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Cardiovascular Risk Genes in Prevention and Treatment Response

Hamrefors, Viktor LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:16.
Abstract
GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD.



SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881).



METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change.



A... (More)
GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD.



SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881).



METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change.



A 13-SNP-myocardial-infarction-(MI)-genetic-risk-score was related to carotid atherosclerosis-markers in 4022 MDC-subjects. The MI-gene-score associated with carotid-bulb-intima-media-thickness (IMT) (beta=0.038 standard deviations of IMT per MI-gene-score-quintile; P-trend=0.005) and plaque (odds-ratio per MI-gene-score-quintile=1.11; 95% confidence interval (CI):1.04-1.18; P=0.001) in multivariable models.



It was tested if eight blood-pressure-associated SNPs affected antihypertensive treatment-response in 3863 Swedish hypertensives from NORDIL. No robust associations were identified.



Finally, interactions between life-style-factors and the CVD-SNP rs4977574 on chromosome 9p21 were evaluated in 24944 MDC-subjects during 15 years follow-up. There were interactions between rs4977574 and smoking on incident CAD (P=0.035) and CVD-mortality (P=0.012). The risk conferred by rs4977574 in never-smokers (n=9642; Hazard-ratio(HR) per risk-allele(CAD)=1.26; 95%CI:1.13-1.40; HR per risk-allele(CVD-mortality)=1.40; 95%CI:1.20-1.63) was attenuated in smokers (n=7000; HR per risk-allele(CAD)=1.05; 95%CI:0.95-1.16; HR per risk-allele(CVD-mortality)=1.08; 95%CI:0.94-1.23).



CONCLUSIONS: CVD-genetics identifies subjects with markers of subclinical atherosclerosis, suggesting that early atherosclerosis-prevention may be targeted to such individuals. Smoking attenuates the relative influence of the thus far strongest identified polygenic CVD-risk-locus, implying potential utility of common CVD-genetics in mainly conventional lower-risk subjects. Lipid-polymorphisms may predict statin-induced HDL-increase in women, but eight blood-pressure-SNPs did not affect antihypertensive treatment-response. (Less)
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author
supervisor
opponent
  • Associate Professor Rankinen, Tuomo, Pennington Biomedical Research Center, Baton Rouge, LA, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
blood pressure treatment, hypertension, statins, dyslipidemia, cardiovascular prevention, cardiovascular genetics, stroke, coronary artery disease, chromosome 9p21, pharmacogenetics, pharmacogenomics
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:16
pages
120 pages
publisher
Hypertension and Cardiovascular Disease
defense location
Aulan, CRC, Skåne University Hospital, Malmö
defense date
2014-02-14 09:00
ISSN
1652-8220
ISBN
978-91-87651-40-3
language
English
LU publication?
yes
id
4460e18c-5cda-49bc-9906-781fc3156d03 (old id 4253338)
date added to LUP
2014-01-23 15:22:05
date last changed
2016-09-19 08:44:49
@phdthesis{4460e18c-5cda-49bc-9906-781fc3156d03,
  abstract     = {GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD.<br/><br>
<br/><br>
SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881).<br/><br>
<br/><br>
METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change.<br/><br>
<br/><br>
A 13-SNP-myocardial-infarction-(MI)-genetic-risk-score was related to carotid atherosclerosis-markers in 4022 MDC-subjects. The MI-gene-score associated with carotid-bulb-intima-media-thickness (IMT) (beta=0.038 standard deviations of IMT per MI-gene-score-quintile; P-trend=0.005) and plaque (odds-ratio per MI-gene-score-quintile=1.11; 95% confidence interval (CI):1.04-1.18; P=0.001) in multivariable models.<br/><br>
<br/><br>
It was tested if eight blood-pressure-associated SNPs affected antihypertensive treatment-response in 3863 Swedish hypertensives from NORDIL. No robust associations were identified.<br/><br>
<br/><br>
Finally, interactions between life-style-factors and the CVD-SNP rs4977574 on chromosome 9p21 were evaluated in 24944 MDC-subjects during 15 years follow-up. There were interactions between rs4977574 and smoking on incident CAD (P=0.035) and CVD-mortality (P=0.012). The risk conferred by rs4977574 in never-smokers (n=9642; Hazard-ratio(HR) per risk-allele(CAD)=1.26; 95%CI:1.13-1.40; HR per risk-allele(CVD-mortality)=1.40; 95%CI:1.20-1.63) was attenuated in smokers (n=7000; HR per risk-allele(CAD)=1.05; 95%CI:0.95-1.16; HR per risk-allele(CVD-mortality)=1.08; 95%CI:0.94-1.23).<br/><br>
<br/><br>
CONCLUSIONS: CVD-genetics identifies subjects with markers of subclinical atherosclerosis, suggesting that early atherosclerosis-prevention may be targeted to such individuals. Smoking attenuates the relative influence of the thus far strongest identified polygenic CVD-risk-locus, implying potential utility of common CVD-genetics in mainly conventional lower-risk subjects. Lipid-polymorphisms may predict statin-induced HDL-increase in women, but eight blood-pressure-SNPs did not affect antihypertensive treatment-response.},
  author       = {Hamrefors, Viktor},
  isbn         = {978-91-87651-40-3},
  issn         = {1652-8220},
  keyword      = {blood pressure treatment,hypertension,statins,dyslipidemia,cardiovascular prevention,cardiovascular genetics,stroke,coronary artery disease,chromosome 9p21,pharmacogenetics,pharmacogenomics},
  language     = {eng},
  pages        = {120},
  publisher    = {Hypertension and Cardiovascular Disease},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Cardiovascular Risk Genes in Prevention and Treatment Response},
  volume       = {2014:16},
  year         = {2014},
}