Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition

Kettunen, J.; Holmes, M. V.; Allara, E.; Anufrieva, O.; Ohukainen, P.; Oliver-Williams, C.; Tillin, T.; Hughes, A.; Kahonen, M.; Lehtimaki, T.; Viikari, J.; Raitakari, O.; Salomaa, V.; Jarvinen, M.-R.; Perola, M.; Davey Smith, G.; Chaturvedi, N.; Danesh, J.; Di Angelantonio, E.; Butterworth, A.; Ala-Korpela, M.

doi:10.1101/295394

Home/Archive/bioRxiv

bioRxiv · 10.1101/295394

Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition

View original source ↗Export metadata ↓

Abstract

BackgroundCETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins.\n\nMethods and ResultsWe used variants associated with CETP (rs247617) and HMGCR (rs12916) expression in 62,400 Europeans with detailed lipoprotein profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% lower risk of coronary heart disease (CHD). Associations of lipoprotein measures with risk of incident CHD in three population-based cohorts (770 cases) were examined.\n\nCETP and HMGCR had near-identical associations with LDL-cholesterol concentration estimated by Friedewald-equation. HMGCR had a relatively consistent effect on cholesterol concentrations across all apolipoprotein B-containing lipoproteins. CETP had stronger effects on remnant and very-low-density lipoprotein cholesterol but no effect on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02SD 95%CI: -0.10, 0.05 for CETP versus -0.24SD, 95%CI -0.30, -0.18 for HMGCR). CETP had profound effects on lipid compositions of lipoproteins, with strong reductions in the triglyceride content of all highdensity lipoprotein (HDL) particles. These alterations in triglyceride composition within HDL subclasses were observationally associated with risk of CHD, independently of total cholesterol and triglycerides (strongest HR per 1-SD higher triglyceride composition in very-large HDL 1.35; 95%CI: 1.18, 1.54).\n\nConclusionCETP inhibition does not affect size-specific LDL cholesterol but may lower CHD risk by lowering cholesterol in other apolipoprotein-B containing lipoproteins and lowering triglyceride content of HDL particles. Conventional composite lipid assays may mask heterogeneous effects of lipid-altering therapies.

Source connections

Published article ↗

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Kettunen, J., Holmes, M. V., Allara, E., Anufrieva, O., Ohukainen, P., Oliver-Williams, C., Tillin, T., Hughes, A., Kahonen, M., Lehtimaki, T., Viikari, J., Raitakari, O., Salomaa, V., Jarvinen, M.-R., Perola, M., Davey Smith, G., Chaturvedi, N., Danesh, J., Di Angelantonio, E., Butterworth, A., Ala-Korpela, M.. 2018-04-05. Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition. https://doi.org/10.1101/295394

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Genetic diversity of endangered Acropora spp. corals in Bonaire: implications for restoration and gene banking

Species restoration is a valuable tool to combat biodiversity loss. However, maintaining genetic diversity in species restoration is challenging, particularly for species that can reproduce asexually, such as plants and corals, because a seemingly diverse collection of individuals could be composed of many clones of a few genotypes. Caribbean elkhorn and staghorn corals (Acropora palmata, A. cervicornis) are critically endangered reef-building corals that are a major target for restoration. To better understand the genetic diversity of an Acropora spp. restoration program and interpret local population genetic structure, we conducted microsatellite genotyping on the gene banks of 35 A. palmata lineages and 25 A. cervicornis lineages maintained by Reef Renewal Foundation Bonaire (RRFB) in the Caribbean Netherlands. We found that RRFB had high genotypic richness for A. palmata (0.971) and A. cervicornis (1.0) and estimated that they captured 88.9% and 74.7% of Bonaires microsatellite asymptotic allelic diversity, respectively. Compared to populations of Acropora spp. studied in other locations across the Caribbean, A. palmata in Bonaire had relatively low expected heterozygosity, while A. cervicornis was greater than approximately half of other populations. Across Bonaire and for both coral species, we did not find evidence for genetic structuring among spatially separated subpopulations, indicating that both species are likely well-connected around the island. Together, these results demonstrate the effectiveness of RRFBs strategies to capture high genetic diversity and can be used to inform future initiatives on coral sexual breeding and assisted gene flow beyond Bonaire.

genetics↗

bioRxiv2026

Unravelling genomic and environmental contributions to nitrogen-use efficiency in tropical maize through Bayesian causal forests

Nitrogen fertilisation is one of the largest variable input costs in maize production, and genotypes differ in how efficiently they convert added nitrogen into yield. Breeding for nitrogen-use efficiency therefore depends on knowing not only the average response of the crop to nitrogen but how that response varies across genotypes and environments. We frame this as a problem of causal inference and estimate the effect of an ideal versus low nitrogen regime on three maize traits jointly (grain yield, plant height and ear height) using a multivariate Bayesian causal forest. To our knowledge, this is among the first studies to quantify the effect of nitrogen in a genotyped breeding panel as a formally identified causal quantity, estimated from a designed contrast within the potential-outcomes framework, rather than as the genotype-environment association that genomic selection and association mapping report. The trial suits a causal reading: 614 single-cross hybrids were grown under both nitrogen levels in adjacent plots sharing weather and soil, so nitrogen was assigned by design rather than confounded with genotype or environment, and the estimated propensity score was close to 0.5. The leading principal components of the additive genomic relationship matrix were placed in the moderator set, so that both the baseline outcome and the treatment effect could vary with genomic background. Ideal nitrogen raised all three traits (grain yield +0.59, 95% credible interval 0.51 to 0.67; plant height +0.095; ear height +0.044, in adjusted-phenotype units). The heterogeneity of the effect was almost entirely environmental, with a small genotypic component and negligible genotype-by-environment interaction; the posterior credible interval of the effect was wider than the spread among genotypes, so differences in responsiveness among hybrids were only weakly resolved. Reading the two tree ensembles separately indicated that genomic background governs the yield level while climate governs the response to nitrogen, the leading genomic contribution being a single axis. A reaction-norm variance decomposition and cross-validated prediction corroborated this reading. A multivariate causal forest with genomic moderators, read through its two ensembles and reported with posterior uncertainty, is a suitable and transparent tool for studying nitrogen response in breeding material.

genetics↗

bioRxiv2026

X-Chromosomal STR-based analysis of genetic diversity, structure, and phylogeny in the Sri Lankan Vedda population

The Vedda people are regarded as the direct descendants of Sri Lanka's Mesolithic hunter-gatherers and represent one of South Asia's oldest surviving indigenous populations. X-chromosomal short tandem repeat (X-STR) analysis provides a powerful framework to examine their genetic distinctiveness, as the X chromosome exhibits sex-biased biparental inheritance and greater sensitivity to demographic and evolutionary forces compared to autosomal markers. However, no X-STR-based genetic investigations have yet been conducted on this population. In the present study, we successfully genotyped 50 unrelated Veddas individuals using a recently developed 16 X-STR multiplex PCR system optimized for Sri Lankan populations. Our analyses revealed a statistically significant genetic differentiation (2.43%) between the Veddas and the principal local ethnic groups; Sinhalese, Sri Lankan Tamils, Indian Tamils, and Moors exceeding previous estimates based on autosomal STR markers. Comparative analysis with 32 global populations positioned the Veddas as a genetically distinct and isolated group, separated from clusters representing South Asians, Europeans, Middle Easterners, and other indigenous populations such as Australian Aboriginals, Bhil Indians, and Kedayans, emphasizing their unique genetic heritage. Reduced allelic (115) and haplotype (62) counts, alongside significant linkage disequilibrium detected among eight pairs of X-STR loci, reflect the influence of genetic drift within this small, endogamous, and historically isolated population. These findings highlight the evolutionary and demographic distinctiveness of the Veddas and provide essential baseline data for future population genomic studies. Furthermore, the demonstrated high discriminatory power of the 16 X-STR loci supports their continued application in population genetics and anthropological research within this unique community.

genetics↗