title: Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.
abstract: There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic ("traffic exposure")-a recognized vascular disease risk factor-on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10-8) in European-Americans. Rs755249 is located in the 3' untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10-6) and rs1180341 (tibial artery, eQTL P = 5.3x10-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes.
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.|Institute of Epidemiology II, Helmholtz Center Munich, Neuherberg, Germany 85764.
authors.forename: Cavin K
authors.initials: CK
authors.lastname: Ward-Caviness
authors.affiliation: National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, North Carolina 27514, United States of America.
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Neas
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Colette
authors.initials: C
authors.lastname: Blach
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Haynes
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: LaRocque-Abramson
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grass
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Elaine
authors.initials: E
authors.lastname: Dowdy
authors.affiliation: National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, North Carolina 27514, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Devlin
authors.affiliation: National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, North Carolina 27514, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Sanchez
authors.affiliation: National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, North Carolina 27514, United States of America.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Cascio
authors.affiliation: National Center for Geospatial Medicine, Rice University, Houston, Texas 77005, United States of America.
authors.forename: Marie
authors.initials: M
authors.lastname: Lynn Miranda
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.|Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.|Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina 27710, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27710, United States of America.|Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, United States of America.|Cooperative Studies Program Epidemiology Center-Durham, Veterans Affairs Medical Center, Durham, North Carolina 27701, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
mesh_terms: D000397:Air Pollution / Q000009:adverse effects* / Q000032:analysis; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects* / Q000032:analysis; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006798:Housing; D006801:Humans; D008297:Male; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014186:Transportation
chemical_list: D019485:Bone Morphogenetic Proteins