Constantinescu Andrei-Emil, Bull Caroline J, Jones Nicholas, Mitchell Ruth, Burrows Kimberley, Dimou Niki, Bézieau Stéphane, Brenner Hermann, Buchanan Daniel D, D'Amato Mauro, Jenkins Mark A, Moreno Victor, Pai Rish K, Um Caroline Y, White Emily, Murphy Neil, Gunter Marc, Timpson Nicholas J, Huyghe Jeroen R, Vincent Emma E
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
Int J Cancer. 2024 Jan 1;154(1):94-103. doi: 10.1002/ijc.34691. Epub 2023 Aug 14.
Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.
观察性研究表明嗜酸性粒细胞在结直肠癌（CRC）发生中具有保护作用，并涉及中性粒细胞，但因果关系仍不清楚。在此，我们旨在使用孟德尔随机化（MR）估计循环白细胞（WBC）计数（N =约550000）中的嗜碱性粒细胞、嗜酸性粒细胞、单核细胞、淋巴细胞和中性粒细胞对CRC风险（N = 52775例病例和45940例对照）的因果效应。为作比较，我们还在一项纵向队列分析中使用英国生物银行的个体水平数据（4043例新发CRC病例和332773例对照）来研究这种关系。逆方差加权（IVW）MR分析表明，嗜碱性粒细胞计数和嗜酸性粒细胞计数增加对CRC风险具有保护作用[每增加1个标准差的OR：0.88，95%CI：0.78 - 0.99，P = 0.04；OR：0.93，95%CI：0.88 - 0.98，P = 0.01]。在使用多变量MR对所有其他WBC亚型进行调整以考虑性状之间的遗传相关性后，嗜酸性粒细胞的保护作用仍然存在[每增加1个标准差的OR：0.88，95%CI：0.80 - 0.97，P = 0.01]。在调整后还发现淋巴细胞计数增加对CRC风险具有保护作用[OR：0.84，95%CI：0.76 - 0.93，P = 6.70×10⁻⁴]。与MR结果一致，在完全调整模型的队列分析中嗜酸性粒细胞具有保护作用[每增加1个标准差的RR：0.96，95%CI：0.93 - 0.99，P = 0.02]，并且在对其他WBC亚型进行调整后[RR：0.96，95%CI：0.93 - 0.99，P = 0.001]也观察到这种作用。我们的研究表明外周血免疫细胞，特别是嗜酸性粒细胞和淋巴细胞，参与了结直肠癌的发生，强调需要进行机制研究来探究这些关系。
