Cardiovascular Risk Genes in Prevention and Treatment Response

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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 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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Cardiovascular Research - Hypertension
Supervisors/Advisors
  • Melander, Olle, Supervisor
  • Hedblad, Bo, Supervisor
Award date2014 Feb 14
Publisher
ISBN (Print)978-91-87651-40-3
Publication statusPublished - 2014

Bibliographical note

Defence details

Date: 2014-02-14
Time: 09:00
Place: Aulan, CRC, Skåne University Hospital, Malmö

External reviewer(s)

Name: Rankinen, Tuomo
Title: Associate Professor
Affiliation: Pennington Biomedical Research Center, Baton Rouge, LA, USA

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Subject classification (UKÄ)

  • Cardiac and Cardiovascular Systems

Free keywords

  • blood pressure treatment
  • hypertension
  • statins
  • dyslipidemia
  • cardiovascular prevention
  • cardiovascular genetics
  • stroke
  • coronary artery disease
  • chromosome 9p21
  • pharmacogenetics
  • pharmacogenomics

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