Zollner Linda, Boekstegers Felix, Barahona Ponce Carol, Scherer Dominique, Marcelain Katherine, Gárate-Calderón Valentina, Waldenberger Melanie, Morales Erik, Rojas Armando, Munoz César, Retamales Javier, De Toro Gonzalo, Kortmann Allan Vera, Barajas Olga, Rivera María Teresa, Cortés Analía, Loader Denisse, Saavedra Javiera, Gutiérrez Lorena, Ortega Alejandro, Bertrán Maria Enriqueta, Bartolotti Leonardo, Gabler Fernando, Campos Mónica, Alvarado Juan, Moisán Fabricio, Spencer Loreto, Nervi Bruno, Carvajal Daniel, Losada Héctor, Almau Mauricio, Fernández Plinio, Olloquequi Jordi, Carter Alice R, Miquel Poblete Juan Francisco, Bustos Bernabe Ignacio, Fuentes Guajardo Macarena, Gonzalez-Jose Rolando, Bortolini Maria Cátira, Acuña-Alonzo Victor, Gallo Carla, Ruiz Linares Andres, Rothhammer Francisco, Lorenzo Bermejo Justo
Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany.
Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany.
Cancers (Basel). 2023 Aug 9;15(16):4033. doi: 10.3390/cancers15164033.
A strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, = 6.7 × 10) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate -0.006 kg/m, 95% CI -0.009 to -0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.
观察性研究报告称，南美洲本土马普切人血统比例与胆囊癌（GBC）风险之间存在密切关联。智利人的GBC发病率在全球最高，而马普切人是智利最大的原住民群体。我们旨在评估马普切人血统个体比例对GBC风险的无混杂效应，并研究胆结石疾病和体重指数（BMI）在这种关联中的中介作用。基于赋值测量的信息量选择马普切人血统的基因标记，然后将其用作两样本孟德尔随机化分析和补充敏感性分析中的工具变量。结果表明，马普切人血统对GBC风险可能存在因果效应（马普切人血统比例每增加1%，逆方差加权（IVW）风险增加0.8%，95%置信区间为0.4%至1.2%，P = 6.7×10），对胆结石疾病也有影响（IVW风险增加3.6%，95%置信区间为3.1%至4.0%），这表明胆结石在马普切人血统与GBC的关联中起中介作用。相比之下，马普切人血统比例对BMI有负面影响（IVW估计值为-0.006 kg/m²，95%置信区间为-0.009至-0.003）。本文给出的结果可能对GBC预防具有重要意义，对未来的混合映射研究也很重要。鉴于观察性研究中先前指出的马普切人血统个体比例与GBC风险之间的关联似乎没有混杂因素，考虑遗传血统的一级和二级预防策略可能特别有效。
