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. 2023 Dec 20;43(12):1989-1997.
doi: 10.12122/j.issn.1673-4254.2023.12.01.

[Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study]

[Article in Chinese]
H Zhao  1 , Y Ling  2 , S Mi  3 , J Zhu  1 , J Fan  4 , Y Yang  1 , J Wang  1 , Y Li  1
Affiliations

[Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study]

[Article in Chinese]
H Zhao et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer.

Methods: We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People's Hospital, and Lin'an District First People's Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer.

Results: High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P < 0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P < 0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05).

Conclusion: Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer.

目的: 探究Leptin循环水平与结直肠腺瘤及结直肠癌发生风险的关联，为结直肠腺瘤及结直肠癌的防治提供依据。

方法: 以浙江大学医学院附属第一医院、浙江省肿瘤医院、浙江省诸暨市人民医院及杭州市临安区第一人民医院为研究现场，共收集结直肠腺瘤患者497例，结直肠癌患者955例，健康对照911例。通过问卷收集研究对象的基本信息，并采集血液样本和提取DNA，选取Leptin的工具变量并进行基因分型检测。采用Logistic回归模型并进行分层分析，评估血清Leptin水平与结直肠腺瘤，结直肠癌以及结直肠腺瘤进展为结直肠癌的关联。进一步将遗传风险评分（GRS）和单核苷酸多态性（SNPs）作为工具变量，采用两阶段最小二乘法和逆方差加权法进行单样本和两样本孟德尔随机化分析，来评估Leptin循环水平与结直肠腺瘤，结直肠癌及结直肠腺瘤进展为结直肠癌风险之间潜在的因果关联。

结果: 病例对照研究结果显示，与最低四分数的Leptin水平相比，高水平的Leptin与结直肠腺瘤呈正相关（OR=1.63，95% CI：1.16~2.30，P=0.005），高水平的Leptin与结直肠癌呈负相关（OR=0.53，95% CI：0.38~0.74，P < 0.001），高水平的Leptin也与结直肠腺瘤患者进展为结直肠癌的风险呈负相关（OR=0.44，95% CI：0.29~0.66，P < 0.001）。而孟德尔随机化分析结果显示，Leptin的GRS无论是否加权，均与结直肠腺瘤，结直肠癌以及结直肠腺瘤进展为结直肠癌的风险无统计学关联。两样本孟德尔随机化研究也未发现Leptin与结直肠癌风险之间的关联（P>0.05）。

结论: 病例对照研究结果提示Leptin可能与结直肠腺瘤，结直肠癌及结直肠腺瘤进展为结直肠癌的风险存在关联，但孟德尔随机化研究尚不支持Leptin与结直肠腺瘤，结直肠癌及结直肠腺瘤进展为结直肠癌风险之间存在因果关联。

Keywords: Mendelian randomization; colorectal adenoma; colorectal cancer; leptin.

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