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Background and PurposeCoronary 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.Participants and MethodsStudy 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 five years. We analyzed a subgroup of 3’459 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.ResultsOf the 3’459 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 1.10–156, P = 2.64e-03) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08–2.45, P = 1.99e-02) were independently associated with incident CHD.ConclusionIn a prospective, population-based cohort, high polygenic risk and infection with Fusobacterium nucleatum have a small, yet independent impact on CHD risk.