title: Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families.
abstract: BACKGROUND
  Carotid intima-media thickness (CIMT) is a subclinical measure for atherosclerosis. Previously, we have mapped quantitative trait loci (QTLs) for CIMT to chromosomes 7p (maximum logarithm of odds=3.1) and to 14q (maximum logarithm of odds=2.3). We sought to identify the underlying genetic variants within those QTLs.
  
  
  RESULTS
  Using the 100 extended Dominican Republican (DR) families (N=1312) used in the original linkage study, we fine mapped the QTLs with 2031 tagging single nucleotide polymorphisms (SNPs). Promising SNPs in the family data set were examined in an independent population-based subcohort comprised of DR individuals (N=553) from the Northern Manhattan Study. Among the families, evidence for association (P<0.001) was found in multiple genes (ANLN, AOAH, FOXN3, CCDC88C, PRiMA1, and an intergenic SNP rs1667498), with the strongest association at PRiMA1 (P=0.00007, corrected P=0.047). Additional analyses revealed that the association at these loci, except PRiMA1, was highly significant (P=0.00004≈0.00092) in families with evidence for linkage, but not in the rest of families (P=0.13≈0.80) and the population-based cohort, suggesting the genetic effects at these SNPs are limited to a subgroup of families. In contrast, the association at PRiMA1 was significant in both families with and without evidence for linkage (P=0.002 and 0.019, respectively) and the population-based subcohort (P=0.047), supporting a robust association.
  
  
  CONCLUSIONS
  We identified several candidate genes for CIMT in DR families. Some of the genes manifest genetic effects within a specific subgroup and others were generalized to all groups. Future studies are needed to further evaluate the contribution of these genes to atherosclerosis.
authors.affiliation: John T. McDonald Department of Human Genetics, John P. Hussman Institute for Human Genomics, Department of Neurology, Epidemiology and Public Health, Miller School of Medicine, University of Miami, 1120 NW 14th St., Miami, FL 33136, USA.
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Ashley
authors.initials: A
authors.lastname: Beecham
authors.forename: Degen
authors.initials: D
authors.lastname: Zhuo
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
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: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015331:Cohort Studies; D004293:Dominican Republic / Q000453:epidemiology; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D055815:Young Adult