Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data

被引：56

作者：

Ponce, Carol Barahona ^{[1
,2
]}

Scherer, Dominique ^{[1
]}

Brinster, Regina ^{[1
]}

Boekstegers, Felix ^{[1
]}

Marcelain, Katherine ^{[2
]}

Garate-Calderon, Valentina ^{[1
,2
]}

Muller, Bettina ^{[3
]}

Toro, Gonzalo ^{[4
,5
]}

Retamales, Javier ^{[3
]}

Barajas, Olga ^{[2
,6
]}

Ahumada, Monica ^{[2
,6
]}

Morales, Erik ^{[7
,8
]}

Rojas, Armando ^{[9
]}

Sanhueza, Veronica ^{[10
]}

Loader, Denisse ^{[10
]}

Rivera, Maria Teresa ^{[11
]}

Gutierrez, Lorena ^{[12
]}

Bernal, Giuliano ^{[13
]}

Ortega, Alejandro ^{[14
]}

Montalvo, Domingo ^{[15
]}

Portino, Sergio ^{[2
,6
]}

Bertran, Maria Enriqueta ^{[16
]}

Gabler, Fernando ^{[17
]}

Spencer, Loreto ^{[18
]}

Olloquequi, Jordi ^{[19
]}

Fischer, Christine ^{[20
]}

Jenab, Mazda ^{[21
]}

Aleksandrova, Krasimira ^{[22
]}

Katzke, Verena ^{[23
]}

Weiderpass, Elisabete ^{[24
]}

Bonet, Catalina ^{[25
]}

Moradi, Tahereh ^{[26
]}

Fischer, Krista ^{[27
]}

Bossers, Willem ^{[28
]}

Brenner, Hermann ^{[29
,30
,31
]}

Hveem, Kristian ^{[32
,33
]}

Eklund, Niina ^{[34
]}

Volker, Uwe ^{[35
]}

Waldenberger, Melanie ^{[36
]}

Guajardo, Macarena Fuentes ^{[37
]}

Gonzalez-Jose, Rolando ^{[38
]}

Bedoya, Gabriel ^{[39
]}

Bortolini, Maria C. ^{[40
]}

Canizales-Quinteros, Samuel ^{[41
]}

Gallo, Carla ^{[42
]}

Ruiz-Linares, Andres ^{[43
,44
,45
,46
,47
]}

Rothhammer, Francisco ^{[37
]}

Bermejo, Justo Lorenzo ^{[1
]}

机构：

[1] Heidelberg Univ, Inst Med Biometry & Informat, Stat Genet Grp, Im Neuenheimer Feld 130-3, D-69120 Heidelberg, Germany

[2] Univ Chile, Med Fac, Dept Basic & Clin Oncol, Santiago, Chile

[3] Inst Nacl Canc, Serv Oncolog Med, Santiago, Chile

[4] Univ Austral Chile Puerto Montt, Escuela Tecnol Med, Puerto Montt, Chile

[5] Hosp Puerto Montt, Serv Anatom Patol, Puerto Montt, Chile

[6] Univ Chile, Oncol Dept, Hosp Clin, Santiago, Chile

[7] Univ Catolica Maule, Fac Med, Talca, Chile

[8] Unidad Anat Patol Hosp Reg Talca, Talca, Chile

[9] Univ Catolica Maule, Lab Invest Biomed, Fac Med, Talca, Chile

[10] Hosp Padre Hurtado, Serv Anatom Patol, Santiago, Chile

[11] Hosp Salvador, Serv Anatom Patol, Santiago, Chile

[12] Hosp San Juan Dios, Serv Anatom Patol, Santiago, Chile

[13] Univ Catolica Norte, Fac Med, Dept Biomed Sci, Lab Mol & Cellular Biol Canc,CancerLab, Coquimbo, Chile

[14] Hosp Reg, Serv Anatom Patol, Arica, Chile

[15] Hosp Juan Noe Crevani, Dept Surg, Arica, Chile

[16] Minist Salud, Secretaria Reg Minist Salud, Valdivia, Chile

[17] Hosp San Borja Arriaran, Serv Anatom Patol Gica, Santiago, Chile

[18] Hosp Reg Guillermo Grant Benavente, Serv Anatom Patol, Concepcion, Chile

[19] Univ Autonoma Chile, Fac Ciencias Salud, Inst Ciencias Biomed, Lab Cellular & Mol Pathol, Talca, Chile

[20] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany

[21] Int Agcy Res Canc, Lyon, France

[22] German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany

[23] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[24] WHO, Int Agcy Res Canc, Lyon, France

[25] Catalan Inst Oncol, Unit Nutr & Canc, Canc Epidemiol Res Programme, Barcelona, Spain

[26] Karolinska Inst, Dept Environm Med, Div Epidemiol, Stockholm, Sweden

[27] Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia

[28] Lifelines Cohort Study, Groningen, Netherlands

[29] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[30] German Canc Res Ctr, Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany

[31] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany

[32] Norwegian Univ Sci & Technol, Nord Trondelag Hlth Res Ctr, Trondheim, Norway

[33] Norwegian Univ Sci & Technol, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, Trondheim, Norway

[34] Natl Inst Hlth & Welf, Genom & Biobank, Helsinki, Finland

[35] Univ Med Greifswald, Interfak Res Inst Genet & Funkt Genomforsch, Greifswald, Germany

[36] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol & Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[37] Tarapaca Univ, Inst Alta Invest, Arica, Chile

[38] Consejo Nacl Invest Cient & Tecn, Inst Patagonico Ciencias Sociales & Humanas, Ctr Nacl Patagonico, Puerto Madryn, Argentina

[39] Univ Antioquia, Fac Ciencias Exactas & Nat, Medellin, Colombia

[40] Univ Fed Rio Grande Do Sul, Inst Biocincias, Puerto Alegre, Brazil

[41] Univ Nacl Autonoma Mexico, Fac Quim, Ciudad De Mexico, Mexico

[42] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosof, Labs Invest & Desarrollo, Unidad Neurobiolog Mol & Gent, Lima, Peru

[43] Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Human Phenome Inst, Shanghai, Peoples R China

[44] Fudan Univ, Minist Educ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, Shanghai, Peoples R China

[45] Aix Marseille Univ, EFS, CNRS, ADES, Marseille, France

[46] UCL, Dept Genet Evolut & Environm, London, England

[47] UCL, UCL Genet Inst, London, England

来源：

HEPATOLOGY | 2021年 / 73卷 / 05期

基金：

欧盟地平线“2020”;

关键词：

REPRODUCTIVE FACTORS; GENETIC-VARIANTS; RISK-FACTORS; LIFE-STYLE; DISEASE; ASSOCIATION; ADIPOSITY; WEIGHT; SUSCEPTIBILITY; INFLAMMATION;

D O I：

10.1002/hep.31537

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and Aims Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach and Results We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 x 10(-5)) and Europeans (P = 9 x 10(-5)). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 x 10(-6)). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

引用

页码：1783 / 1796

页数：14

共 57 条

[41] Gallbladder cancer in Chile: what have we learned? [J].