is suggestively associated with overall OC, HGSOC, and EOC subtypes. Although smoking has been strongly linked to mucinous OC in previously pooled analyses, we didn’t observe a consistent result. However, we still emphasize that independent GWAS and large prospective studies by OC subtypes are warranted to further validate our findings in other cohorts and ethnicities.
Results from epidemiological studies on the association between alcohol drinking and OC risk are inconsistent, reporting either a null association [66]–[69], a positive association [70], or a negative association [71], [72]. A recent study focused on overall OC and alcohol consumption, including single instrument MR using rs1229984 and multiple instruments MR using 34 SNPs, showed no causal evidence of association [15]. In our subtype analyses with 83 SNPs, we further found no causal effect of alcohol drinking on the development of OC histotypes, which complement findings of overall OC from previous studies.
Sleeping disorders are associated with the poor quality of life of women suffering from OC. However, there are limited data about the effect of sleeping disorders and lack of a proper amount of sleep on the occurrence of OC. A previous prospective study reported a null association between sleep duration and OC risk [18]. A recent observational study also shows no association between sleep duration, sleep quality, or insomnia with the risk of overall OC among postmenopausal women. Nevertheless, in subtype analyses, restful sleep quality was associated with a lower risk of invasive serous OC, and insomnia was associated with a higher one [19]. In our MR analyses by using up to 74 and 702 SNPs, we didn’t observe a causal effect of sleep duration or insomnia on the development of any type of OC.
The major strengths of the present study are the MR design, the systematic assessment of multiple lifestyle factors, and the inclusion of well-classified OC subtypes. MR design strengthened the causal inference by diminishing residual confounding and other biases. In addition, consistent results from several sensitivity analyses guaranteed the robustness of our findings. Our analysis was confined to individuals of European ancestry, which largely diminished population stratification bias. However, the population confinement might limit the generalization of our findings to other populations. Limitations in our study need consideration. Although indicative pleiotropy was observed in a few analyses of BMI by the MR-Egger regression, several aspects of our results suggested a minimal probability that pleiotropy would bias our results, including a few outliers detected in the MR-PRESSO analysis and consistent results from multiple sensitivity models. In addition, we were unable to examine possible pre- and post-menopausal differences in associations of studied exposures with OC due to a lack of menopause data. However, given that most OC cases occur after menopause and that age-matched controls were used, the inclusion of some pre- or perimenopausal women in these analyses would less likely have biased results. Finally, further experimental studies to reveal the possible mechanisms, through which factors that appear to influence OC in these analyses, could help to expand the scope for prevention opportunities across the life course.