Associations of genetic and infectious risk factors with coronary heart disease
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eLife assessment
This study confirms a role of traditional cardiovascular risk factors (age, sex, cholesterol levels, weight) and polygenetic risk scores when predicting coronary heart disease in a large prospective cohort. It further reports an independent effect of seropositivity from past infection with a commensal bacterium F. nucleatum as a risk factor. The work is based on solid data and methodology and constitutes an important contribution to the understanding of disease risk, but the role of infection needs independent replication.
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Abstract
Coronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD. Study participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every 5 years. We analyzed a subgroup of 3459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multivariable stepwise Cox proportional hazards regression analyses. Of the 3459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status, and statin intake, revealed that high polygenic risk (hazard ratio [HR] 1.31, 95% CI 1.10–1.56, p=2.64 × 10 −3 ) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08–2.45, p=1.99 × 10 −2 ) were independently associated with incident CHD. In a prospective, population-based cohort, high polygenic risk and infection with F. nucleatum have a small, yet independent impact on CHD risk.
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eLife assessment
This study confirms a role of traditional cardiovascular risk factors (age, sex, cholesterol levels, weight) and polygenetic risk scores when predicting coronary heart disease in a large prospective cohort. It further reports an independent effect of seropositivity from past infection with a commensal bacterium F. nucleatum as a risk factor. The work is based on solid data and methodology and constitutes an important contribution to the understanding of disease risk, but the role of infection needs independent replication.
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Reviewer #1 (Public Review):
This is a well-written report on one of the biggest killer diseases. The report is based on a large longitudinal cohort and uses solid analytical methodologies. Three main valuable findings are reported: association between coronary heart disease (CHD) and a polygenic risk score (PRS), a combination of multiple traditional risk factors (SCORE2), and history of Fusobacterium nucleatum infection. While the first 2 associations are not novel, they are welcome independent replications of previous findings in a novel design. A putative role of F. nucleatum and other infections in increasing CHD risk has also been reported before but remains more elusive with some suggestion that they may increase CHD risk by promoting arterial inflammation. The strength of this study is to demonstrate an independent role of this …
Reviewer #1 (Public Review):
This is a well-written report on one of the biggest killer diseases. The report is based on a large longitudinal cohort and uses solid analytical methodologies. Three main valuable findings are reported: association between coronary heart disease (CHD) and a polygenic risk score (PRS), a combination of multiple traditional risk factors (SCORE2), and history of Fusobacterium nucleatum infection. While the first 2 associations are not novel, they are welcome independent replications of previous findings in a novel design. A putative role of F. nucleatum and other infections in increasing CHD risk has also been reported before but remains more elusive with some suggestion that they may increase CHD risk by promoting arterial inflammation. The strength of this study is to demonstrate an independent role of this bacterium after controlling inflammation markers as well as other risk factors in a prospective study. If this finding can be confirmed, the prevalence of the bacterium (15% in the cohort) means it should be considered as another serious CHD risk factor. The authors should discuss the implications of multiple testing.
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Reviewer #2 (Public Review):
Coronary heart disease (CHD) is a major form of cardiovascular disease, the first cause of mortality in the world. The etiology of CHD is multifactorial and polygenic, with atherosclerosis as the main cause of coronary stenosis and ischemic events. Evidence from basic research in small animal models and clinical trials aiming at lowering proinflammatory cytokines such as IL-1β implicated low-grade inflammation in atherosclerosis pathogenesis. Genetic studies in humans report large numbers of risk variants and genes related to macrophages, monocytes and T-lymphocytes biology supporting further immunity and inflammation in CHD risk. The study conducted by this group reports the results of the investigation of the potential association between 22 persistent or frequently recurring pathogen infections with the …
Reviewer #2 (Public Review):
Coronary heart disease (CHD) is a major form of cardiovascular disease, the first cause of mortality in the world. The etiology of CHD is multifactorial and polygenic, with atherosclerosis as the main cause of coronary stenosis and ischemic events. Evidence from basic research in small animal models and clinical trials aiming at lowering proinflammatory cytokines such as IL-1β implicated low-grade inflammation in atherosclerosis pathogenesis. Genetic studies in humans report large numbers of risk variants and genes related to macrophages, monocytes and T-lymphocytes biology supporting further immunity and inflammation in CHD risk. The study conducted by this group reports the results of the investigation of the potential association between 22 persistent or frequently recurring pathogen infections with the risk of CHD in a CoLaus|PsyCoLaus study, a prospective population-based and urban cohort of European ancestry. The authors accessed data over 12 years and assessed the association between traditional risk factors through the SCORE2 estimation of risk, a recently validated score specifically developed to predict cardiovascular risk in European countries, genetic risk scores based on GWAS findings, and seropositivity to infections. They were able to confirm the utility of the application of SCORE2 in their population, and report a significant association of the genetic score with the incidence of CHD, both traditional and genetic factors being independent predictors, which was expected. An intriguing result regards reported seropositivity with F. nucleatum to significantly predict incident CHD. This a commensal bacterium that belongs to the normal oral microbiome reported playing an important role in the development and progression of gingivitis (gum inflammation) and periodontitis (infection of the gums). There are several existing lines of evidence connecting oral infections as an independent risk factor for CHD. The results reported by this study provide support for the increased risk of CHD in oral infection through seropositivity to F. nucleatum. However, the direct clinical implications, through the recommendation to search for prior infection with this bacterium as a predicting biomarker of this disease are not on the clinical application agenda yet. The infection seropositivity was measured only at the beginning of the study, with no information on how the oral seropositivity to this pathogen may have evolved over time. And given the novelty of this association, these results need to be replicated in independent cohorts with similar designs (prospective cohorts) before recommendation to screen for seropositivity could be recommended.
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