Associations of genetic and infectious risk factors with coronary heart disease

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.

Keywords: Cox regression; coronary heart disease; genetics; genomics; human; human genomics; inflammation; persistent infections.

Figure 1.. Prevalence of tested pathogens in CoLaus|PsyCoLaus study in participants with and without coronary heart disease (CHD).

Overall serostatus for the 22 pathogens are shown in the CHD-positive group (individuals with at least one CHD event during follow-up) or CHD-negative group. The y-axis indicates the relative percentage within each group. Pathogens are ranked in ascending order of overall seropositivity (all individuals combined).

Figure 2.. Hazard ratio (HR) and 95% confidence intervals of coronary heart disease (CHD) occurrence according to associated factors.

HR > 1 indicates an increased risk of CHD, whereas HR < 1 indicates a protective effect. p-Values (p) for each factor based on the multivariable Cox regression are shown.

Appendix 2—figure 1.. Pairwise correlations between quantitative characteristics significantly associated with coronary heart disease (CHD) risk in the univariable Cox proportional hazard models.

Pearson’s correlation values are displayed, along with linear fits between variables.

Appendix 2—figure 2.. Strength of association for each pair of categorical variables significantly associated with coronary heart disease (CHD) risk in univariable Cox proportional hazard models.

Cramer’s V values are displayed.

Appendix 2—figure 3.. Graphical test of proportional hazards assumption (Schoenfeld test).

The graphs show the scaled Schoenfeld residuals over time. The p-values (p) of the variables and the model as a whole were shown in the plot. A significant p-value (< 0.05) indicates that the variable violates the proportional hazard assumption. The solid line represents the smoothing fitted spline, and the dashed lines the confidence bands at two standard errors. Global Schoenfeld test p=0.58.

Appendix 2—figure 4.. Distribution of individuals according to their exposure to infectious agents (pathogen burden).

Bar plot showing the number of participants for each cumulative number of positive serological results, reflecting simultaneous ongoing chronic/latent infections. Sample sizes for each group are shown above the box.