Mechanisms underlying adiposity–colorectal cancer (CRC) association are incompletely understood. Using UK Biobank data, we investigated the role of C‐reactive protein (CRP), hemoglobin‐A1c (HbA1c) and (jointly) sex hormone‐binding globulin (SHBG) and testosterone, in explaining this association. Total effect of obesity versus normal‐weight (based on waist circumference, body mass index, waist–hip ratio) on CRC risk was decomposed into natural direct (NDE) and indirect (NIE) effects using sequential mediation analysis. After a median follow‐up of 7.1 years, 2070 incident CRC cases (men = 1,280; postmenopausal women = 790) were recorded. For men, the adjusted risk ratio (RR) for waist circumference (≥102 vs . ≤94 cm) was 1.37 (95% confidence interval [CI], 1.19–1.58). The RRs^NIE were 1.08 (95% CI: 1.01–1.16) through all biomarkers, 1.06 (95% CI: 1.01–1.11) through pathways influenced by CRP, 0.99 (95% CI: 0.97–1.01) through HbA1c beyond (the potential influence of) CRP and 1.03 (95% CI: 0.99–1.08) through SHBG and testosterone combined beyond CRP and HbA1c. The RR^NDE was 1.26 (95% CI: 1.09–1.47). For women, the RR for waist circumference (≥88 vs . ≤80 cm) was 1.27 (95% CI: 1.07–1.50). The RRs^NIE were 1.08 (95% CI: 0.94–1.22) through all biomarkers, 1.08 (95% CI: 0.99–1.17) through CRP, 1.00 (95% CI: 0.98–1.02) through HbA1c beyond CRP and 1.00 (95% CI: 0.92–1.09) through SHBG and testosterone combined beyond CRP and HbA1c. The RR^NDE was 1.18 (95% CI: 0.96–1.45). For men and women, pathways influenced by CRP explained a small proportion of the adiposity‐CRC association. Testosterone and SHBG also explained a small proportion of this association in men. These results suggest that pathways marked by these obesity‐related factors may not explain a large proportion of the adiposity‐CRC association.

中文翻译：

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解释英国生物库中男性和绝经后女性肥胖与结直肠癌风险之间的联系：序贯因果中介分析。


肥胖与结直肠癌（CRC）关联的潜在机制尚不完全清楚。利用英国生物银行的数据，我们研究了 C 反应蛋白 (CRP)、糖化血红蛋白 (HbA1c) 以及（联合）性激素结合球蛋白 (SHBG) 和睾酮的作用，以解释这种关联。使用序贯中介分析，肥胖与正常体重（基于腰围、体重指数、腰臀比）对 CRC 风险的总影响被分解为自然直接（NDE）和间接（NIE）影响。经过中位随访 7.1 年，记录了 2070 例 CRC 病例（男性 = 1,280 例；绝经后女性 = 790 例）。对于男性，腰围（≥102 厘米与≤94 厘米）的调整后风险比 (RR) 为 1.37（95% 置信区间 [CI]，1.19–1.58）。所有生物标志物的 RR ^NIE为 1.08 (95% CI: 1.01–1.16)，受 CRP 影响的途径为 1.06 (95% CI: 1.01–1.11)，HbA1c 超出（潜在水平）为 0.99 (95% CI: 0.97–1.01)。通过 SHBG 和睾酮组合超越 CRP 和 HbA1c，对 CRP 和 1.03 (95% CI: 0.99–1.08) 的影响。 RR ^NDE为 1.26（95% CI：1.09–1.47）。对于女性，腰围（≥88与≤80 cm）的 RR 为 1.27（95% CI：1.07–1.50）。所有生物标志物的 RR ^NIE为 1.08 (95% CI: 0.94–1.22)，CRP 为 1.08 (95% CI: 0.99–1.17)，CRP 之外的 HbA1c 为 1.00 (95% CI: 0.98–1.02)，HbA1c 为 1.00 (95% CI)。 CI：0.92–1.09）通过 SHBG 和睾酮组合超越 CRP 和 HbA1c。 RR ^NDE为 1.18（95% CI：0.96–1.45）。对于男性和女性来说，受 CRP 影响的途径解释了一小部分肥胖与结直肠癌关联。睾酮和性激素结合球蛋白也解释了男性中这种关联的一小部分。 这些结果表明，以这些肥胖相关因素为标志的途径可能无法解释大部分肥胖与结直肠癌的关联。