title: Follow-up association study of linkage regions reveals multiple candidate genes for carotid plaque in Dominicans.
abstract: OBJECTIVE
  Carotid plaque is a marker of subclinical atherosclerosis with a genetic component. The aim of this follow-up fine mapping study was to identify candidate genes for carotid plaque within four linkage regions.
  
  
  METHODS
  We successfully genotyped 3712 single nucleotide polymorphisms (SNPs) under the four linkage regions that were previously identified in 100 extended Dominican families. Family-based association tests were performed to investigate their associations with carotid plaque. Promising SNPs were evaluated in an independent population-based subcohort (N=941, 384 Dominicans) from the Northern Manhattan Study (NOMAS).
  
  
  RESULTS
  In the family study, evidence for association (p<0.0005) was found regarding several genes (NAV2, EFCAB11/TDP1, AGBL1, PTPN9, LINGO1 and LOC730118), with the strongest association at rs4143999 near EFCAB11/TDP1 (p=0.00001 for carotid presence and 0.00003 for plaque area, multiple testing corrected p≤0.02). The association in AGBL1 and PTPN9 was mainly driven by the families with linkage evidence (p=0.00008-0.00001 and 0.76-0.32, respectively, in the families with and without linkage evidence). However, these associations explained only a small portion of the observed linkage. In NOMAS, replication (p<0.05 in the whole NOMAS subcohort and p<0.10 in the smaller Dominican subcohort) was found for SNPs within/near EFCAB11, NAV2, AGBL1 and other genes.
  
  
  CONCLUSIONS
  This follow-up study has identified multiple candidate genes for carotid plaque in the Dominican population. Many of these genes have been implicated in neurodegenerative and cardiovascular diseases. Further studies with in-depth re-sequencing are needed to uncover both rare and common functional variants that contribute to the susceptibility to atherosclerosis.
authors.affiliation: Department of Neurology, Miller School of Medicine, University of Miami, FL, USA.
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
authors.forename: Ashley
authors.initials: A
authors.lastname: Beecham
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.forename: Tatjana
authors.initials: T
authors.lastname: Rundek
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Sacco
mesh_terms: D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D004293:Dominican Republic / Q000208:ethnology; D005500:Follow-Up Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D009519:New York City / Q000453:epidemiology; D010375:Pedigree; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D018570:Risk Assessment; D012307:Risk Factors; D014463:Ultrasonography