Advanced

Genetics of coronary heart disease: towards causal mechanisms, novel drug targets and more personalized prevention.

Orho-Melander, Marju LU (2015) In Journal of Internal Medicine 278(5). p.433-446
Abstract
Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has... (More)
Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has already been made for several genetic loci. Furthermore, identification of rare loss-of-function variants in genes such as PCSK9, NPC1L1, APOC3 and APOA5, which cause a markedly decreased risk of CHD and no adverse side effects, illustrates the power of translating genetic findings into novel mechanistic information and provides some optimism for the future of developing novel drugs, given the many genes associated with CHD in GWASs. Finally, Mendelian randomization can be used to reveal or exclude causal relationships between heritable biomarkers and CHD, and such approaches have already provided evidence of causal relationships between CHD and LDL cholesterol, triglycerides/remnant particles and lipoprotein(a), and indicated a lack of causality for HDL cholesterol, C-reactive protein and lipoprotein-associated phospholipase A2. Together, these genetic findings are beginning to lead to promising new drug targets and novel interventional strategies and thus have great potential to improve prevention, prediction and therapy of CHD. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Internal Medicine
volume
278
issue
5
pages
433 - 446
publisher
Wiley-Blackwell Publishing Ltd
external identifiers
  • pmid:26477595
  • wos:000363278500002
  • scopus:84944691045
ISSN
1365-2796
DOI
10.1111/joim.12407
language
English
LU publication?
yes
id
da8d1a1d-ef22-4718-a13c-4cef1b51d750 (old id 8149067)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26477595?dopt=Abstract
date added to LUP
2015-11-03 16:11:13
date last changed
2017-09-17 03:14:01
@article{da8d1a1d-ef22-4718-a13c-4cef1b51d750,
  abstract     = {Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has already been made for several genetic loci. Furthermore, identification of rare loss-of-function variants in genes such as PCSK9, NPC1L1, APOC3 and APOA5, which cause a markedly decreased risk of CHD and no adverse side effects, illustrates the power of translating genetic findings into novel mechanistic information and provides some optimism for the future of developing novel drugs, given the many genes associated with CHD in GWASs. Finally, Mendelian randomization can be used to reveal or exclude causal relationships between heritable biomarkers and CHD, and such approaches have already provided evidence of causal relationships between CHD and LDL cholesterol, triglycerides/remnant particles and lipoprotein(a), and indicated a lack of causality for HDL cholesterol, C-reactive protein and lipoprotein-associated phospholipase A2. Together, these genetic findings are beginning to lead to promising new drug targets and novel interventional strategies and thus have great potential to improve prevention, prediction and therapy of CHD.},
  author       = {Orho-Melander, Marju},
  issn         = {1365-2796},
  language     = {eng},
  number       = {5},
  pages        = {433--446},
  publisher    = {Wiley-Blackwell Publishing Ltd},
  series       = {Journal of Internal Medicine},
  title        = {Genetics of coronary heart disease: towards causal mechanisms, novel drug targets and more personalized prevention.},
  url          = {http://dx.doi.org/10.1111/joim.12407},
  volume       = {278},
  year         = {2015},
}