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Sex differential genetic effect of chromosome 9p21 on subclinical atherosclerosis.

ABSTRACT: BACKGROUND: Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p=0.021) and internal carotid artery (ICA) IMT (p=0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p=0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p=0.010) and the greater risk for the presence of carotid plaque (OR=1.57 for heterozygous carriers; OR=1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women. CONCLUSIONS: Chromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.

SUBMITTER: Lin HF

PROVIDER: S-EPMC2994883 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Sex differential genetic effect of chromosome 9p21 on subclinical atherosclerosis.

Lin Hsiu-Fen HF Tsai Pei-Chien PC Lin Ruey-Tay RT Khor Gim-Thean GT Sheu Sheng-Hsiung SH Juo Suh-Hang Hank SH

PloS one 20101130 11

<h4>Background</h4>Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated.<h4>Methodology/principal findings</h4>Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single ...[more]

PMID: 21152093

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Project description:BACKGROUND: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis. METHODS: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect. RESULTS: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27). CONCLUSIONS: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.

Dataset Information

Sex differential genetic effect of chromosome 9p21 on subclinical atherosclerosis.

Publications

Sex differential genetic effect of chromosome 9p21 on subclinical atherosclerosis.

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