Browsing by Author "Gabler, F."

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    Mendelian Randomization Analysis of the Relationship Between Native American Ancestry and Gallbladder Cancer Risk
    (2022) Zollner, L.; Boekstegers, F.; Ponce, C.B.; Scherer, D.; Marcelain, K.; Gárate-Calderón, V.; Waldenberger, M.; Morales, E.; Rojas, A.; Munoz, C.; Müller, B.; Retamales, J.; de Toro, G.; Kortmann, A.V.; Barajas, O.; Rivera, M.T.; Cortés, A.; Loader, D.; Saavedra, J.; Gutiérrez, L.; Ortega, A.; Bertrán, M.E.; Bartolotti, L.; Gabler, F.; Campos, M.; Alvarado, J.; Moisán, F.; Spencer, L.; Nervi Nattero, Bruno; Carvajal, D.; Losada, H.; Almau, M.; Fernández, P.; Olloquequi, J.; Carter, A.R.; Miquel, Juan Francisco; Bustos, B.I.; Guajardo, M.F.; Gonzalez-Jose, R.; Bortolini, M.C.; Acuña-Alonzo, V.; Gallo, C.; Linares, A.R.; Rothhammer, F.; Bermejo, J.L.
    Background A strong association between the proportion of Native American 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 Native American people in Chile. We set out to investigate the causal association between Native American Mapuche ancestry and GBC risk, and the possible mediating effects of gallstone disease and body mass index (BMI) on this association. Methods Markers of Mapuche ancestry were selected based on the informativeness for assignment measure and then used as instrumental variables in two-sample mendelian randomization (MR) analyses and complementary sensitivity analyses. Result We found evidence of a causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% for every 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.6×10-5). Mapuche ancestry was also causally linked to gallstone disease (IVW risk increase of 3.6% per 1% increase in Mapuche proportion, 95% CI 3.1% to 4.0%, p = 1.0×10-59), suggesting a mediating effect of gallstones in the relationship between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative causal effect on BMI (IVW estimate -0.006 kg/m2 per 1% increase in Mapuche proportion, 95% CI -0.009 to -0.003, p = 4.4×10-5). Conclusions The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between Mapuche ancestry and GBC risk previously noted in observational studies appears to be causal, primary and secondary prevention strategies that take into account the individual proportion of Mapuche ancestry could be particularly efficient.
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    The identification of two subgroups of obese women with differing endometrial proliferation levels: potential consequences in the development of endometrial cancer
    (2012) Villavicencio, A.; Aguilar, G.; Acuna, J.; Gabler, F.; Soto, E.; Gaete, F.; Penaloza, P.; Celis, M.; Owen, G. I.
    Enhanced endometrial proliferation correlates obesity to type-I (estrogen-dependent) endometrial cancer (EC). Our aim was to distinguish obese women (without EC) with differing endometrial proliferation. Endometrial and blood samples were obtained from normal-weight and obese women without EC. Type-I EC samples were obtained from obese patients. On measuring endometrial proliferation (Ki67 and phosphorylated histone H3 (p-H3)), two groups of obese women without EC were identified: obese(High Proliferating) (O-HP) and obese(Low Proliferating) (O-LP). Increased Ki67 (88.5%, P<0.001), p-H3 (62.6%, P<0.01), 17 beta-estradiol/progesterone ratio (46.3%, P<0.01) and endometrial estrogen receptor alpha (ER alpha) (82.2%, P<0.001) were observed in O-HP compared with O-LP patients. ECs possessed similar ER alpha and enhanced proliferation as O-HP, suggesting that O-HP women are at higher risk of type-I EC. O-LP women were indistinguishable from normal-weight women regarding these determinants of endometrial proliferation, ER alpha and 17 beta-estradiol/progesterone ratio. Our data may further define the obesity phenotype in regards to type-I EC risk and may help identify obese women more susceptible to develop type-I EC, allowing early intervention and a potential reduction in mortality.