Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Endocrinol (Lausanne). 2022 Feb 3;12:742411. doi: 10.3389/fendo.2021.742411. eCollection 2021.
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. However, whether UA is causally induced by BMI and functioned in the BMI-breast cancer relationship remains unclear.
To 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.
In 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), < 0.001], but not vice versa. In the DFTJ cohort, each standard deviation (SD) increment in BMI (3.5 kg/m) 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.
The 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.
观察性流行病学研究报告称，高体重指数（BMI）与血清尿酸（UA）水平升高和绝经后乳腺癌风险增加有关。然而，UA 是否由 BMI 引起以及是否在 BMI-乳腺癌关系中起作用尚不清楚。
为了阐明 BMI 和血清 UA 之间的因果关系方向，我们使用来自超过 150,000 名日本人群的最大亚洲全基因组关联研究（GWAS）中汇总的 BMI 和 UA 的双向 Mendelian 随机化（MR）分析数据进行分析。然后，我们共纳入 19,518 名来自东风-同济（DFTJ）队列的绝经后妇女（平均随访 8.2 年），并使用多变量 Cox 比例风险回归模型分析 BMI 和血清 UA 与绝经后乳腺癌发病风险的相关性。在 DFTJ 队列中进一步进行中介分析，以评估血清 UA 在 BMI-乳腺癌关联中的中间作用。
在双向 MR 分析中，我们观察到遗传决定的 BMI 与血清 UA 升高有关[β（95% CI）= 0.225（0.111，0.339），< 0.001]，但反之则不然。在 DFTJ 队列中，BMI（3.5 kg/m）和 UA（75.4 μmol/l）每增加一个标准差（SD），绝经后乳腺癌的风险分别增加 24%和 22%[HR（95% CI）= 1.24（1.07，1.44）和 1.22（1.05，1.42）]。更重要的是，血清 UA 可以介导 BMI 与绝经后乳腺癌发病之间 16.9%的关联。
本研究结果表明 BMI 对血清 UA 升高有因果作用，并强调了 UA 在 BMI-乳腺癌关系中的中介作用。控制超重绝经后妇女的血清 UA 水平可能有助于降低其乳腺癌发病风险。
