Implications of discoveries from genome-wide association studies in current cardiovascular practice

Jeemon, Panniyammakal; Pettigrew, Kerry A.; Sainsbury, Christopher; Prabhakaran, Dorairaj; Padmanabhan, Sandosh

doi:10.4330/wjc.v3.i7.230

Cited by 59 publications

(57 citation statements)

References 64 publications

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“…Genome-wide association studies (GWAS) have identified LDLcholesterol-associated loci near HMGCR, ABO and TOMM40 [66], and also an association of TOMM40 with blood lipid levels [67,68] and body mass index [69]. Genetic variants in TOMM40/APOE-C1-C2-C4 genes have also been found to be associated with multiple cardiovascular-related traits [70][71][72].…”

Section: Introductionmentioning

confidence: 99%

APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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Section: Introductionmentioning

confidence: 99%

APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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“…Genomewide association studies (GWAS) have iden tified LDLcholesterolassociated loci near HMGCR, ABO and TOMM40 [145], and also an association of TOMM40 with blood lipid levels [146,147] and body mass index [148]. Genetic variants in TOMM40/APOE-C1-C2-C4 genes have also been found to be associated with multiple cardiovascularrelated traits [149][150][151]. Several ABC transporters (ABCA1, ABCG1, ABCG5, ABCG8) have been shown to play important roles in the regulation of cellular cholesterol homeostasis by mediating cholesterol efflux.…”

Section: Cholesterol Dysregulationmentioning

confidence: 97%

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

et al. 2016

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The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.

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“…Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes both encode putative regulators of cyclin-dependent kinases on chromosome 9p21. Genome-wide association studies have identified that some CDKN2A or CDKN2B genetic variants are susceptible to CHD (8)(9)(10). As recently reported, many human diseases, including cardiovascular disease, could be influenced by aberrant DNA methylation modification (11).…”

Section: Introductionmentioning

confidence: 92%

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

Zhong

Chen

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation-specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non-CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73±5.88 vs. 62.62±5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26±5.48 vs. 58.33±7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation. IntroductionCoronary heart disease (CHD) is a complex chronic disease that is caused by an imbalance between blood supply and demand in myocardium. Various environmental and genetic factors are known to contribute to onset and development of CHD (1). As of 2010, CHD was the leading cause of mortality globally, resulting in over 7 million cases of mortality (2). Therefore, association studies for CHD biomarkers have been performed worldwide (3-5) for future forefront diagnostics for the early assessment of cardiac risks.The genetic locus at chromosome 9p21 has been demonstrated to be strongly associated with the risk of CHD (6,7). Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes both encode putative regulators of cyclin-dependent kinases on chromosome 9p21. Genome-wide association studies have identified that some CDKN2A or CDKN2B genetic variants are susceptible to CHD (8-10). As recently reported, many human diseases, including cardiovascular disease, could be influenced by aberrant DNA methylation modification (11). Aberrant methylation of cytosine-phosphate-guanine (CpG) islands in gene promoters is associated with transcription silencing and activity (3). However, the exact role of CDKN2A and CDKN2B methylation in cardiovascular system has not yet been fully elucidated.CDKN2A gene is involved in the regulation of cell proliferation, cell aging and apoptosis (12). However, a bidirectional role of CDKN2A gene expression has been reported in previous studies. Knösel et al (13) reported...

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Implications of discoveries from genome-wide association studies in current cardiovascular practice

Abstract: Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to

Cited by 59 publications

References 64 publications

APOE-TOMM40 in the Pharmacogenomics of Dementia

APOE-TOMM40 in the Pharmacogenomics of Dementia

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

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