Abstract
BackgroundObservational epidemiological studies have reported the associations of high body mass index (BMI) with elevated serum uric acid (UA) level and increased risk of postmenopausal breast cancer. However, whether UA is causally induced by BMI and functioned in the BMI–breast cancer relationship remains unclear.MethodsTo elucidate the causality direction between BMI and serum UA, the bidirectional Mendelian randomization (MR) analyses were performed by using summarized data from the largest Asian genome-wide association studies (GWAS) of BMI and UA carried out in over 150,000 Japanese populations. Then, a total of 19,518 postmenopausal women from the Dongfeng–Tongji (DFTJ) cohort (with a mean 8.2-year follow-up) were included and analyzed on the associations of BMI and serum UA with incidence risk of postmenopausal breast cancer by using multivariable Cox proportional hazard regression models. Mediation analysis was further conducted among DFTJ cohort to assess the intermediate role of serum UA in the BMI–breast cancer association.ResultsIn the bidirectional MR analyses, we observed that genetically determined BMI was causally associated with elevated serum UA [β(95% CI) = 0.225(0.111, 0.339), p < 0.001], but not vice versa. In the DFTJ cohort, each standard deviation (SD) increment in BMI (3.5 kg/m2) and UA (75.4 μmol/l) was associated with a separate 24% and 22% increased risk of postmenopausal breast cancer [HR(95% CI) = 1.24(1.07, 1.44) and 1.22(1.05, 1.42), respectively]. More importantly, serum UA could mediate 16.9% of the association between BMI and incident postmenopausal breast cancer.ConclusionsThe current findings revealed a causal effect of BMI on increasing serum UA and highlighted the mediating role of UA in the BMI–breast cancer relationship. Controlling the serum level of UA among overweight postmenopausal women may help to decrease their incident risk of breast cancer.
Highlights
Breast cancer is the most commonly diagnosed cancer (2.3 million, 11.7% of the total cancer cases) and the leading cause of cancer deaths among females (0.7 million, 15.0% of the total cancer deaths) [1]
The inverse-variance weighted (IVW) method by using 76 BMIrelated singlenucleotide polymorphism (SNP) as instrument variable (IV) revealed that the genetically predicted increase of body mass index (BMI) was causally associated with elevated serum Uric acid (UA) [b = 0.183 (0.118, 0.248), p < 0.001] (Table 1)
To attenuate the impact of pleiotropy, we excluded 44 SNPs significantly associated with traits other than BMI (Table S2), and the Mendelian randomization (MR) analysis by using the left 32 SNPs still yielded a significant causal effect of BMI on serum UA [IVW method, b = 0.225 (0.111, 0.339) and p < 0.001] (Table 1)
Summary
Breast cancer is the most commonly diagnosed cancer (2.3 million, 11.7% of the total cancer cases) and the leading cause of cancer deaths among females (0.7 million, 15.0% of the total cancer deaths) [1]. As summarized in a meta-analysis of 34 prospective studies with more than 2.5 million females all over the world, higher body mass index (BMI) was observed to be associated with decreased breast cancer risk among premenopausal women but with increased breast cancer risk among postmenopausal women [4]. A cross-sectional epidemiology study has reported a positive association between serum UA and BMI among 144,856 Chinese aged 20 to 79 years [6]. Another longitudinal study among 2,611 young black and white adults revealed that baseline BMI was positively related to a 10-year change in serum UA [7]. Observational epidemiological studies have reported the associations of high body mass index (BMI) with elevated serum uric acid (UA) level and increased risk of postmenopausal breast cancer. Whether UA is causally induced by BMI and functioned in the BMI–breast cancer relationship remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
