Effect Of High-density Lipoprotein Cholesterol Research Articles

Higher high-density lipoprotein cholesterol levels increased vertebral osteoporotic fracture, but reduced hip fracture in men based on the National Health Insurance Service-National Health Screening Cohort

BACKGROUND CONTEXTLipids are currently known to play an important role in bone metabolism. PURPOSEThis study aimed to investigate the effect of high-density lipoprotein cholesterol (HDL-C) on osteoporotic fractures beyond its beneficial effects on the cardiovascular system. STUDY DESIGN/SETTINGThis was a retrospective, observational study that used data from the National Health Insurance Service-Health Screening cohort database. PATIENT SAMPLEThis study included 318,237 participants who were 50 years or older and with HDL-C levels of 10 to 200 mg/dL. OUTCOMES MEASURESPhysiologic measure—Diagnosis of osteoporotic fracture during the follow-up period. METHODSThe study participants were categorized into four quartiles according to baseline HDL-C levels. The Cox proportional hazards model was used to assess osteoporotic fracture risk according to HDL-C levels. RESULTSAfter full adjustment and with the Q1 group as the reference group, estimates of hazard ratios (HRs; 95% confidence intervals [CIs]) for any osteoporotic fracture in men were 1.03 (0.94–1.12), 1.02 (0.93–1.11), and 1.07 (0.98–1.18) for the Q2, Q3, and Q4 groups, respectively. After classifying osteoporotic fractures according to the body location, the fully adjusted HRs for vertebral and hip fractures in the men's Q4 groups were 1.16 (1.02–1.31) and 0.74 (0.57–0.96), respectively. In women, fully adjusted HRs (95% CIs) of the female Q4 group for any osteoporotic, vertebral, and hip fractures were 1.03 (0.95–1.11), 0.96 (0.86–1.07), and 1.06 (0.80–1.41), respectively. CONCLUSIONIn this study, HDL-C levels were positively associated with vertebral fractures in both men and women but inversely related to hip fractures in men. Therefore, monitoring the lipid profiles of patients with osteoporosis may be beneficial for the prevention of osteoporotic fractures.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study

BackgroundObstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. MethodsA drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. ResultsGenetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60–0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93–1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. ConclusionsThe present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Discrepant effect of high-density lipoprotein cholesterol on esophageal and gastric cancer risk in a nationwide cohort.

The relationship between high-density lipoprotein cholesterol (HDL-C) and gastroesophageal cancer is not constant. In this population-based cohort study, 4.518 million cancer-free individuals among those who underwent national cancer screening in 2010 were enrolled and followed up until December 2017. HDL-C level was classified into eight groups at 10mg/dL intervals. The risk of gastroesophageal cancers by HDL-C was measured using adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). During 8years of follow-up, 38,362 gastric and 3022 esophageal cancers developed. Low HDL-C level was associated with an increased risk of gastric cancer; aHR was 1.19 (95% CI 1.09-1.30) for HDL-C < 30mg/dL, 1.07 (95% CI 1.03-1.12) for HDL-C of 30-39mg/dL, and 1.07 (95% CI 1.03-1.12) for HDL-C of 40-49mg/dL comparing to HDL-C of 60-69mg/dL. HDL-C was positively associated with esophageal cancer risk; aHR was 1.30 (1.12-1.51) for HDL-C of 70-79mg/dL, 1.84 (1.53-2.22) for HDL-C of 80-89mg/dL, 2.10 (1.67-2.61) for HDL-C ≥ 90mg/dL. These site-specific effects of HDL-C were robust in sensitivity analyses. The range of HDL-C for the lowest cancer risk was different by sex and site. The hazardous effect of low HDL-C on gastric cancer was prominent in never and past smokers, and extremely high HDL-C increased gastric cancer risk (aHR 1.19; 95% CI 1.04-1.36) only in current smokers. Unfavorable effect of high HDL-C on gastroesophageal cancer risk was remarkable in smokers. Low HDL-C increased the risk of gastric cancer, wherein high HDL-C was associated with esophageal cancer risk with discrepancies by sex and smoking status.

Constant Association between Low High-Density Lipoprotein Cholesterol and Gastric Cancer Regardless of Site.

Some epidemiologic factors and body mass index (BMI) have site-specific effects on gastric cancer. The site-specific effect of high-density lipoprotein cholesterol (HDL-C) and hyperglycemia on gastric cancer has not been reported. This study included adults who underwent national gastric cancer screening in 2011 (n=5.49 million). The validation set included gastric cancer patients (n=3,262) and gastric cancer-free persons who underwent health screening (n=14,121) in a single hospital. The site-specific effects of metabolic components and epidemiologic factors on gastric cancer were investigated. Among 5.49 million individuals, 10,417 gastric cancer cases (6,764 non-cardiac gastric cancer [NCGC] and 152 cardiac gastric cancer [CGC]) were detected. BMI was inversely associated with NCGC (P for trend <0.001) but not with CGC. Low HDL-C was associated with both CGC (adjusted odds ratio [aOR], 1.90; 95% confidence interval [CI], 1.34 to 2.71) and NCGC (aOR, 1.41; 95% CI, 1.34 to 1.49). Fasting glucose ≥110 mg/dL was associated with NCGC (aOR, 1.19) and CGC (aOR, 1.50). Men predominance was larger in CGC (aOR, 3.28) than in NCGC (aOR, 1.98). Smoking, alcohol drinking, and family history were associated with NCGC but not with CGC. In the validation set, low HDL-C was associated with CGC (aOR, 2.80) and NCGC (aOR, 2.32). BMI was inversely associated with NCGC (P for trend <0.001), and hyperglycemia was positively associated with both NCGC and CGC. Many epidemiologic factors had site-specific effects on gastric cancer, whereas low HDL-C and hyperglycemia were constantly associated with gastric cancer regardless of the site in two independent sets.

Curcumin from turmeric is an extremely efficient agent in increasing cholesterol uptake by the liver cells

Medicinal plants have a long history of usage and today, they are being extensively used for various diseases. There are several reasons for increasing the use of medicinal plants. Many plants from different parts of the world have been investigated for hypolipidemic effects. Based on strong epidemiological evidence on the relationship between high LDL-C and an increased risk of CVD, treatment and control of elevated LDL-C are as primary goals of CVD prevention in guidelines. In the meantime, both epidemiological and experimental studies confirm the protective effect of high-density lipoprotein cholesterol (HDL-C) on the onset of CAD despite LDL-C level, owing to the reverse cholesterol transport process of HDL-C. However, in recent decades, some researchers assert that other newer lipid measurements, including non-HDL-C, apolipoprotein (apo)A-I, apoB, and lipid ratios, are superior to traditional LDL-C in predicting adverse outcomes in general population. Some researchers even suggest that apoB can replace the standard “lipid profile” as a target for motoring and therapy in at-risk patients. High plasma lipids interact with free radicals in human body leading to develop coronary artery disease. We in this study have compared hypolipidemic effects of Fenugreek, Curcuma longa, and Lemon. Study was conducted at Jinnah Hospital Lahore-Pakistan from January 2018 to May 2018. Ninety hyperlipidemic patients of age group 19 to 70 were included in the study. Exclusion criteria were diabetic, alcoholic additives, hypertensive patients and those whose kidney or liver functions were impaired. Consent was taken from all participants. Their base line lipid profile was taken in biochemistry laboratory of the hospital. They were divided in three groups i.e. 30 patients in each group. Group-I was advised to take 500 mg of Curcuma longa (haldi) mixed in fresh milk without cream, thrice daily for two months. Group-II patients were advised to take 100 grams of Fenugreek leaves mixed with salad in each meal (thrice daily) for the period of two months. Group-III patients were advised to take 40 ml of fresh lemon juice mixed with 40 ml mineral water thrice daily for two months. They all were advised not to take heavy meal rich with any type of fat like junk food etc. One hour daily brisk walk was advised to all participants. 15 days follow up visit was scheduled for them. After two months their lipid profile was re-determined. When results were compiled and statistically analyzed by applying paired ‘t’ test, it revealed that Curcuma longa decreased total cholesterol, TG, LDL cholesterol 16.10, 20.01, and 17.59 mg/dl respectively. Fenugreek decreased total cholesterol, TGs, and LDL cholesterol 14.70, 17.33, and 17.06 mg/dl respectively. Lemon in two months therapy decreased total cholesterol, TGs, and LDL cholesterol 15.45, 10.13, and 11.97 mg/dl respectively. None of the above-mentioned herbs raised HDL cholesterol significantly. It was concluded from this research work that Curcuma longa, Fenugreek leaves and Lemon are mild to moderately effective hypolipidemic herbs to lower total plasma cholesterol, triglycerides, and LDL cholesterol but have no potential to raise HDL cholesterol when analyzed biostatistically.

Favorable Effect of High-Density Lipoprotein Cholesterol on Gastric Cancer Mortality by Sex and Treatment Modality.

Studies on the effects of high-density lipoprotein cholesterol (HDL-C) on gastric cancer mortality are few, and the results are inconsistent. In this study, we investigated the effects of HDL-C on gastric cancer mortality and conducted sub-group analysis by sex and treatment modality. Newly diagnosed patients with gastric cancer (n = 22,468) who underwent gastric cancer screening between January 2011 and December 2013 were included and followed up until 2018. A validation cohort (n = 3379) that had newly diagnosed gastric cancer from 2005 to 2013 at a university hospital, was followed up until 2017. HDL-C was inversely related with mortality; adjusted hazard ratio (aHR) 0.90 (95% confidence interval [CI], 0.83-0.98) for HDL-C of 40-49 mg/dL, 0.86 (0.79-0.93) for HDL-C of 50-59 mg/dL, 0.82 (0.74-0.90) for HDL-C of 60-69 mg/dL, and 0.78 (0.69-0.87) for HDL-C ≥ 70 mg/dL compared to HDL-C < 40 mg/dL. In the validation cohort, HDL-C was also inversely associated with mortality; aHR 0.81 (0.65-0.99) for HDL-C of 40-49 mg/dL, 0.64 (0.50-0.82) for HDL-C of 50-59 mg/dL, and 0.46 (0.34-0.62) for HDL-C ≥ 60 mg/dL compared to HDL-C < 40 mg/dL. The two cohorts demonstrated that higher HDL-C was associated with a low risk of mortality in both sexes. In validation cohort, this association was observed in both gastrectomy and endoscopic resection (p for trend < 0.001) as more remarkable in endoscopic resection group. In this study, we explored that an increased HDL-C reduced mortality in both sexes and curative resection group.

Robust multivariable Mendelian randomization based on constrained maximum likelihood

Mendelian randomization (MR) is a powerful tool for causal inference with observational genome-wide association study (GWAS) summary data. Compared to the more commonly used univariable MR (UVMR), multivariable MR (MVMR) not only is more robust to the notorious problem of genetic (horizontal) pleiotropy but also estimates the direct effect of each exposure on the outcome after accounting for possible mediating effects of other exposures. Despite promising applications, there is a lack of studies on MVMR's theoretical properties and robustness in applications. In this work, we propose an efficient and robust MVMR method based on constrained maximum likelihood (cML), called MVMR-cML, with strong theoretical support. Extensive simulations demonstrate that MVMR-cML performs better than other existing MVMR methods while possessing the above two advantages over its univariable counterpart. An application to several large-scale GWAS summary datasets to infer causal relationships between eight cardiometabolic risk factors and coronary artery disease (CAD) highlights the usefulness and some advantages of the proposed method. For example, after accounting for possible pleiotropic and mediating effects, triglyceride (TG), low-density lipoprotein cholesterol (LDL), and systolic blood pressure (SBP) had direct effects on CAD; in contrast, the effects of high-density lipoprotein cholesterol (HDL), diastolic blood pressure (DBP), and body height diminished after accounting for other risk factors.

High-density lipoprotein cholesterol modifies the association between blood lead and uric acid: results from NHANES 2005-2016.

The association between blood lead (PbB) and uric acid (SUA) remains unclear in US adults without a high level of lead exposure. Additionally, the effects of high-density lipoprotein cholesterol (HDL-C) modifying this association are still unclear. Therefore, this study aims to assess the effect of modification of high-density lipoprotein cholesterol on the association between PbB and SUA. This research analyzed National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2016. Through several screenings, 18,578 participants over the age of 20 were eligible for the analysis. Multivariable linear regression was used to evaluate the association between PbB and SUA. By having stratified participants based on the HDL-C intake category (low HDL-C intake < 50mg/dl; high HDL-C intake ≥ 50mg/dl), effect modification by HDL-C was assessed through a likelihood ratio test between PbB and SUA. Multivariable linear regression indicated that PbB positively affects SUA (β = 0.19, 95% CI 0.16-0.22). The relationship between PbB and SUA was different in the low and high HDL-C intake group (β 0.12 95% Cl 0.08-0.16 vs. β 0.26 95% Cl 0.22 ~ -0.30). Furthermore, high-density lipoprotein cholesterol significantly modified the relationship between PbB and SUA in all models which indicates that the interaction of lead exposure and HDL-C is more dangerous than the sum of the individual effects. Our study shows that high-density lipoprotein cholesterol and blood lead have an interactive effect on increasing uric acid, which may have great importance for clinical medication.

Cardiac valves calcification and HDL-C in patients with aortic valve sclerosis

Background and Aims : Growing evidence has demonstrated the influence of many atherosclerotic risk factors on cardiac valve calcification (CVC), which is correlated with higher cardiovascular and all-cause mortality risk. The aim of this study was to investigate the effect of high-density lipoprotein cholesterol (HDL-C) on both mitral and aortic valve calcification (AVC) in individuals with AVC.Methods: Sixty-four patients with AVC, prior the intervention, were prospectively enrolled and underwent blood sampling for biochemical analysis and multi-slice computed tomography (MSCT) without contrast. Primary end points were the quantification of (1) mitral annulus calcification (MAC) and AVC, calculated by the median MAC and AVC scores (both were defined by Agatston units (AU) according to MSCT findings) and (2) the HDL-C level (defined by a direct enzymatic method). The study took place between 3 tertiary hospitals in Greece from October 2019 to November 2020.Results: The median age of all participants was 75.3 years (IR=7.4). The median HDL-C, MAC and AVC score was 46.9 mg/dl (IR 12.4) and 737.4 AU (IR=1218.5), respectively. According to the bivariate analysis results, a statistically significant correlation was found between HDL-C levels and the MAC and AVC score, with increased levels of HDL-C being related to decreased levels of CVC (r=-0.318, p=0.014).Conclusions: A significant inverse correlation between the HLD-C and CVC was confirmed in individuals with AVC. The above findings raise great interest for further research on pathophysiological mechanisms of valvular calcification and suggest that HDL-C may be an important treatment target to attenuate the development and progress of CVC. Background and Aims : Growing evidence has demonstrated the influence of many atherosclerotic risk factors on cardiac valve calcification (CVC), which is correlated with higher cardiovascular and all-cause mortality risk. The aim of this study was to investigate the effect of high-density lipoprotein cholesterol (HDL-C) on both mitral and aortic valve calcification (AVC) in individuals with AVC. Methods: Sixty-four patients with AVC, prior the intervention, were prospectively enrolled and underwent blood sampling for biochemical analysis and multi-slice computed tomography (MSCT) without contrast. Primary end points were the quantification of (1) mitral annulus calcification (MAC) and AVC, calculated by the median MAC and AVC scores (both were defined by Agatston units (AU) according to MSCT findings) and (2) the HDL-C level (defined by a direct enzymatic method). The study took place between 3 tertiary hospitals in Greece from October 2019 to November 2020. Results: The median age of all participants was 75.3 years (IR=7.4). The median HDL-C, MAC and AVC score was 46.9 mg/dl (IR 12.4) and 737.4 AU (IR=1218.5), respectively. According to the bivariate analysis results, a statistically significant correlation was found between HDL-C levels and the MAC and AVC score, with increased levels of HDL-C being related to decreased levels of CVC (r=-0.318, p=0.014). Conclusions: A significant inverse correlation between the HLD-C and CVC was confirmed in individuals with AVC. The above findings raise great interest for further research on pathophysiological mechanisms of valvular calcification and suggest that HDL-C may be an important treatment target to attenuate the development and progress of CVC.

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins.

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

Effects of blood lipids and lipid-modifying drugs on intracranial aneurysms.

We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-modifying drugs on intracranial aneurysm (IA). Genetic variants for the effects of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides and targets for lipid-modifying drugs were selected from the genome-wide discovery analyses of the UK Biobank. Summary-level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. Univariate MR analyses showed that the HDL-C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715-0.932, p= 0.003) and ruptured IA (rIA; OR=0.775, 95% CI=0.663-0.906, p= 0.001). The multivariate MR-inverse variance weighted analysis showed that the HDL-C was negatively correlated with IA (OR=0.655, 95% CI=0.434-0.988, p= 0.043) and rIA (OR=0.563, 95% CI=0.347-0.913, p= 0.02), and the LDL-C was negatively correlated with IA (OR=0.402, 95% CI=0.191-0.848, p= 0.017) and rIA (OR=0.376, 95% CI=0.160-0.883, p= 0.025). Using genetic proxies of known lipid-modifying drugs, we found that the increased HDL-C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR=0.852, 95% CI=0.747-0.973, p= 0.018), and the decreased LDL-C with 3-hydroxy-3-methylglutaryl-coenzyme A reductase proxies was associated with increased risk of IA (OR=1.772, 95% CI=1.080-2.908, p= 0.024) and rIA (OR=1.856, 95% CI=1.022-3.371, p= 0.042). Genetically determined HDL-C and LDL-C reduce the risk of IA and rIA. The effects of different lipid-modifying drugs on IA need to be further investigated.

Dose-Response Association Between High-Density Lipoprotein Cholesterol and Stroke: A Systematic Review and Meta-Analysis of Prospective Cohort Studies.

IntroductionStudies investigating the effect of high-density lipoprotein cholesterol (HDL-C) on stroke and stroke subtypes have reached inconsistent conclusions. The purpose of our study was to clarify the dose–response association between HDL-C level and risk of total stroke and stroke subtypes by a systematic review and meta-analysis.MethodsWe performed a systematic search of PubMed, Embase, and Web of Science databases through July 30, 2020, for prospective cohort studies that reported the HDL-C–stroke association and extracted the estimate that was adjusted for the greatest number of confounding factors. Restricted cubic splines were used to evaluate the linear and nonlinear dose–response associations.ResultsWe included 29 articles, which reported on 62 prospective cohort studies including 900,501 study participants and 25,678 with stroke. The summary relative risk per 1-mmol/L increase in HDL-C level for total stroke was 0.82 (95% CI, 0.76–0.89; I 2 = 42.9%; n = 18); ischemic stroke (IS), 0.75 (95% CI, 0.69–0.82; I 2 = 50.1%; n = 22); intracerebral hemorrhage (ICH), 1.21 (95% CI, 1.04–1.42; I 2 = 33.4%; n = 10); and subarachnoid hemorrhage (SAH), 0.98 (95% CI, 0.96–1.00; I 2 = 0%; n = 7). We found a linear inverse association between HDL-C level and risk of total stroke and SAH, a nonlinear inverse association for IS risk, but a linear positive association for ICH risk. The strength and the direction of the effect size estimate for total stroke, IS, ICH, and SAH remained stable for most subgroups. We found no publication bias with Begg’s test and Egger’s test for the association of HDL-C level with risk of total stroke, IS, and ICH.ConclusionA high HDL-C level is associated with reduced risk of total stroke and IS and an increased risk of ICH.

Functional Haplotype of LIPC Induces Triglyceride-Mediated Suppression of HDL-C Levels According to Genome-Wide Association Studies.

Hepatic lipase (encoded by LIPC) is a glycoprotein in the triacylglycerol lipase family and mainly synthesized in and secreted from the liver. Previous studies demonstrated that hepatic lipase is crucial for reverse cholesterol transport and modulating metabolism and the plasma levels of several lipoproteins. This study was conducted to investigate the suppression effect of high-density lipoprotein cholesterol (HDL-C) levels in a genome-wide association study and explore the possible mechanisms linking triglyceride (TG) to LIPC variants and HDL-C. Genome-wide association data for TG and HDL-C were available for 4657 Taiwan-biobank participants. The prevalence of haplotypes in the LIPC promoter region and their effects were calculated. The cloned constructs of the haplotypes were expressed transiently in HepG2 cells and evaluated in a luciferase reporter assay. Genome-wide association analysis revealed that HDL-C was significantly associated with variations in LIPC after adjusting for TG. Three haplotypes (H1: TCG, H2: CTA and H3: CCA) in LIPC were identified. H2: CTA was significantly associated with HDL-C levels and H1: TCG suppressed HDL-C levels when a third factor, TG, was included in mediation analysis. The luciferase reporter assay further showed that the H2: CTA haplotype significantly inhibited luciferase activity compared with the H1: TCG haplotype. In conclusion, we identified a suppressive role for TG in the genome-wide association between LIPC and HDL-C. A functional haplotype of hepatic lipase may reduce HDL-C levels and is suppressed by TG.

Role of high-density lipoprotein cholesterol in health and diseases

Primary function of high-density lipoprotein cholesterol is to reverse transport the cholesterol from extrahepatic cell to liver for its metabolism and excretion. Studies have demonstrated the anti-inflammatory, anti-atherogenic, anti-oxidant, and anti-diabetic property of the high-density lipoprotein cholesterol. Although the exact mechanism still remains unelucidated, high-density lipoprotein cholesterol is a complex of lipids and proteins carrying many associated cargo molecules such as enzymes, signaling molecules, miRNA, which imparts overall functionality of high-density lipoprotein cholesterol for its beneficial health effects. However, the protein and lipids components get transform by the enzymes associated with high-density lipoprotein cholesterol, hyperglycemia, oxidative stressor, and free radicals, leading to qualitative and quantitative alterations in high-density lipoprotein cholesterol (HDLc) and diminishes its beneficial effects. In this review, we have discussed the different property of high-density lipoprotein cholesterol, its function and factors influencing HDLc property in light of anti-inflammatory activity in rheumatoid arthritis and the role of cholesterol-lowering statin drug in enhancing the beneficial effect of high-density lipoprotein cholesterol in different cell types.

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy

The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IVs) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we proposed a probabilistic model for MR analysis in identifying the causal effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP) and develop a computationally efficient algorithm to make the causal inference. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods. Moreover, we used two real exposure–outcome pairs to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all-instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol on peripheral vascular disease and a positive causal effect of BMI on hemorrhoids.

Correlation without a cause: an epidemiological odyssey.

In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of 'good cholesterol', strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies-that began to appear at the same time as the initial negative randomized controlled trials-made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure-such as that with respect to vitamin E supplementation and CHD risk-rather than pass them over in silence.

Intra-individual variability in high density lipoprotein cholesterol and risk of end-stage renal disease: A nationwide population-based study

Background and aimsThere is a growing evidence demonstrating an association between dyslipidemia and progression of chronic kidney disease (CKD), but results on the effects of high-density lipoprotein cholesterol (HDL-C) on renal outcome have been conflicting. In this study, the relationship between HDL-C variability and the risk for progression to end-stage renal disease (ESRD) was investigated. MethodsThis study analyzed data of 4,283,318 subjects who were free of ESRD at the time of enrollment, received more than three medical examinations from 2009 to 2012, and were followed to the end of 2015, based on the Korean National Health Insurance Service database. HDL-C variability was measured using the standard deviation, coefficient of variation, average real variability and variability independent of the mean (VIM). ResultsA total of 2,095 new cases of ESRD were observed during a median follow up of 3.38 years. There was a graded association between higher HDL-C variability and incident ESRD. In the multivariable adjusted model, hazard ratio comparing the highest and lowest quartiles of VIM of HDL-C was 1.82 (95% confidence interval, 1.58–2.09). The results were consistent when the variability of HDL-C was modeled using standard deviation, coefficient of variation and average real variability and were independent of other confounding factors, including the presence of CKD. ConclusionsHDL-C variability independently predicted an increased risk for developing ESRD. Our findings suggest that identification of HDL-C variability may help improve risk stratification for the prevention of ESRD.

The Protective Effect of HDL-Cholesterol in Patients with Essential Hypertension

High blood pressure (HPB) is considered a major health problem affecting more than one billion people worldwide. Hypertension is the most common cardiovascular disorder that increases the risk of cardiovascular morbidity and mortality. HDL-cholesterol, considered to be an independent risk factor for cardiovascular events, presents pleiotropic effects that can influence arterial status and blood pressure. The aim of this study was to determine the correlation between HDL-cholesterol levels and blood pressure in normotensive and hypertensive patients (untreated and 1-month treated with statins) and to evaluate the arterial stiffness as a marker of endothelial dysfunction in these patients.

Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator.

ABSTRACTDevelopments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.

Abstract 119: Identifying and Quantifying Eight ApoA-I HDL Subspecies by a Novel Modified Sandwich ELISA

HDL-cholesterol is a well-established independent risk factor used in CVD risk stratification. However, the cardioprotective effect of HDL-cholesterol is challenged by genetic studies and pharmaceutical trials, which do not support the causal relationship between increased HDL-cholesterol levels and CVD. Previously, our lab found that HDL can be classified into subspecies based on the presence of apoC-III, where for example 7% of the total plasma apoA-I in HDL has apoC-III. We also showed that the apoA-I concentration of HDL that has apoC-III predicts increased risk of CHD, whereas that of HDL that does not have apoC-III predicts decreased risk of CHD. We hypothesized that some of the many other proteins that are located in HDL are present in apoA-I HDL subspecies. We developed a novel sandwich ELISA to measure apoA-I in HDL that is associated with a specific protein of interest, and applied it to apoA-II, apoC-III, and apoE, which define known subspecies of apoA-I HDL. We also applied the ELISA to apoC-I, apoC-II, and plasminogen, to determine whether their association with HDL constitutes a subspecies of apoA-I HDL, and in what concentrations they exist in HDL. We confirmed the existence of all the apoA-I lipoprotein subtypes using pooled plasma samples collected from healthy men and women (age: 40±14 (mean±SD), triglyceride: 116±63 mg/dl, LDL-cholesterol: 118±28 mg/dl, HDL-cholesterol: 45±10 mg/dl). The concentration (percentage) of total plasma apoA-I in HDL associated with apoA-II was 103±11 mg/dl (71±12%), with apoC-I was 23±4 mg/dl (16±2%), with apoC-II was 4±1 mg/dl (2±1%), with apoC-III was 9±3 mg/dl (6±1%), with apoE was 8±5 mg/dl (5±3 %) and with plasminogen was 4±1 mg/dl (3±1%). The results for apoA-II, apoC-III, and apoE are consistent with previously reported values. In conclusion, we established a convenient sandwich ELISA, which demonstrated the existence of new apoA-I HDL subspecies that are defined by presence of apoC-I, apoC-II, and plasminogen, as well as known subspecies of apoA-I HDL; and we quantified the concentration of such subspecies. Future studies will investigate these abundant HDL subtypes in relation to CVD risk.