Genetic association and gene-smoking interaction study of carotid intima-media thickness at five GWAS-indicated genes: the Bogalusa Heart Study.
OBJECTIVE
To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions.


METHODS
Far wall IMTs of common carotid arteries were measured using high-resolution B-mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied.


RESULTS
Marker rs7840785 (PINX1) was significantly associated with right carotid IMT (p=0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p=0.0031) and whites (p=0.0118). Marker rs7844465 (ZHX2) was significantly associated with left carotid IMT in whites (p=0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 (EDNRA) modified the association between smoking and left carotid IMT in blacks (p=2.79×10(-5)). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites.


CONCLUSIONS
We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants.
Department of Epidemiology, Tulane University, New Orleans, LA, USA. Electronic address: cli8@tulane.edu.
Changwei
C
Li
Tulane Center for Cardiovascular Health, Tulane University, New Orleans, LA, USA. Electronic address: wchen1@tulane.edu.
Wei
W
Chen
Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China. Electronic address: riversailer@hotmail.com.
Fan
F
Jiang
Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. Electronic address: jsimino@umc.edu.
Jeannette
J
Simino
Tulane Center for Cardiovascular Health, Tulane University, New Orleans, LA, USA. Electronic address: ssriniv1@tulane.edu.
Sathanur R
SR
Srinivasan
Center for Cardiovascular Health, 1440 Canal St, Suite 1829, New Orleans, LA 70112, USA. Electronic address: berenson@tulane.edu.
Gerald S
GS
Berenson
Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China; Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. Electronic address: hmei@umc.edu.
Hao
H
Mei
D000328:Adult; D002339:Carotid Arteries / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D018797:Cell Cycle Proteins; D003430:Cross-Sectional Studies; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008145:Louisiana; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C440808:PINX1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C476826:ZHX2 protein, human
Gene association; Gene-smoking interaction; IMT; SNP association