Rioux, J. | Search bioRxiv

bioRxiv2021

Human enteric viruses shape disease phenotype through divergent innate immunomodulation

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched Picornovirus Enterovirus B, not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential. One Sentence SummaryHuman viromes divergently shape host immunity and disease

immunology↗

bioRxiv2019

The effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death

BackgroundSudden cardiac death (SCD) accounts for ~300,000 deaths annually in the US. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease (CAD) than women. In contrast, women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the underlying genetics of QT interval duration. Using sex- and CAD-stratified analyses, we assess differences in genetic association between prolonged QT interval and SCD risk.\n\nMethodsWe examined 2,282 SCD subjects with autopsy-confirmed underlying disease from the Fingesture cohort and 3,561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic vs. non-ischemic) and by sex. We used logistic regression to test for association between the top QT interval associated SNP, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups.\n\nResultsFemale SCD victims with underlying non-ischemic disease had the strongest association between rs12143842 and SCD risk (OR=1.37; 95% CI, 1.07-1.75) and the strongest causal association, established using Mendelian randomization, between prolonged QT interval and SCD (OR in SCD risk per SD increase in QT, 3.60; 95% CI, 1.22-10.49). Ischemic SCD victims, irrespective of sex, did not show an association between rs12143842 and SCD risk or a causal association for QT interval.\n\nConclusionsThis study provides evidence that the causal effect of QT prolongation on SCD risk differs by sex and underlying disease.

genetics↗