Sequence Variations in<i>PCSK9,</i>Low LDL, and Protection against Coronary Heart Disease

Cohen, Jonathan C.; Boerwinkle, Eric; Mosley, Thomas H.; Hobbs, Helen H.

doi:10.1056/nejmoa054013

Cited by 2,855 publications

(1,997 citation statements)

References 24 publications

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“…Can we identify women who are more or less susceptible to the higher risk factor levels in terms of the development of atherosclerosis and clinical CAD through genomic analysis? (45)(46)(47) Most likely, the prevention of the development of atherosclerosis from premenopause through the postmenopause would reduce the incidence and disability due to CHD and probably other vascular diseases among women. Thus, prevention of atherosclerosis and subsequent CVD among women may need to focus on the pre-to perimenopause than on the postmenopause.…”

Section: Discussionmentioning

confidence: 99%

Incident coronary artery calcium among postmenopausal women

et al. 2008

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Recent studies have shown that individuals with 0 coronary artery calcium (CAC) scores have very low risk of coronary heart disease. In the Healthy Women Study, we evaluated development of new CAC among postmenopausal women (n=272) over a 6 year period, age 62 at the 1 st and 68 at the 3 rd electron beam tomography (EBT) examination. At the 1 st EBT, 155 of 272 (57%) women had 0 CAC. By the 3 rd , 56 (36%) of these women had developed new CAC, including 38 with >5 Agatston units. There was practically no regression from having CAC at with the 1 st EBT to no CAC at the 3 rd EBT. The risk of developing new CAC over 6 years among women with 0 CAC on their 1 st EBT was strongly and significantly related to presence of both aortic calcium and carotid plaque at the time of 1 st EBT. Baseline premenopausal risk factors, age 47, apolipoprotein B, body mass index (BMI) and triglycerides, were significant predictors of incident CAC as were the changes in BMI and low density lipoprotein cholesterol between premenopause and the 1 st post exam, age 53. Risk factors measured premenopause and change in risk factors from premenopause to the 1 st post exam and the extent of subclinical disease in other vascular beds are primary determinants of the risk of developing incident CAC in women over a 6 year period.

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Section: Discussionmentioning

confidence: 99%

Incident coronary artery calcium among postmenopausal women

et al. 2008

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“…PCSK9 is the most established one, since it has been known for more than a decade that gain‐of‐function and loss‐of‐function variants in the PCSK9 gene increase (Abifadel et al , 2003) and decrease (Cohen et al , 2006) the risk of CAD and MI, respectively. GWAS also identified an association between common variants in the PCSK9 gene and both cholesterol levels (Teslovich et al , 2010) and CAD (Myocardial Infarction Genetics Consortium et al , 2009).…”

Section: Novel Therapeutics In Lipid Metabolismmentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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“…22 PCSK9 inhibitors are being tested in phase III trials 23 now, and are expected to be highly effective in FH patients. 24,25 Our definition of extreme groups might have been too restrictive, as it constitutes a very small proportion of the FH sample (500 out of 17 000).…”

Section: Discussionmentioning

confidence: 99%

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

et al. 2014

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Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (Po1 Â 10 À4 ). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

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Sequence Variations inPCSK9,Low LDL, and Protection against Coronary Heart Disease

Abstract: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.

Cited by 2,855 publications

References 24 publications

Incident coronary artery calcium among postmenopausal women

Incident coronary artery calcium among postmenopausal women

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

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