The interplay between human genetic variation, chronic inflammation and persistent infection: relevance for cardiovascular morbidity

Contemporary genomic approaches allow us to seek answers to biological questions that were previously out of reach. Genome-wide association studies (GWAS) have identified numerous genetic polymorphisms associated with human diseases, providing new insight into the genes and pathways involved in pathogenesis. The work presented in this thesis aimed to harness the power of large-scale genomics, statistical methods and bioinformatic tools to explore the interactions between persistent infections, chronic low-grade inflammation, and coronary heart disease (CHD). To achieve this, we used data collected from large population-based studies of individuals of European ancestry.

To identify human genetic determinants of the humoral immune response against persistent or frequently recurring infections, with a special focus on human polyomaviruses, we performed GWAS and meta-analyses of serostatus and quantitative immunoglobulin G responses. We identified NFKB1 as a common locus associated with antibody response to multiple pathogens. For polyomaviruses, we found strong associations of HLA class II, FUT2, STING1, and MUC1 genetic variants with the intensity of the humoral response. Together, these results demonstrate the modulating contribution of host genetic variation to the individual response against some of the most prevalent human viruses.

Even when they are latent, chronic infections can trigger some degree of local or systemic immune response, resulting in low-grade inflammation. In an effort to better understand the variability of humoral immune response and inflammation patterns in response to pathogen exposure, we found evidence for an association between Chlamydia trachomatis and Helicobacter pylori seropositivity, and higher plasma levels of C-reactive protein (CRP), a sensitive indicator of inflammation. High polygenic risk was also significantly associated with CRP levels, confirming that human genetic variation plays a modulating role in systemic inflammation. These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.

Finally, we developed statistical models to explore the influences of genetic variation, persistent infections and low-grade inflammation on incident CHD. We identified high polygenic risk and Fusobacterium nucleatum infection as associated with an increased risk of developing CHD, in addition to conventional risk factors. These results confirm that CHD is a multicomponent disease that is caused by demographic, genetic and environmental factors. Moreover, they might allow for better identification of individuals at high risk for CHD and provide a rationale for future anti-infective prevention trials.

Together, this research demonstrates that current genomic and serological technology, bioinformatic analysis and functional follow-up studies have the potential to provide new insight into the molecular basis of ho