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Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families.

ABSTRACT: 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.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.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.

SUBMITTER: Wang L

PROVIDER: S-EPMC3341091 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families.

Wang Liyong L Beecham Ashley A Zhuo Degen D Dong Chuanhui C Blanton Susan H SH Rundek Tatjana T Sacco Ralph L RL

Circulation. Cardiovascular genetics 20120314 2

<h4>Background</h4>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.<h4>Methods and results</h4>Using the 100 extended Dominican Republican (DR) families (N=1312) used in the original linkage study, we fine mapped the QTLs with 2031 ...[more]

PMID: 22423143

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Project description:BackgroundIntima-media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.MethodsWe measured the mean intima-media thickness of the common carotid artery and the maximum intima-media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima-media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima-media thickness values.ResultsA total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima-media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima-media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima-media thickness of the internal carotid artery (7.6%, P<0.001) but not intima-media thickness of the common carotid artery (0.0%, P=0.99). With the presence of plaque, defined as intima-media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P=0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025).ConclusionsThe maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intima-media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.).

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Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families.

Publications

Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families.

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