Dataset Information

Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol: The Very Large Database of Lipids Study (VLDL-2B).

ABSTRACT: The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non-HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non-HDL-C, because discordance suggests the possibility of additional information.We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non-HDL-C in 1?310?432 US adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (Vertical Auto Profile, Atherotech, AL). One in 3 patients had ?25 percentile units discordance between TC/HDL-C and LDL-C, whereas 1 in 4 had ?25 percentile units discordance between TC/HDL-C and non-HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ?25 percentile units increased from 3% at triglycerides <100 mg/dL to 51% at triglycerides 200 to 399 mg/dL. On a smaller scale, TC/HDL-C > non-HDL-C discordance by ?25 percentile units increased from 6% to 21%. In those with <15th percentile levels of LDL-C (<70 mg/dL) or non-HDL-C (<93 mg/dL), a respective 58% and 46% were above the percentile-equivalent TC/HDL-C of 2.6. Age, sex, and directly measured components of the standard lipid profile explained >86% of the variance in percentile discordance between TC/HDL-C versus LDL-C and non-HDL-C.In this contemporary, cross-sectional, big data analysis of US adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non-HDL-C. Future studies are required to determine the clinical implications of this observation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01698489.

SUBMITTER: Elshazly MB

PROVIDER: S-EPMC4550508 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol: The Very Large Database of Lipids Study (VLDL-2B).

Elshazly Mohamed B MB Quispe Renato R Michos Erin D ED Sniderman Allan D AD Toth Peter P PP Banach Maciej M Kulkarni Krishnaji R KR Coresh Josef J Blumenthal Roger S RS Jones Steven R SR Martin Seth S SS

Circulation 20150702 8

<h4>Background</h4>The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non-HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non-HDL-C, because discordance suggests the possibility of additional information.<h4>Methods and results</h4>We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and ...[more]

PMID: 26137953

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Project description:Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Project description:Adipose harbors a large depot of free cholesterol. However, a role for adipose in cholesterol lipidation of high-density lipoprotein (HDL) in vivo is not established. We present the first evidence that adipocytes support transfer of cholesterol to HDL in vivo as well as in vitro and implicate ATP-binding cassette subfamily A member 1 (ABCA1) and scavenger receptor class B type I (SR-BI), but not ATP-binding cassette subfamily G member 1 (ABCG1), cholesterol transporters in this process.Cholesterol efflux from wild-type, ABCA1(-/-), SR-BI(-/-), and ABCG1(-/-) adipocytes to apolipoprotein A-I (apoA-I) and HDL3 were measured in vitro. 3T3L1 adipocytes, labeled with (3)H-cholesterol, were injected intraperitoneally into wild-type, apoA-I transgenic, and apoA-I(-/-) mice, and tracer movement onto plasma HDL was monitored. Identical studies were performed with labeled wild-type, ABCA1(-/-), or SR-BI(-/-) mouse embryonic fibroblast adipocytes. The effect of tumor necrosis factor-alpha on transporter expression and cholesterol efflux was monitored during adipocyte differentiation. Cholesterol efflux to apoA-I and HDL3 was impaired in ABCA1(-/-) and SR-BI(-/-) adipocytes, respectively, with no effect observed in ABCG1(-/-) adipocytes. Intraperitoneal injection of labeled 3T3L1 adipocytes resulted in increased HDL-associated (3)H-cholesterol in apoA-I transgenic mice but reduced levels in apoA-I(-/-) animals. Intraperitoneal injection of labeled ABCA1(-/-) or SR-BI(-/-) adipocytes reduced plasma counts relative to their respective controls. Tumor necrosis factor-alpha reduced both ABCA1 and SR-BI expression and impaired cholesterol efflux from partially differentiated adipocytes.These data suggest a novel metabolic function of adipocytes in promoting cholesterol transfer to HDL in vivo and implicate adipocyte SR-BI and ABCA1, but not ABCG1, in this process. Furthermore, adipocyte modulation of HDL may be impaired in adipose inflammatory disease states such as type 2 diabetes mellitus.

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Dataset Information

Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol: The Very Large Database of Lipids Study (VLDL-2B).

Publications

Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol: The Very Large Database of Lipids Study (VLDL-2B).

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