Sarah Silva, Dorothea Nitsch, Segun Fatumo
Abstract
Background
Cardiovascular diseases are some of the leading causes of death worldwide, with coronary artery disease leading as one of the primary causes of mortality in both the developing and developed worlds. Despite its prevalence, there is a disproportionately small number of studies conducted in populations of non-European ancestry, with the limited sample sizes of such studies further restricting the power and generalizability of respective findings. This research aimed at understanding the differences in the genetic architecture of coronary artery disease (CAD) in populations of diverse ancestries in order to contribute towards the understanding of the pathophysiology of coronary artery disease.
Methods
We performed a systematic review on the 6th of October, 2022 summarizing genome-wide association studies on coronary artery disease, while employing the GWAS Catalog as an independent database to support the search. We developed a framework to assess the methodological quality of each study. We extracted and grouped associated single nucleotide polymorphisms and genes according to ancestry groups of participants.
Introduction
Coronary artery disease (CAD) is the leading cause of death worldwide, characterized by the build-up of atherosclerotic plaque in the arteries which supply oxygenated blood to the heart [1–3]. Over the past decade, age-adjusted cardiovascular death rates have been decreasing in high-income countries, whilst the opposite is being observed in low- and middle-income countries with a substantial increase in death rates due to cardiovascular diseases [4]. Although there is a general understanding of the modifiable risk factors for CAD, between ancestries there is an evident disproportionality in the frequency of these CAD risk factors, and consequently the observed prevalence and severity of the disease [5]. Moreover, there may be risk factors for CAD in low- and middle-income settings that have not been observed in high-income settings, whereby the pathobiology of CAD may be different in contexts with additional yet-undefined risk factors. This has prompted efforts in the discovery of population-specific genetic drivers of CAD, which in combination with findings from causal risk factors of CAD, may reveal previously overlooked or otherwise unidentified opportunities to improve public health efforts in reducing the burden of CAD globally.
Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol of the systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 25th August 2021, with the registration ID: CRD42021272726.
Search strategy
A search was conducted in the databases Embase, Medline, Global Health, Web of Science and Cochrane Library on the 6th of October, 2022. The terms “coronary artery disease”, “CAD”, “coronary heart disease”, “genome-wide association study” and “GWAS” were used in the search string, with a full record of the respective search strategies employed for the review shown in Fig 1 in S1 File.
Results
Identified studies in the systematic review
Searches conducted in Embase, Medline, Global Health, Web of Science and the Cochrane Library identified a total of 3159 studies which matched the search criteria, with an additional 5 studies identified as potentially relevant through other sources, such as frequently referenced papers (total n = 3164). Papers included in the GWAS Catalog that were not identified in this search strategy were included as well in the identification process in order to capture the full known research landscape for GWAS on CAD (n = 12). Following de-duplication, a total of 2960 studies were excluded through title and abstract screening, with the primary reasons for exclusion being: not having CAD as a primary outcome of interest (n = 1465) and employing a primary methodology other than GWAS (n = 1175). After full-text screening of 114 studies following the previously stated eligibility criteria, 36 studies were selected to be included in the review [Fig 1 and Table 1 in S1 File].
Discussion
In this review, including a total of 743,919 CAD case participants from 25 different countries, 631 unique genetic loci have been identified to be associated with CAD. Despite representing participants from a number of major ancestry groupings, the distribution of studies included in this review remains reflective of the current study landscape, with only approximately 42% of the studies included in this review including participants of non-European ancestry. This underrepresentation of non-European individuals in genetic studies, specifically indigenous groups, admixed Americans, South Asians living in Asia and populations of African ancestry who are living in continental Africa, results in many conclusions regarding what we understand about SNP-trait associations to be drawn from a biased ancestry cohort.
Conclusion
This systematic review summarized what is currently known with regards to GWAS findings of CAD in diverse ancestry populations. We were able to highlight the existence of both shared and ancestry-specific genetic factors underlying CAD, and brought to attention the lack of representation of non-European ancestry populations in the research landscape. Significant gaps exist in the representation of both South Asian populations and populations from continental Africa, with research from both population groups likely allowing for a more complete understanding of disease mechanisms and pathophysiology in the future. As more GWAS on CAD begin to be carried out, it is with hope that the inclusion of greater sample sizes representative of the global population will allow for better interrogation and extrapolation of disease-specific genetic findings.
Citation: Silva S, Nitsch D, Fatumo S (2023) Genome-wide association studies on coronary artery disease: A systematic review and implications for populations of different ancestries. PLoS ONE 18(11): e0294341. https://doi.org/10.1371/journal.pone.0294341
Editor: Xiang Zhu, Penn State: The Pennsylvania State University, UNITED STATES
Received: June 5, 2023; Accepted: October 28, 2023; Published: November 29, 2023
Copyright: © 2023 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data generated or analysed during this study are included in this published article and its supplementary information files.
Funding: Segun Fatumo is funded by the Wellcome International Intermediate fellowship (220740/Z/20/Z) at the MRC/UVRI and LSHTM Uganda. The views expressed here do not necessarily reflect the views of the funders.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AFR-AMR, African-American; CAD, Coronary artery disease; CI, Confidence interval; EAS, East Asian; EUR, European; GWAS, Genome-wide association study; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PROSPERO, Prospective Register of Systematic Reviews; SAS, South Asian; SNP, Single-nucleotide polymorphism
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0294341#abstract0
