前瞻性和孟德尔随机化分析循环脂肪酸结合蛋白 4（FABP-4）与结直肠癌风险的关联。
Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer.
机构信息
Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Department Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany.
出版信息
BMC Med. 2023 Oct 13;21(1):391. doi: 10.1186/s12916-023-03104-1.
BACKGROUND
Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach.
METHODS
The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry.
RESULTS
In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37).
CONCLUSIONS
Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.
背景
脂肪酸结合蛋白 4（FABP-4）是一种脂肪结合的脂肪因子，在肥胖症中上调，它可能促进脂肪酸供应肿瘤生长，并促进胰岛素抵抗和炎症，因此可能在结直肠癌（CRC）的发展中发挥作用。我们旨在通过孟德尔随机化（MR）方法研究循环 FABP-4 与 CRC 之间的关联，并评估潜在的因果关系。
方法
在欧洲前瞻性癌症与营养研究（EPIC）队列中，对 1324 例 CRC 病例和相同数量的匹配对照进行了嵌套病例对照研究，以调查 FABP-4 术前血浆测量与 CRC 风险之间的关联。基于已发表的全基因组关联研究（发现 n=20,436）中鉴定出的与循环 FABP-4 相关的三个遗传变异（1 个顺式，2 个反式）进行了两样本孟德尔随机化研究，该研究的数据来自遗传与流行病学结直肠癌联合会、结直肠肿瘤跨学科研究和结肠癌家族登记处的 58,131 例 CRC 病例和 67,347 例对照。
结果
在调整了包括身体大小在内的潜在混杂因素的条件逻辑回归模型中，FABP-4 浓度每增加一个标准差（8.9ng/mL），总体估计的相对风险，RR（95%置信区间，CI）为 1.01（0.92,1.12），男性为 0.95（0.80,1.13），女性为 1.09（0.95,1.25）。然而，在顺式-MR 方法中，在女性中观察到统计学上显著的关联（RR 为 1.56，1.09，2.23），而不是总体（RR 为 1.23，0.97，1.57）或男性（0.99，0.71，1.37）。
结论
综上所述，这些分析结果不支持循环 FABP-4 在 CRC 发展中起因果作用，尽管顺式-MR 提供了一些女性中阳性关联的证据，但这可能值得进一步研究。
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