title: Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.
abstract: A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Eckert
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Cooper
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Vanyukov
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.affiliation: Department of Pediatric Dentistry, School of Dentistry, University of Washington, Seattle, WA, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Slayton
authors.affiliation: Division of Genetics and Genomics, Department of Pediatrics, School of Medicine, Washington University at St Louis, St Louis, MO, USA.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Willing
authors.affiliation: Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Reis
authors.affiliation: Department of Dental Practice and Rural Health, West Virginia University, Morgantown, WV, USA.|Department of Psychology, West Virginia University, Morgantown, WV, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McNeil
authors.affiliation: Department of Periodontics, School of Dentistry, West Virginia University, Morgantown, WV, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Crout
authors.affiliation: Department of Dental Public Health and Information Management, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weyant
authors.affiliation: Department of Preventive and Community Dentistry, University of Iowa College of Dentistry, Iowa City, IA, USA.|Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Levy
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.|Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: John R
authors.identifier: http://orcid.org/0000-0003-1897-1131
authors.initials: JR
authors.lastname: Shaffer
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003731:Dental Caries / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D000091283:Protein Kinase D2; D011494:Protein Kinases