Browsing by Author "Hampe, Jochen"

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    Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
    (2018) Bustos, Bernabé I.; Pérez Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras, Eleodoro; Ugarte, Giorgia D.; Toliat, Mohammad; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; von Schönfels, Witigo; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Gutiérrez Ilabaca, Rodrigo Antonio; Hampe, Jochen; de Ferrari, Giancarlo V.; Miquel, Juan Francisco
    Background Latin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.Methods We performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1×10−5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.Results We consistently replicated the ABCG8 gene (rs11887534; P=3.24×10−8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11×10−7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.Conclusions We confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
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    Genetics of biliary lithiasis from an ethnic perspective
    (2013) Krawczyk, Marcin; Miquel Poblete, Juan Francisco; Stokes, Caroline S.; Zuniga, Silvia; Hampe, Jochen; Mittal, Balraj; Lammert, Frank
    Gallstone disease represents one of the most common gastroenterological disorders worldwide. Gallstones affect over 15% of adults in Europe and 25-30% of Hispanic populations in Central and South America. The heritability of gallstones varies considerably according to ethnicity, with Native Americans and Hispanics with Amerindian admixture being the most susceptible populations. Genetic factors have been shown to account for 25-30% of total gallstone risk in Europe, however, in Hispanic populations, this risk percentage may increase to 45-65%. Recent genome-wide association and candidate gene studies have identified common polymorphisms in enterohepatic transporters (ABCG5/8, SLC10A2) and the Gilbert syndrome UGT1A1 variant as genetic determinants of gallstone formation. Together, these polymorphisms cover a significant proportion of the previously predicted genetic background of gallstones in European populations. New lithogenic genes need to be discovered in future studies in high-risk populations. In this review, we address the latest developments in the genetic analysis of gallstones and discuss the ethnic background of this condition in European, Central and South American and Asian populations. (C) 2012 Elsevier Masson SAS. All rights reserved.
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    Loci From a Genome-Wide Analysis of Bilirubin Levels Are Associated With Gallstone Risk and Composition
    (W B SAUNDERS CO-ELSEVIER INC, 2010) Buch, Stephan; Schafmayer, Clemens; Voelzke, Henry; Seeger, Marcus; Miquel, Juan F.; Sookoian, Silvia C.; Egberts, Jan H.; Arlt, Alexander; Pirola, Carlos J.; Lerch, Markus M.; John, Ulrich; Franke, Andre; von Kampen, Oliver; Brosch, Mario; Nothnagel, Michael; Kratzer, Wolfgang; Boehm, Bernhard O.; Broering, Dieter C.; Schreiber, Stefan; Krawczak, Michael; Hampe, Jochen
    BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0 x 10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1 x 10(-7); odds ratio(recessive), 2.34; P-women = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P-men = .046; odds ratio(recessive), 2.19; P-women = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.
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    Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
    (2019) Bustos, Bernabé I.; Pérez-Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras Hernández, Eleodoro Javier; Ugarte, Giorgia D.; Gutiérrez Ilabaca, Rodrigo Antonio; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; Schönfels, Witigo von; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Roa Strauch, Juan Carlos Enrique; Toliat, Mohammad; Hampe, Jochen; Ferrari, Giancarlo V. de; Miquel P., Juan Francisco
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    Whole genome sequence of Mapuche-Huilliche Native Americans
    (2018) Vidal Olate, Elena Alejandra; Moyano Yugovic, Tomás Custodio; Bustos, Bernabé I.; Pérez-Palma, Eduardo; Moraga Marín, Carol Mabel; Montecinos López, Alejandro; Azócar López, Lorena Karina; Soto Wilder, Daniela Constanza; Riveras, Eleodoro; Vidal, Mabel; Genova, Alex Di; Puschel Illanes, Klaus; Nürnberg, Peter; Buch, Stephan; Hampe, Jochen; Eyheramendy Duerr, Susana; Miquel Poblete, Juan Francisco; Gutiérrez Ilabaca, Rodrigo Antonio
    Background Whole human genome sequencing initiatives provide a compendium of genetic variants that help us understand population history and the basis of genetic diseases. Current data mostly focuses on Old World populations and information on the genomic structure of Native Americans, especially those from the Southern Cone is scant. Results Here we present a high-quality complete genome sequence of 11 Mapuche-Huilliche individuals (HUI) from Southern Chile (85% genomic and 98% exonic coverage at > 30X), with 96-97% high confidence calls. We found approximately 3.1x106 single nucleotide variants (SNVs) per individual and identified 403,383 (6.9%) of novel SNVs that are not included in current sequencing databases. Analyses of large-scale genomic events detected 680 copy number variants (CNVs) and 4,514 structural variants (SVs), including 398 and 1,910 novel events, respectively. Global ancestry composition of HUI genomes revealed that the cohort represents a marginally admixed population from the Southern Cone, whose genetic component is derived from early Native American ancestors. In addition, we found that HUI genomes display highly divergent and novel variants with potential functional impact that converge in ontological categories essential in cell metabolic processes. Conclusions Mapuche-Huilliche genomes contain a unique set of small- and large-scale genomic variants in functionally linked genes, which may contribute to susceptibility for the development of common complex diseases or traits in admixed Latinos and Native American populations. Our data represents an ancestral reference panel for population-based studies in Native and admixed Latin American populations