Author Correction: The power of genetic diversity in genome-wide association studies of lipids

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doi:10.1038/s41586-023-06194-2

Cited by 7 publications

(3 citation statements)

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“…Lipid measurements were reported in mg/dl. To eliminate potential biases introduced by sample overlap, meta-analysis summary statistics ( n = 930,672) were screened to exclude individuals from the UK Biobank study ( n = 389,344) ( 18 ) while ensuring a homogeneous population of European descent. These data were used to perform TSMR and MVMR.…”

Section: Methodsmentioning

confidence: 99%

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis

Lou,

Meng,

Shi

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis.Materials and methodsData on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy.ResultsIn the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780–0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598–0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802–0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (1OR, 0.719 per SD reduction in LDL-C; 95% CI, 0.540–0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis.ConclusionsOur MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

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Section: Methodsmentioning

confidence: 99%

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis

Lou,

Meng,

Shi

et al. 2023

Front. Cardiovasc. Med.

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“…Accordingly, endogenous CLCC1 could be isolated from the endogenous TMEM41B immune-complex (Figure 2b). Moreover, genetic analysis based on the recently available GLGC (Global Lipid Genetics Consortium) data 25 uncovered strong associations between genetic variants in the human CLCC1 gene and plasma lipids in populations (Figure 2c&d and Extended Data Figure 3), particularly in atherogenic LDL levels (p = 1.69E - 41 , β = −0.078). Of note, the minor allele is present in rather low frequency in different ethnicities (less than or close to 0.01, Figure 2e), indicating possible strong biological effects of CLCC1 on lipid homeostasis.…”

Section: Leaflet Imbalance Directs Lipids Into Giant Er-enclosed Lipi...mentioning

confidence: 99%

“…GWAS summary statistics of the CLCC1 gene and plasma lipid levels were obtained from the GLGC dataset 25 and performed using LocusZoom (http://locuszoom.org/). The allele frequency in humans of rs149700491 SNP was available from 1000 Genome Phase 3.…”

Section: Association Analyses Of the Snps With Plasma Lipid Levelmentioning

confidence: 99%

CLCC1 Governs Bilayer Equilibration at the Endoplasmic Reticulum to Maintain Cellular and Systemic Lipid Homeostasis

Wu,

Wang,

Wang

et al. 2024

Preprint

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The intricate orchestration of lipid production, storage, and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardio-metabolic diseases, the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospho-lipids onto the lumenal apolipoprotein B (APOB), in a poorly-defined process7–10. Here we show that trans-bilayer equilibration of phospholipids, regulated by the ER protein CLCC1, determines lipid partition across the ER membrane and consequently systemic lipid homeostasis. CLCC1 partners with the phospholipid scramblase TMEM41B11,12to recognize imbalanced bilayers and promote lipid scrambling, thereby licensing lipoprotein biogenesis and the subsequent bulk lipid transport. Strikingly, loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by extensively imbalanced ER bilayers, and consequently drastically accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis (MASH). The above results establish phospholipid scrambling at the ER as the lynchpin to maintain a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13–16, our study may enable further elucidation of a previously under-appreciated homeostatic control mechanism intrinsic to the ER function in lipid biogenesis and distribution.

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Why the world needs more transparency on the origins of novel pathogens

Venter

2023

Nature

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Author Correction: The power of genetic diversity in genome-wide association studies of lipids

Cited by 7 publications

References 0 publications

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis

CLCC1 Governs Bilayer Equilibration at the Endoplasmic Reticulum to Maintain Cellular and Systemic Lipid Homeostasis

Why the world needs more transparency on the origins of novel pathogens

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