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Sex-specificity at the UGT2B17 Locus. A. The association signal for LDL-C (top
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Genetic variants within nearly 1,000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. To expand our understanding of the underl...
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Context 1
... of these loci also show a sex-biased eQTL effect in at least one tissue in the direction concordant with the observed sex-specificity of the GWAS effect (Table S19). Amongst these ten is CETP, a gene with strong prior evidence for association with lipids, and UGT2B17 20 (Supplementary Note, Figure 3). The lead variant of UGT2B17, rs4860987, shows a significantly stronger effect on LDL-C in males (Beta male =0.042, ...
Context 2
... of these loci also show a sex-biased eQTL effect in at least one tissue in the direction concordant with the observed sex-specificity of the GWAS effect (Table S19). Amongst these ten is CETP, a gene with strong prior evidence for association with lipids, and UGT2B17 20 (Supplementary Note, Figure 3). The lead variant of UGT2B17, rs4860987, shows a significantly stronger effect on LDL-C in males (Beta male =0.042, ...
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Background
Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.
Results
To expand our understa...
Citations
... It has been shown that PRSs for around half of the blood cell traits result in different levels of stratification between men and women (Xu et al., 2022). Furthermore, when a sex-stratified GWAS meta-analysis for lipid levels was performed to evaluate the underlying biological pathways and mechanisms of blood lipid levels (Kanoni et al., 2021), it was discovered that three to five percent of autosomal lipid-associated loci had sex-biased effects and that many of these sex-biased autosomal lipid loci have pleiotropic associations with sex hormones (Kanoni et al., 2021). Some of these sex differences are thought to be explained by genotype-by-sex interactions (GxS). ...
... It has been shown that PRSs for around half of the blood cell traits result in different levels of stratification between men and women (Xu et al., 2022). Furthermore, when a sex-stratified GWAS meta-analysis for lipid levels was performed to evaluate the underlying biological pathways and mechanisms of blood lipid levels (Kanoni et al., 2021), it was discovered that three to five percent of autosomal lipid-associated loci had sex-biased effects and that many of these sex-biased autosomal lipid loci have pleiotropic associations with sex hormones (Kanoni et al., 2021). Some of these sex differences are thought to be explained by genotype-by-sex interactions (GxS). ...
The polygenic risk score (PRS) is calculated as the weighted sum of an individual’s genotypes and their estimated effect sizes, which is often used to estimate an individual’s genetic susceptibility to complex traits and disorders. It is well known that some complex human traits or disorders have sex differences in trait distributions, disease onset, progression, and treatment response, although the underlying mechanisms causing these sex differences remain largely unknown. PRSs for these traits are often based on Genome-Wide Association Studies (GWAS) data with both male and female samples included, ignoring sex differences. In this study, we present a benchmark study using both simulations with various combinations of genetic correlation and sample size ratios between sexes and real data to investigate whether combining sex-specific PRSs can outperform sex-agnostic PRSs on traits showing sex differences. We consider two types of PRS models in our study: single-population PRS models (PRScs, LDpred2) and multiple-population PRS models (PRScsx). For each trait or disorder, the candidate PRSs were calculated based on sex-specific GWAS data and sex-agnostic GWAS data. The simulation results show that applying LDpred2 or PRScsx to sex-specific GWAS data and then combining sex-specific PRSs leads to the highest prediction accuracy when the genetic correlation between sexes is low and the sample sizes for both sexes are balanced and large. Otherwise, the PRS generated by applying LDpred2 or PRScs to sex-agnostic GWAS data is more appropriate. If the sample sizes between sexes are not too small and very unbalanced, combining LDpred2-based sex-specific PRSs to predict on the sex with a larger sample size and combining PRScsx-based sex-specific PRSs to predict on the sex with a smaller size are the preferred strategies. For real data, we considered 19 traits from Genetic Investigation of ANthropometric Traits (GIANT) consortium studies and UK Biobank with both sex-specific GWAS data and sex-agnostic GWAS data. We found that for waist-to-hip ratio (WHR) related traits, accounting for sex differences and incorporating information from the opposite sex could help improve PRS prediction accuracy. Taken together, our findings in this study provide guidance on how to calculate the best PRS for sex-differentiated traits or disorders, especially as the sample size of GWASs grows in the future.
Background: Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, gene APOA5) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring human APOA5 variants can provide novel insights.
Methods: We used hydrogen-deuterium exchange mass spectrometry to determine the secondary structure of human apoA-V in lipid-free and lipid-associated conditions and identified a C-terminal hydrophobic face. Then, we used genomic data in the Penn Medicine Biobank to identify a rare variant, Q252X, predicted to specifically eliminate this region. We interrogated the function of apoA-V Q252X using recombinant protein in vitro and in vivo in apoa5 knockout mice.
Results: Human apoA-V Q252X carriers exhibited elevated plasma TG levels consistent with loss of function. Apoa5 knockout mice injected with AAV vectors expressing wildtype and variant APOA5-AAV recapitulated this phenotype. Part of the loss of function is due to reduced mRNA expression. Functionally, recombinant apoA-V Q252X was more readily soluble in aqueous solutions and more exchangeable with lipoproteins than WT apoA-V. Despite lacking the C-terminal hydrophobic region (a putative lipid binding domain) this protein also decreased plasma TG in vivo.
Conclusions: Deletion of apoA-V's C-terminus leads to reduced apoA-V bioavailability in vivo and higher TG levels. However, the C-terminus is not required for lipoprotein binding or enhancement of intravascular lipolytic activity. WT apoA-V is highly prone to aggregation, and this property is markedly reduced in recombinant apoA-V lacking the C-terminus.
Background
Despite well‐recognized differences in the atherosclerotic cardiovascular disease risk between men and women, sex differences in risk factors and sex‐specific mechanisms in the pathophysiology of atherosclerotic cardiovascular disease remain poorly understood. Lipid metabolism plays a central role in the development of atherosclerotic cardiovascular disease. Understanding sex differences in lipids and their genetic determinants could provide mechanistic insights into sex differences in atherosclerotic cardiovascular disease and aid in precise risk assessment. Herein, we examined sex differences in plasma lipidome and heterogeneity in genetic influences on lipidome in men and women through sex‐stratified genome‐wide association analyses.
Methods and Results
We used data consisting of 179 lipid species measured by shotgun lipidomics in 7266 individuals from the Finnish GeneRISK cohort and sought for replication using independent data from 2045 participants. Significant sex differences in the levels of 141 lipid species were observed ( P <7.0×10 ⁻⁴ ). Interestingly, 121 lipid species showed significant age‐sex interactions, with opposite age‐related changes in 39 lipid species. In general, most of the cholesteryl esters, ceramides, lysophospholipids, and glycerides were higher in 45‐ to 50‐year‐old men compared with women of same age, but the sex differences narrowed down or reversed with age. We did not observe any major differences in genetic effect in the sex‐stratified genome‐wide association analyses, which suggests that common genetic variants do not have a major role in sex differences in lipidome.
Conclusions
Our study provides a comprehensive view of sex differences in circulatory lipids pointing to potential sex differences in lipid metabolism and highlights the need for sex‐ and age‐specific prevention strategies.
