title: Shared and independent colorectal cancer risk alleles in TGFβ-related genes in African and European Americans.
abstract: Genome-wide association studies (GWAS) in colorectal cancer (CRC) identified five regions near transforming growth factor β-related genes BMP4, GREM1, CDH1, SMAD7 and RPHN2. The true risk alleles remain to be identified in these regions, and their role in CRC risk in non-European populations has been understudied. Our previous work noted significant genetic heterogeneity between African Americans (AAs) and European Americans (EAs) for single nucleotide polymorphisms (SNPs) identified in GWAS. We hypothesized that associations may not have been replicated in AAs due to differential or independent genetic structures. In order to test this hypothesis, we genotyped 195 tagging SNPs across these five gene regions in 1194 CRC cases (795 AAs and 399 EAs) and 1352 controls (985 AAs and 367 EAs). Imputation was performed, and association testing of genotyped and imputed SNPs included ancestry, age and sex as covariates. In two of the five genes originally associated with CRC, we found evidence for association in AAs including rs1862748 in CDH1 (OR(Add) = 0.82, P = 0.02) and in GREM1 the SNPs rs10318 (OR(Rec) = 60.1, P = 0.01), rs11632715 (OR(Rec) = 2.36; P = 0.004) and rs12902616 (OR(Rec) = 1.28, P = 0.005), the latter which is in linkage disequilibrium with the previously identified SNP rs4779584. Testing more broadly for associations in these gene regions in AAs, we noted three statistically significant association peaks in GREM1 and RHPN2 that were not identified in EAs. We conclude that some CRC risk alleles are shared between EAs and AAs and others are population specific.
authors.affiliation: Department of Medicine, University of Chicago Medicine, 900 E. 57th Street, MB #9, Chicago, IL 60637, USA, Department of Medicine, University of Illinois Chicago, 900 S. Ashland Avenue, MC 767, Chicago, IL 60607, USA, Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and Department of Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA skupfer@medicine.bsd.uchicago.edu.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Kupfer
authors.affiliation: Department of Medicine, University of Chicago Medicine, 900 E. 57th Street, MB #9, Chicago, IL 60637, USA, Department of Medicine, University of Illinois Chicago, 900 S. Ashland Avenue, MC 767, Chicago, IL 60607, USA, Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and Department of Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Skol
authors.affiliation: Department of Medicine, University of Chicago Medicine, 900 E. 57th Street, MB #9, Chicago, IL 60637, USA, Department of Medicine, University of Illinois Chicago, 900 S. Ashland Avenue, MC 767, Chicago, IL 60607, USA, Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and Department of Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Hong
authors.affiliation: Department of Medicine, University of Chicago Medicine, 900 E. 57th Street, MB #9, Chicago, IL 60637, USA, Department of Medicine, University of Illinois Chicago, 900 S. Ashland Avenue, MC 767, Chicago, IL 60607, USA, Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and Department of Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Ludvik
authors.affiliation: Department of Medicine, University of Illinois Chicago, 900 S. Ashland Avenue, MC 767, Chicago, IL 60607, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
authors.affiliation: Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and.
authors.forename: Temitope O
authors.initials: TO
authors.lastname: Keku
authors.affiliation: Department of Medicine, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599, USA and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001741:Black or African American; D000368:Aged; D000483:Alleles; D015703:Antigens, CD; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051906:Smad7 Protein / Q000235:genetics; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C513384:CDH1 protein, human; D015820:Cadherins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C471419:RHPN2 protein, human; C497806:SMAD7 protein, human; D051906:Smad7 Protein
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