Jacques Fellay | EPFL Graph Search

Jacques Fellay is a medical scientist with expertise in infectious diseases and human genomics. He obtained his MD from the University of Lausanne in 2002 and his PhD from University of Utrecht. After a clinical training in infectious diseases in Switzerland and a 4-years postdoctoral fellowship at Duke University, he joined the EPFL in April 2011 with an SNF Professorship.

On top of his EPFL affiliation, Jacques is also Head of Precision Medicine at the University Hospital (CHUV) in Lausanne, Group Leader at the Swiss Institute of Bioinformatics, and Co-director of the Health2030 Genome Center at Campus Biotech in Geneva.

Associations of genetic and infectious risk factors with coronary heart disease

Roxane De La Harpe, Jacques Fellay, Flavia Aurelia Shoko Hodel, Prunelle Louise Cécile Letang-Mathieu, Christian Axel Wandall Thorball, Zhi Ming Xu

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 x 10(-3)) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, p=1.99 x 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.

eLIFE SCIENCES PUBL LTD2023

Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania

Jacques Fellay, Zhi Ming Xu

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam. Author summaryTuberculosis (TB) is among the deadliest human infectious diseases caused by one single agent, Mycobacterium tuberculosis (Mtb). The origins of Mtb have been traced to East Africa millennia ago, where it likely became adapted to infect and transmit in humans. Here, we show that in Dar es Salaam, Tanzania, an East African setting with a high burden of TB, infections are caused by distinct Mtb genotypes introduced in recent evolutionary times from different parts of the world. These genotypes differed in traits important to Mtb transmission; while some Mtb genotypes transmitted more efficiently during a given period of time, patients infected by other genotypes remained infectious for longer. These traits evolved independently in the different Mtb genotypes and could not be explained by the time of co-existence between the host population and the pathogen. This suggests that bacterial factors are important determinants of the TB epidemic. More generally, we demonstrate that distinct pathogenic life history characteristics can co-exist in one host population.

PUBLIC LIBRARY SCIENCE2023

Combining European and US risk prediction models with polygenic risk scores to refine cardiovascular prevention: the CoLaus|PsyCoLaus Study

Roxane De La Harpe, Jacques Fellay, Stéphane Fournier, Christian Axel Wandall Thorball

Lay Summary The aim of this study is to determine whether using polygenic risk scores improves the prediction of atherosclerotic cardiovascular disease risk when combined with clinical scores currently recommended by European and US guidelines on cardiovascular prevention. Aims A polygenic risk score (PRS) has the potential to improve individual atherosclerotic cardiovascular disease (ASCVD) risk assessment. To determine whether a PRS combined with two clinical risk scores, the Systematic COronary Risk Evaluation 2 (SCORE2) and the Pooled Cohort Equation (PCE) improves the prediction of ASCVD. Methods and results Using a population-based European prospective cohort, with 6733 participants at the baseline (2003-2006), the PRS presenting the best predictive accuracy was combined with SCORE2 and PCE to assess their joint performances for predicting ASCVD Discrimination, calibration, Cox proportional hazard regression, and net reclassification index were assessed. : 4218 subjects (53% women; median age, 53.4 years), with 363 prevalent and incident ASCVD, were used to compare four PRSs. The metaGRS_CAD PRS presented the best predictive capacity (AUROC = 0.77) and was used in the following analyses. 3383 subjects (median follow-up of 14.4 years), with 190 first-incident ASCVD, were employed to test ASCVD risk prediction. The changes in C statistic between SCORE2 and PCE models and those combining metaGRS_CAD with SCORE2 and PCE were 0.008 (95% CI, -0.00008-0.02, P = 0.05) and 0.007 (95% CI, 0.005-0.01, P = 0.03), respectively. Reclassification was improved for people at clinically determined intermediate-risk for both clinical scores [NRI of 9.6% (95% CI, 0.3-18.8) and 12.0% (95% CI, 1.5-22.6) for SCORE2 and PCE, respectively]. Conclusion Combining a PRS with clinical risk scores significantly improved the reclassification of risk for incident ASCVD for subjects in the clinically determined intermediate-risk category. Introducing PRSs in clinical practice may refine cardiovascular prevention for subgroups of patients in whom prevention strategies are uncertain.

OXFORD UNIV PRESS2023