Biology subjects

Rheaume, E.

Publications and source records attributed to Rheaume, E..

3 recordsLinked to original sources

bioRxiv2026

CETP alternative splicing variation impacts human traits

The cholesteryl ester transfer protein (CETP) is an important protein in reverse cholesterol transport and has been identified as a significant factor associated with cardiovascular disease (CVD), making it a widely studied pharmaceutical target. Three protein-coding isoforms of CETP exist, distinguished by the alternative splicing of one exon each. The isoform primarily responsible for cholesterol-related functions in the plasma is well studied, but specific functions of each isoform remain poorly understood. In this study, we demonstrate the significance of considering CETPs isoforms in analyses of human traits. Using bulk RNA-seq data from multiple tissues, we characterized the expression patterns and genetic regulation determinants of CETP transcripts. Leveraging publicly available GWAS summary statistics, we conducted multivariable Mendelian Randomisation (MVMR) to estimate the impact of variation in isoform proportions on phenotypes, highlighting the importance of CETPs isoforms in pituitary and thyroid glands. Furthermore, we uncovered tissue-specific associations between CETPs isoforms and CVD-associated phenotypes. Additionally, we observed that the epistatic interaction previously reported between CETP and ADCY9, a gene implicated in modulating a CETP modulators response, may be mediated through the regulation of alternative splicing of exon 9. Our results underscore the importance of a comprehensive understanding of CETPs isoforms, which can significantly impact both fundamental and clinical research efforts.

genetics↗

bioRxiv2025

Manganese homeostasis modulates glucan and chitin unmasking in the opportunistic yeast Candida albicans

Candida albicans is a commensal fungus and also the most prevalent human fungal pathogen. The ability of this opportunistic yeast to acquire and maintain homeostatic levels of manganese (Mn), particularly in the metal-limited host environment, is an important determinant of its fitness. Recent studies have underscored the importance of Mn acquisition through members of Smf transporters, in C. albicans virulence and its ability to withstand various stresses. In the present study, we undertook transcriptional profiling in the mutant of the Mn transporter Smf12 under restricted Mn availability to identify processes that are directly affected in defective Mn uptake. Our analysis revealed that smf12 displayed a transcriptional pattern suggestive of a cell wall defect, with many transcripts associated with cell wall biogenesis being differentially regulated. smf12 together with smf11, a mutant of the closest homolog of Smf12, exhibited hypersensitivity to cell wall stressors and an altered cell wall ultrastructure. The smf mutants also exhibited unmasking of both {beta}-glucan and chitin, which unexpectedly resulted in a decreased rate of phagocytosis by macrophages, suggesting impaired recognition or internalization--an observation that challenges the prevailing paradigm. Furthermore, we showed that Mn-mediated unmasking of {beta}-glucan required modulation of glucanase activity and was not mediated through the calcineurin pathway. This study uncovers a novel role for Mn in maintaining cell wall integrity and modulating the exposure of fungal antigenic determinants, further emphasizing the critical role of this metal in supporting the opportunistic nature of C. albicans.

microbiology↗

bioRxiv2021

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapibs pharmacogene ADCY9 and its therapeutic target CETP.

genetics↗