Effects Of Low-density Lipoprotein Cholesterol Research Articles

Genetically predicted lipid traits mediate the association between folic acid and atherosclerosis

Atherosclerosis (AS) is one of the most common causes of death from cardiovascular disease, and low folic acid (FA) levels have been reported to be strongly associated with an increased risk of AS. We aimed to obtain causal estimates of the association between FA and AS and to quantify the mediating role of known modifiable risk factors. Based on the largest genome-wide association study (GWAS) from the IEU Open GWAS Project for all human studies, we conducted a two-sample Mendelian randomization (MR) study of genetically predicted FA and AS. A two-step MR design was then used to assess the causal mediating effect of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) on the relationship between FA and AS. This MR analysis showed that genetically determined FA levels [IVW: Odds Ratio (OR) = 0.623, 95% CI 0.421–0.924, P = 0.018] were associated with a reduced risk of AS. Inverse variance weighted (IVW) MR analysis also showed that genetically predicted FA was positively correlated with HDL-C levels (OR = 1.358, 95% CI 1.029–1.792, P = 0.031) and negatively correlated with LDL-C (OR = 0.956, 95% CI 0.920–0.994, P = 0.023) and TG levels (OR = 0.929, 95% CI 0.886–0.974, P = 0.003). LDL-C, HDL-C, and TG mediate 3.00%, 6.80%, and 4.40%, respectively, of the total impact of FA on AS. The combined effect of these three factors accounts for 13.04% of the total effect. Sensitivity analysis verifies the stability and reliability of the results. These results support a potential causal protective effect of FA on AS, with considerable mediation through many modifiable risk factors. Thus, interventions on levels of LDL-C, HDL-C, and TG have the potential to substantially reduce the burden of AS caused by low FA.

Effects of low-density lipoprotein cholesterol on sleep apnea: Insights from a rat model of cardiovascular autonomic dysregulation

IntroductionThe levels of low-density lipoprotein (LDL) cholesterol in plasma are important risk factors for coronary heart disease. Several reports suggest that elevated plasma cholesterol is associated with cardiac arrhythmias. In a subsequent study investigating LDL cholesterol levels and the frequency of LDL cholesterol measurements, a positive correlation was observed between the severity of sleep apnea and visit-to-visit LDL cholesterol variability. Our objective was to assess the effects of hypercholesterolemia on cardiac autonomic activity, disordered sleep patterns, and increased incidence of arrhythmias in freely moving rats. MethodsWireless transmission of polysomnographic recordings was performed in control and high cholesterol male rats during normal daytime sleep. Spectral analyses were conducted on the electroencephalogram and electromyogram (EMG) recordings to distinguish active waking, quiet sleep, and paradoxical sleep. Heart rate variability power spectrum analysis was used to measure cardiac autonomic activity. ResultsThe high cholesterol group exhibited a higher low-frequency (LF)/high-frequency (HF) power ratio during all sleep stages compared to the control group. Additionally, the frequency of sleep interruptions was increased in the high cholesterol group compared to the control group. ConclusionsOur results show significant sleep fragmentation with sympathetic hyperactivity after exposure to high cholesterol. This indicates that high cholesterol may increase the risk of sleep apnea and poor sleep quality by disrupting autonomic homeostasis.

The effect of low-density lipoprotein cholesterol on T-cell mitochondrial respiration

Aging is associated with an increase in chronic, sterile, low-grade inflammation, known as “inflammaging” that is implicated in the development of multiple diseases, including cardiovascular disease. Immune cells are the primary source of inflammaging, of which T-cells play a major contributing role. Mitochondria are essential for maintaining proper T-cell function and reduced mitochondrial respiration (MitoRESP) induces T-cell dysfunction and shifts T-cells towards a pro-inflammatory phenotype. Elevated low-density lipoprotein cholesterol (LDL-C) is cross-sectionally associated with lower MitoRESP in circulating immune cells and may contribute to the inflammaging phenotype, but whether LDL-C is causally related to impaired MitoRESP in T-cells is not known. We hypothesized that treating T-cells in vitro with a high concentration of exogenous LDL-C would mimic accelerated aging by impairing T-cell MitoRESP from young adults. Seven young adults were recruited for this study (6 female / 1 male, age: 23 ± 2 years, BMI: 23.29 ± 6.4 kg/m2, total cholesterol: 154 ± 16 mg/dl, high-density lipoprotein cholesterol: 59 ± 17 mg/dL, & LDL-C: 78 ± 14 mg/dL). CD4+ and CD8+ T-cells were separated from peripheral blood mononuclear cells isolated using magnetic bead separation (Miltenyi). CD4+ and CD8+ T-cells were treated exogenously with a physiologically normal (1.8 mMol/L) and high (4.9 mMol/L) concentration of LDL-C for 24 hours. MitoRESP was assessed using extracellular flux analysis (Agilent). Compared with the low LDL condition, the high LDL-C condition lowered basal (0.47 ± 0.06 vs. 0.35 ± 0.10 pMol/min/105 cells, p=0.031) and ATP-linked oxygen consumption rate (OCR) (0.51 ± 0.13 vs. 0.35 ± 0.12 pMol/min/105 cells, p=0.016) in CD8+ T-cells. High LDL-C also lowered non-mitochondrial OCR (0.71 ± 0.22 vs. 0.57 ± 0.20 pMol/min/105 cells, p=0.016) and augmented basal glycolysis (0.097 ± 0.049 vs. 0.14 ± 0.036 pMol/min/105 cells, p=0.031) in CD8+ T-cells. High LDL-C lowered ATP-linked OCR (0.69 ± 0.23 vs. 0.54 ± 0.22 pMol/min/105 cells, p=0.031) and non-mitochondrial OCR (0.80 ± 0.17 vs. 0.68 ± 0.21 pMol/min/105 cells, p=0.016), but did not statistically alter basal OCR (0.47 ± 0.056 vs. 0.35 ± 0.10 pMol/min/105 cells, p=0.063) or basal glycolysis (0.14 ± 0.031 vs. 0.18 ± 0.028 pMol/min/105 cells, p=0.063) in CD4+ T-cells. Treatment with a high LDL-C accelerated aging in T-cells from young adults by impairing MitoRESP and shifting T-cells towards glycolytic metabolism. Future studies should explore the relation between age-related impairments in T-cell MitoRESP and cardiovascular function in humans. Funding Sources: P20GM113125 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Serum LDL-C, CysC, and D-D in Patients with Coronary Atherosclerotic Heart Disease

Objective To investigate the effects of low-density lipoprotein cholesterol (LDL-C) and serum cystatin C (CysC) combined with D-dimer (D-D) on patients with coronary atherosclerotic heart disease (CHD). Methods 90 patients with CHD who were admitted to our hospital and diagnosed by coronary angiography (CAG) from February 2020 to June 2021 were selected as the study subjects. 90 patients were grouped according to different types and branches of coronary lesions, and 30 patients with outpatient health check-ups at the same period were selected as the control group, and the differences in serum LDL-C, CysC, and D-D levels between the groups were compared. The logistic regression model was built to explore risk factors affecting the occurrence of CHD. Also, receiver operating characteristic (ROC) curves were drawn to analyze the diagnostic value of LDL-C, CysC, and D-D in CHD. Results In the comparison of LDL-C, CysC, and D-D levels, CHD group > control group (P < 0.05); stable angina (SAP) group > unstable angina (UAP) group > acute myocardial infarction (AMI) group (P < 0.05); three-branch group > two-branch group > single-branch group (P < 0.05). The logistic regression model showed that high expression levels of LDL-C, CysC, and D-D, male gender, and combined hypertension were risk factors for CHD. The area under the curve (AUC) of the combination of LDL-C, CysC, and D-D was 0.868, and the sensitivity and specificity were 88.89% and 73.33%, respectively, which are higher than those in single diagnosis (P < 0.05). Conclusions LDL-C, CysC, and D-D are highly expressed in CHD samples, and the combination of the three is beneficial to enhance the diagnostic accuracy of clinical CHD.

The Effect of Low-Density Lipoprotein Cholesterol (LDL-C) 1-Year Post-PCI on Long-Term Mortality and MACE: Results From a Large Multi-Centre Registry

Patients undergoing PCI remain at high residual risk of further major adverse. Although lipid-lowering therapy is recommended post-PCI, specific LDL-C targets are lacking. This study investigated the impact of progressively lower levels of LDL-C reduction 1 year post PCI (<1.4 vs ≥1.4 mmol/L group A, <1.8 vs ≥1.8 mmol/L group B, or <2.6 vs ≥2.6 mmol/L group C) on death and MACE 3 years post-PCI.

The effects of LDL cholesterol and pitavastatin treatment on fibroblast migration, SREBP-2, and LDLr expression

Most non-healing wounds show a lack of cell migration contributing to chronic inflammation and infection. Cholesterol levels in the blood may have an impact on cell migration, as migrating cells demonstrate a need for cholesterol in order to synthesize additional cell membranes. Statins are a popular drug used for lowering blood cholesterol by competitive inhibition of HMG CoA reductase, a pivotal step in the cholesterol synthesis pathway. In this study, we examined the effects of low-density lipoprotein (LDL) and statin treatment on fibroblasts in vitro. A cholesterol ELISA was utilized to examine cholesterol levels in cultured fibroblasts following treatment with pitavastatin or LDL. A scratch-test assay was performed to examine fibroblast migration following treatment in addition to the MTT cell proliferation assay. Western blot analysis was used to examine the cholesterol signalling protein SREBP-2 and LDLr expression in treated cells. LDL treatment enhanced cell proliferation and migration, while both were inhibited by pitavastatin. Pitavastatin increased both SREBP-2 and LDLr expression in treated cells compared to LDL and vehicle control treatments. These results indicate pitavastatin inhibits cell migration and the cellular response is to increase cholesterol levels to make up for the inhibition of cholesterol synthesis though the mevalonate pathway. This could have significant effects on cell migration and wound healing in vivo for patients with inhibited wound healing responses on statin therapy.

The Effect of Low-Density Lipoprotein Cholesterol (LDL-C) 1 Year Post-PCI on Long-Term Unplanned Readmissions: Results From a Large Multi-Centre Registry

Patients undergoing PCI remain at high residual risk of further major adverse events. Although lipid-lowering therapy is recommended post-PCI, specific LDL-C targets are lacking. This study investigated the impact of progressively lower levels of LDL-C reduction 1 year post PCI (<1.4 vs ≥1.4 mmol/L group A, <1.8 vs ≥1.8 mmol/L group B or <2.6 vs ≥2.6 mmol/L group C) on unplanned readmission 3 years post-PCI.

POSA136 What Are the Benefits of Treatment of Familial Hypercholesterolaemia? A Cost-Effectiveness Model Based on Real-World Data Considering Cholesterol Burden

To develop a new cost-effectiveness model, using real-world data, to predict long-term health outcomes and costs of patients with familial hypercholesterolaemia (FH), with and without treatment, and considering the increased effect of low-density lipoprotein cholesterol (LDL-C) over time on cardiovascular risk (known as cholesterol burden).

A Role for ER-Beta in the Effects of Low-Density Lipoprotein Cholesterol and 27-Hydroxycholesterol on Breast Cancer Progression: Involvement of the IGF Signalling Pathway?

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

Association Between Genetically Proxied Lipid-Lowering Drug Targets and Renal Cell Carcinoma: A Mendelian Randomization Study.

Observational studies suggested inconsistent associations between lipid-lowering drugs, such as statins, and renal cell carcinoma (RCC) risk. In a two-sample Mendelian randomization (MR) framework, we assessed the causal influence of lipid-lowering agents and circulating lipid traits on overall and sex-specific RCC risk. Genetic variants of six drug-target genes were selected to proxy the effects of low-density lipoprotein cholesterol (LDL-C) lowering therapies. Instrumental variables for circulating lipid traits were constructed from two large genome-wide association studies. We used endpoints for RCC from summary statistics of two studies [International Agency for Research on Cancer [IARC], N = 13,230; National Cancer Institute [NCI], N = 4,735]. The robustness of results was assessed through conventional MR sensitivity analyses. Overall, there was no significant association between genetically proxied HMG-CoA reductase (HMGCR) inhibition and RCC risk [Odds ratio [OR] = 1.42, 95% CI, 0.29–6.99]. In the sex-stratified analysis, we observed a positive association for genetically proxied drug targets with RCC risk. Specifically, genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition was associated with a higher risk of RCC in men [OR = 2.20 [95% CI, 1.24–3.89]], and the difference by sex was moderate. This study suggested genetically proxied inhibition of HMGCR was not associated with RCC risk, while genetically proxied PCSK9 inhibition might be associated with a higher risk of RCC in male.

Effects of low-density lipoprotein cholesterol on cardiovascular disease and all-cause mortality in elderly patients (≥75 years old).

Although increased low-density lipoprotein cholesterol (LDL-C) is one of the major risk factors for the cardiovascular disease (CVD), the associations of LDL-C with CVD and all-cause mortality are unclear in elderly (≥75 years) individuals. A total of 3674 individuals aged 75 or older underwent medical examinations at the Kailuan Group from 2006 to 2007, including 3478 males (94.67%) and 196 females (5.33%). Participants were divided into three groups based on the LDL-C level: the ideal level (LDL-C < 100 mg/dl), appropriate level (100 mg/dl ≤ LDL-C < 130 mg/dl) and elevated level (LDL-C ≥ 130 mg/dl) groups. CVD and all-cause mortality events were recorded during the follow-up period. The Cox proportional hazards regression model was applied to evaluate the effects of LDL-C on CVD and all-cause mortality events. The average follow-up time was 9.87 ± 3.60 years. After adjustment for confounding factors, the multivariate Cox proportional hazards regression model showed that the CVD risk in the elevated level group was 1.45 (95% CI, 1.08-1.95), acute myocardial infarction risk was 1.96 (95% CI, 1.19-3.24) and all-cause mortality risk was 1.18 (95% CI, 1.02-1.37) compared with those in the ideal level group. For every standard deviation increase in LDL-C levels, the CVD risk increased by 10%, acute myocardial infarction risk increased by 21% and all-cause mortality event risk increased by 4%. No association was observed between elevated LDL-C levels and the risk of stroke. In the sample of older Chinese individuals investigated in the present study, elevated LDL-C levels (≥130 mg/dl) are a risk factor for CVD and all-cause mortality.

Synergistic Neuroprotective Effects of Mature Silkworm and Angelica gigas Against Scopolamine-Induced Mild Cognitive Impairment in Mice and H2O2-Induced Cell Death in HT22 Mouse Hippocampal Neuronal Cells.

We previously reported that mature Bombyx mori silkworm (SW) ameliorated scopolamine (Sco)-induced amnesia, and Angelica gigas (AG) prevented cognitive impairment. SW is known for its gastroprotective effects such as improving liver function and alleviating the effects of Parkinson's disease. AG is known for its neuroprotective effects and for lowering the effects of low-density lipoprotein cholesterol. However, the neuroprotective effect of combined SW and AG (SWA-1) treatment and the underlying molecular mechanism by which SWA-1 regulates neurodegenerative diseases remains unclear. We evaluated the neuroprotective effect of SWA-1 against Sco-induced mild cognitive impairment in mice and H2O2-induced cell death in HT22 mouse hippocampal neuronal cells and elucidated the underlying molecular mechanism. Morris water maze and Y-maze tests were performed to examine the learning and memory abilities of mice. The underlying molecular mechanism was investigated by using western blotting. We demonstrated that SWA-1 significantly protects against H2O2-induced cell death in HT22 mouse hippocampal neuronal cells. SWA-1 also significantly reversed Sco-induced spatial learning and memory impairment. Specifically, SWA-1 upregulates the protein levels of phosphorylated extracellular signal-related kinase (Erk1/2) and phosphorylated p38 MAP kinase (p38). SWA-1 remarkably decreased the apoptotic index Bax/Bcl2 expression in the hippocampus of Sco-treated mice. Our results suggest that SWA-1 may be administered as alternative therapy for cognitive impairment and neurodegenerative diseases and should be studied further in human trials.

Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.

Studying drug-metabolizing enzymes, encoded by pharmacogenes, may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, pharmacogenes could not be studied at biobank scale. In 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, we associated pharmacogene haplotypes from 50 genes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models. In EUR, N-acetyltransferase 2 (NAT2) metabolizer phenotype and activity score were associated with simvastatin use. The dose of NAT2*1 was associated with simvastatin use when compared with NAT2*5 (the most common haplotype). This association was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 odds ratio (OR)=1.07, 95% CI: 1.05-1.09, P=1.14×10-8 ) and polygenic risk for LDL-C concentration (NAT2*1 OR=1.09, 95% CI: 1.04-1.14, P=2.26×10-4 ). Interactive effects between NAT2*1 and simvastatin use on LDL-C concentration (OR = 0.957, 95% CI: 0.916-0.998, P=0.045) were replicated in the electronic Medical Records and Genomics Pharmacogenetic Sequencing Pilot (eMERGE-PGx) cohort (OR = 0.987, 95% CI: 0.976-0.998, P=0.029). We used biobank-scale data to uncover and replicate an association between NAT2 locus variation and better response to statin therapy. Testing NAT2 alleles may be useful for making clinical decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment.

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

The Association of Syntax Score with Levels of Lipoprotein(a) and Inflammatory Biomarkers in Patients with Stable Coronary Artery Disease and Different Low-Density Lipoprotein Cholesterol Levels.

IntroductionLipoprotein(a) (Lp(a)) is associated with the severity of coronary lesions evaluated using Syntax score in patients with stable coronary artery disease (CAD). However, the effect of low-density lipoprotein cholesterol (LDL-C) levels on the association of Lp(a) levels with Syntax score remains unclear.MethodsA total of 646 patients with stable CAD were enrolled in the present study. Lp(a) levels were measured with an AU5800 Chemistry Analyzer. Syntax scores were calculated by two advanced interventional cardiologists. SPSS 22.0 was used for statistical analyses.ResultsThe concentration of Lp(a) ranged from 1 to 192 mg/dL. Pearson’s correlation analysis showed a positive correlation between Syntax score and the level of Lp(a) (r = 0.108, p = 0.006). The LDL-C ≥100 mg/dL group presented with a higher Lp(a) level, 16 (9–29) vs 13 (7–24). Pearson’s correlation analysis identified a correlation between Lp(a) level and Syntax score (r = 0.249, p < 0.001) only in the LDL-C ≥100 mg/dL group. Multivariate logistic regression analysis revealed the positive predictive value of an Lp(a) level >30 mg/dL for a Syntax score ≥23 only in the LDL-C ≥100 mg/dL group, adjusted odds ratio 2.895, p = 0.010. A receiver operating characteristic curve analysis confirmed the predictive value of Lp(a) levels for a Syntax score ≥23 in the LDL-C ≥100 mg/dL group with a cutoff value for Lp(a) >30 mg/dL.DiscussionThe association between Lp(a) level and Syntax score was only maintained in the LDL-C ≥100 mg/dL group. An Lp(a) level >30 mg/dL was an independent predictor of a Syntax score ≥23 only in the LDL-C ≥100 mg/dL group. The effect of LDL-C levels on the association of Lp(a) levels with Syntax score requires further investigations.

Robust methods in Mendelian randomization via penalization of heterogeneous causal estimates.

Methods have been developed for Mendelian randomization that can obtain consistent causal estimates under weaker assumptions than the standard instrumental variable assumptions. The median-based estimator and MR-Egger are examples of such methods. However, these methods can be sensitive to genetic variants with heterogeneous causal estimates. Such heterogeneity may arise from over-dispersion in the causal estimates, or specific variants with outlying causal estimates. In this paper, we develop three extensions to robust methods for Mendelian randomization with summarized data: 1) robust regression (MM-estimation); 2) penalized weights; and 3) Lasso penalization. Methods using these approaches are considered in two applied examples: one where there is evidence of over-dispersion in the causal estimates (the causal effect of body mass index on schizophrenia risk), and the other containing outliers (the causal effect of low-density lipoprotein cholesterol on Alzheimer’s disease risk). Through an extensive simulation study, we demonstrate that robust regression applied to the inverse-variance weighted method with penalized weights is a worthwhile additional sensitivity analysis for Mendelian randomization to provide robustness to variants with outlying causal estimates. The results from the applied examples and simulation study highlight the importance of using methods that make different assumptions to assess the robustness of findings from Mendelian randomization investigations with multiple genetic variants.

Real-world study of low-density lipoprotein cholesterol levels and cardiovascular outcomes in Chinese: A retrospective cohort study in post-percutaneous coronary intervention acute coronary syndrome patients

BackgroundThis study aimed to assess the effect of low-density lipoprotein cholesterol (LDL-C) goal attainments (of <2.6mmol/L and <1.8mmol/L) on first major adverse cardiovascular events (MACEs) for acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI). MethodsA retrospective cohort study was conducted using case reviews of post-PCI ACS patients at an acute public hospital in Hong Kong between January 2009 and August 2015. Patients were followed from the date of PCI procedure until the first documented MACE (including all-cause death, myocardial infarction, heart failure, documented unstable angina, revascularization, and stroke) or to the end of the first year. Kaplan-Meier estimates were used to evaluate the impact of LDL-C goal attainments prior to the event on event-free time. ResultsA total of 1684 patients were identified (79.0% males). At one-year endpoint, 658 (39.1%) attained the LDL-C goal of <1.8mmol/L, 727 (43.2%) had the LDL-C level between 1.8mmol/L and 2.6mmol/L, and 299 (17.8%) had the LDL-C level≥2.6mmol/L. About 10% experienced a MACE within one year. After adjustment for other available risk factors, attainment of LDL-C goal <2.6mmol/L was significantly associated with lower rates of MACEs during the one-year follow-up; and those who achieved the LDL-C level of 1.8mmol/L did not seem to carry any incremental clinical benefits. ConclusionsAmong post-PCI ACS patients, we merely observed a high correlation between the lipid goal attainment of <2.6mmol/L and MACEs through one-year follow-up, but not for the goal of <1.8mmol/L.

Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia

Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486–0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.

Sex-specific nonlinear associations between serum lipids and different domains of cognitive function in middle to older age individuals.

To examine how serum lipids relates to specific cognitive ability domains between the men and women in Chinese middle to older age individuals. A complete lipid panel was obtained from 1444 individuals, ages 50-65, who also underwent a selection of cognitive tests. Participants were 584 men and 860 women from Linyi city, Shandong province. Multiple linear regression analyses examined serum lipids level as quadratic predictors of sex-specific measure of performance in different cognitive domains, which were adjusted for sociodemographic and lifestyle characteristics. In men, a significant quadratic effect of total cholesterol (TC) was identified for Digit Symbol (B=-0.081, P=0.044) and also quadratic effect of low density lipoprotein-cholesterol (LDL-C) was identified for Trail Making Test B (B=-0.082, P=0.045). Differently in women, there were significant quadratic associations between high density lipoprotein-cholesterol (HDL-C) and multiple neuropsychological tests. The nonlinear lipid-cognition associations differed between men and women and were specific to certain cognitive domains and might be of potential relevance for prevention and therapy of cognitive decline.

Effects of Low-density Lipoprotein Cholesterol on Coronary Artery Calcification Progression According to High-density Lipoprotein Cholesterol Levels

Previous studies reported that many patients are at high risk for cardiovascular disease (CVD) despite achieving recommended low-density lipoprotein cholesterol (LDL-C) levels. Therefore, we investigated whether the association between LDL-C and the risk for incident CVD differed according to high-density lipoprotein cholesterol (HDL-C) levels using coronary artery calcium score (CACS) progression as a surrogate marker for predicting CVD. We investigated 2132 Korean men in a health screening program, in which CACS was measured at baseline and after 4years. Coronary artery calcification (CAC) progression was defined as a change in CACS ≥0 over 4years. We divided the subjects into nine groups according to baseline HDL-C and LDL-C levels and compared their risks for CAC progression. After 4years, 475 subjects (22.3%) exhibited CAC progression. We identified a positive relationship between baseline LDL-C levels and the risk for incident CAC. However, this association was attenuated by high baseline HDL-C levels. Multivariate logistic regression analysis adjusted for age, body mass index, systolic blood pressure, fasting glucose, smoking, and exercise status revealed that the odds ratios for incident CAC in the lowest HDL-C tertile were 3.08 for LDL-C tertile 3 and 2.02 for LDL-C tertile 2 compared to LDL-C tertile 1. However, these differences disappeared in the highest HDL-C tertile (HDL-C ≥54.0mg/dL). In this longitudinal study, we found that the positive relationship between LDL-C and the relative risk for incident CAC was attenuated by higher HDL-C levels. Therefore, HDL-C levels should be considered when estimating CVD risk.