Adjustment For Triglycerides Research Articles

Elevated plasma apolipoprotein E levels in people living with HIV: Associations with biomarkers and HIV-specific risk factors

Background and aimsApolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. MethodsWe included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. ResultsMean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. ConclusionsPWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.

KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study

Background and aimsHDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants. MethodsWe measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.1 macrophages using serum samples from 4,981 participants in the German Chronic Kidney Disease (GCKD) study. Variance of CEC explained by clinical and biochemical parameters in a multivariable linear regression model was calculated by proportional marginal variance decomposition. A genome-wide association study with 7,746,917 variants was performed based on an additive genetic model. The main model was adjusted for age, sex and principal components 1-10. Further models were selected for sensitivity analysis and to reduce residual variance by known CEC pathways. ResultsVariables that explained 1% and more of the variance of CEC were concentrations of triglycerides (12.9%), HDL-cholesterol (11.8%), LDL-cholesterol (3.0%), apolipoprotein A-IV (2.8%), PCSK9 (1.0%), and eGFR (1.0%). The KLKB1 (chr4) and APOE/C1 (chr19) loci were genome-wide significantly (p < 5x10−8) associated with CEC in our main model (p = 8.8x10−10 and p = 3.3x10−10, respectively). KLKB1 remained significantly associated after additional adjustment for either kidney parameters, HDL-cholesterol, triglycerides or apolipoprotein A-IV concentrations, while the APOE/C1 locus was not significantly associated anymore after adjustment for triglycerides. Adjustment for triglycerides also revealed an association with the CLSTN2 locus (chr3; p = 6.0x10−9). ConclusionsWe identified HDL-cholesterol and triglycerides as the main determinants of CEC. Furthermore, we newly found a significant association of CEC with the KLKB1 and the CLSTN2 locus and confirmed the association with the APOE/C1 locus, likely mediated by triglycerides.

The association of parity/live birth number with incident type 2 diabetes among women: over 15\xa0years of follow-up in The Tehran Lipid and Glucose Study

BackgroundChildbearing may increase the future risk of developing type 2 diabetes mellitus (T2DM) in mothers. However, the issue is not clear completely and not investigated in the Middle East, a region with a high burden of T2DM. In the current study, we examined the association of parity/live birth number with incident T2DM among Iranian women.MethodsThe study population included 2552 women aged 30–65 years recruited in 1999–2001 and were followed for incident T2DM by 3-year intervals. Multivariable Cox proportional hazard models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the parity/live birth number for incident T2DM. Parity number was defined as the number of live childbirth (number of live birth) plus the number of stillbirth (defined as birth of an infant that died after the 20th week of pregnancy in the uterus).ResultsDuring a median follow-up of 15.4 years, 557 incident T2DM cases have occurred. After adjustment for potential T2DM risk factors and reproductive factors, each additional parity caused a 9% higher risk for incident T2DM. Moreover, compared to women with one parity, those with 3 and ≥ 4 parity had HRs of 1.73 [95% CI: 1.06–2.83] and 2.23 [1.36–3.65], respectively. After further adjustment for body mass index (BMI) and waist circumference, although the HRs were attenuated prominently, parity ≥ 4 was associated with significantly higher risk (HR: 1.72 [1.05–2.83]); even after further adjustment for triglycerides (TG)/ high-density lipoprotein cholesterol (HDL-C), the risk remained marginally significant (HR: 1.64 [1.00–2.70; P value: 0.051]). For the number of live birth, the results were also similar. Moreover, in a sensitivity analysis, when we considered BMI change during follow-up as another covariate, generally, the effect sizes did not change; the trend of HRs across categories of parity number remained marginally significant (P value: 0.064).ConclusionsDuring a long-term follow-up, after adjustment for potential T2DM risk factors, reproductive factors, obesity indices, and TG/HDL-C (insulin resistance surrogate), we demonstrated that higher parity/live birth numbers could be associated with increased risk of T2DM development among Iranian women. Moreover, even after further adjustment for BMI change, the suggestive higher risk was still found.

The Vessels-Bone Axis: Iliac Artery Calcifications, Vertebral Fractures and Vitamin K from VIKI Study.

Vascular calcification and fragility fractures are associated with high morbidity and mortality, especially in end-stage renal disease. We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aortic calcifications (AACs) with the risk for vertebral fractures (VFs) in hemodialysis patients. The VIKI study was a multicenter cross-sectional study involving 387 hemodialysis patients. The biochemical data included bone health markers, such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, and phosphate. VF, IACs and AACs was determined through standardized spine radiograms. VF was defined as >20% reduction of vertebral body height, and VC were quantified by measuring the length of calcium deposits along the arteries. The prevalence of IACs and AACs were 56.1% and 80.6%, respectively. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p = 0.028), whereas we found no association (p = 0.294) for AACs. IACs were associated with VF irrespective of calcification severity. Patients with IACs had lower levels of vitamin K2 and menaquinone 7 (0.99 vs. 1.15 ng/mL; p = 0.003), and this deficiency became greater with adjustment for triglycerides (0.57 vs. 0.87 ng/mL; p < 0.001). IACs, regardless of their extent, are a clinically relevant risk factor for VFs. The association is enhanced by adjusting for vitamin K, a main player in bone and vascular health. To our knowledge these results are the first in the literature. Prospective studies are needed to confirm these findings both in chronic kidney disease and in the general population.

The associations between individual plasma SFAs, serine palmitoyl-transferase long-chain base subunit 3 gene rs680379 polymorphism, and type 2 diabetes among Chinese adults

Several individual studies have shown that circulating levels of odd-chain SFAs and very-long-chain SFAs (VLSFAs) may have beneficial effects, but the results are mixed. While the dietary and metabolic factors that may influence VLSFAs are not well-known, a previous study observed associations of VLSFA concentrations with variants in serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3) gene. We investigated the associations of individual plasma SFAs and SPTLC3 gene rs680379 polymorphism with metabolic risk factors and type 2 diabetes (T2D). We measured plasma SFAs using gas chromatography among 898 T2D cases and 1618 matched controls, and genotyped the SPTLC3 gene rs680379 polymorphism using the MassArray System among 1178 T2D cases and 1907 matched controls. Conditional logistic regression was used to estimate ORs and 95% CIs. We found that plasma odd-chain SFAs and VLSFAs were correlated with favorable blood lipids and insulin resistance marker profiles. After multivariable adjustment, pentadecanoic acid (15:0) was inversely associated with the odds of T2D (OR per 1 SD difference: 0.63; 95% CI: 0.57, 0.70), as were measurements of 3 individual VLSFAs [arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)], with ORs ranging from 0.60 to 0.72 (95% CIs ranging between 0.52 and 0.79). The associations between 3 individual VLSFAs and T2D were attenuated after further adjustment for triglycerides. Meanwhile, compared with the rs680379 GG genotype carriers, the ORs of T2D for the GA and AA genotype carriers were 0.81 (95% CI: 0.68-0.97) and 0.76 (95% CI: 0.61-0.96), respectively. Plasma 15:0 and VLSFAs were inversely associated with T2D. Meanwhile, compared with the rs680379 GG genotype carriers, subjects with GA and AA genotypes were associated with decreased odds of T2D. More investigations are warranted to confirm our findings.

Smoking results in accumulation of ectopic fat in the liver.

ObjectiveAn association between smoking and nonalcoholic fatty liver disease has been reported. However, objective quantification of intrahepatic fat via magnetic resonance spectroscopy (MRS) in relation to smoking has rarely been performed in previous studies. Moreover, the possible pathways via which smoking could induce ectopic fat accumulation have not yet been addressed. The current study aimed to examine the association between smoking status and intrahepatic fat quantity and explore the possible mediating effects of triglycerides (TG) and adiponectin.Subjects and methodsMagnetic resonance imager (MRI) spectra were analyzed to quantify intrahepatic fat in 45 men who were on average 62.3 years of age. Smoking status and alcohol intake were self-reported. Accelerometers were used to record daily total physical activity. Fasting blood TG and adiponectin levels were measured enzymatically. Differences in mean intrahepatic fat values according to smoking status were assessed using analysis of covariance.ResultsA stepwise increase in mean intrahepatic fat was observed between never, former, and current smokers, respectively, independent of age, physical activity, alcohol intake, and body mass index (BMI) (P=0.005). Adjustment for TG and adiponectin significantly attenuated this association (P=0.074).ConclusionCurrent smoking was significantly associated with increased intrahepatic fat, which may be a result of adipocyte dysfunction, manifested as high circulating TG concentrations and low adiponectin levels.

Associations of Lipid-related SNPs with Circulating Phylloquinone Are Proportional with Triglycerides (P15-008-19)

ObjectivesPhylloquinone is transported on triglyceride-rich lipoproteins. Preliminary evidence from a genome-wide association meta-analysis suggests that genetic variants that influence triglycerides (TGs), such as rs964184 at the APOA1/C3/A4/A5 gene cluster, also influence circulating phylloquinone. To further evaluate this overlap, we examined the linear relationship between a weighted TG genetic risk score (wTG-GRS) with circulating phylloquinone. MethodsWe constructed a wTG-GRS comprised of 20 SNPs that were previously associated with TGs in a genome-wide association meta-analysis for blood lipids (n > 188,000 individuals of European ancestry). The assigned weights corresponded to the effect-sizes (β) reported for each SNP’s association with TGs. With meta-analytic summary statistic data from a separate genome-wide association meta-analysis of circulating phylloquinone (n = 2138 individuals of European ancestry), a statistical technique was used to approximate the linear association of the wTG-GRS with circulating phylloquinone. A p-value of 0.05 for the estimate was considered statistically significant. First, the estimate was calculated without adjustment for TGs using Model 1 summary statistics, then calculated with adjustment for TGs using Model 2 summary statistics. ResultsThe estimate for the linear association of the wTG-GRS with circulating phylloquinone was significant without and with adjustment for TGs (Model 1: β = 0.052, P = < 0.0001, Model 2: β = 0.027, P = 0.0001, respectively). The goodness-of-fit of the model was improved from Model 1 (p-het = 0.022) to Model 2 (p-het = 0.054). ConclusionsThe associations of TG-related SNPs with circulating phylloquinone were proportional to their associations with TGs. This provides further evidence of the shared genetic links between TGs and phylloquinone and suggests genetic studies of vitamin K should consider TGs. Funding SourcesStudy supported by the USDA Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707 and NHLBI T32HL069772.

Plasma calprotectin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study

Background and aimsWe aimed to assess the association of circulating calprotectin, an inflammation-associated protein, with cardiovascular disease (CVD) risk and determine whether it improves risk prediction. MethodsPlasma calprotectin measurements were made at baseline in 5290 participants in the PREVEND prospective study. Hazard ratios (95% confidence intervals [CI]) for CVD were calculated. ResultsAfter a median follow-up of 8.3 years, 339 first CVD events were recorded. Calprotectin concentration was correlated with several conventional risk factors as well as with high-sensitivity C-reactive protein (hsCRP) (r = 0.42). Calprotectin was log-linearly associated with CVD risk. The risk for CVD adjusted for conventional cardiovascular risk factors was 1.26 (95% CI, 1.13–1.41) per 1 standard deviation higher baseline loge calprotectin, and was 1.24 (95% CI, 1.11–1.39) following further adjustment for triglycerides, body mass index, and other potential confounders. The association remained present after further adjustment for hsCRP 1.15 (95% CI, 1.02–1.30). Comparing extreme quartiles of plasma calprotectin levels, the corresponding adjusted HRs for CVD were 1.96 (1.37–2.82), 1.89 (1.31–2.72), and 1.56 (1.07–2.29). The association of calprotectin with CVD risk did not vary importantly in several relevant clinical subgroups. Adding calprotectin to the Framingham CVD Risk Score was associated with a C-index change (0.0016; p=0.42) difference in −2 log likelihood (p=0.038), IDI (0.0080; p < 0.001), and NRI (4.03%; p=0.024). ConclusionsThere is a log-linear association of calprotectin concentration with risk of CVD, which may be partly dependent on hsCRP. Adding calprotectin to conventional risk factors improves CVD risk assessment using measures of reclassification and −2 log likelihood.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Māori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.

Evaluation of various biomarkers as potential mediators of the association between Δ5 desaturase, Δ6 desaturase, and stearoyl-CoA desaturase activity and incident type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition–Potsdam Study

An association between desaturase activity and risk of type 2 diabetes (T2D) has been found in epidemiologic studies, but little is known about potential mediators of this association. We aimed to investigate the potential role of diabetes-related biomarkers as mediators of the association between estimated Δ5 desaturase (D5D), Δ6 desaturase (D6D), and stearoyl-CoA desaturase (SCD) activity and T2D risk. We analyzed a case-cohort study (subcohort: n = 1533; verified incident T2D cases: n = 400), nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam Study involving 27,548 middle-aged participants. We evaluated the impact of adjustment for several T2D-related biomarkers reflecting liver fat accumulation [reflected by γ-glutamyltransferase (GGT), alanine transaminase (ALT), fetuin-A, and the algorithm-based fatty liver index (FLI)], dyslipidemia (high-density lipoprotein cholesterol, triglycerides), inflammation [C-reactive protein (CRP)], and adiponectin on the association between D5D, D6D, and SCD activity, estimated with fatty acid product-to-precursor ratios derived from erythrocyte membrane proportions, and T2D risk. Estimated D5D activity was inversely associated with T2D risk, whereas D6D and SCD activities were positively associated with risk of T2D [HRs (95% CIs) (highest vs. lowest tertile): 0.51 (0.36, 0.73), 1.68 (1.18, 2.39), and 1.82 (1.29, 2.58), respectively]. The association between estimated D5D, D6D, and SCD activities and risk of T2D was statistically significantly and markedly attenuated after adjustment for the FLI and, to a lesser extent, after adjustment for triglycerides, whereas adjustment for other desaturase-associated biomarkers (CRP, fetuin-A, ALT, and GGT) did not lead to appreciable attenuations. Liver fat accumulation, as reflected by the FLI, and dyslipidemia, as reflected by triglycerides, may partly explain the association between estimated D5D, D6D, and SCD activity and T2D risk.

Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study

Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes. By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes. A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes. Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47% lower risk of diabetes (95% CI: 23%, 63%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33% (95% CI: 6%, 53%; P-trend: 0.02) and 37% (95% CI: 11%, 55%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32% lower risk for fourth vs. first quartile; P-trend: 0.04). These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease

BackgroundCompare gradient gel electrophoresis (GGE), vertical auto profile ultracentrifugation (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low- (LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression. Methods and resultsRegression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline.Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P = 10−6; LDLIVa, P = 0.006; LDLIVb, P = 0.02), VAP-II (LDL4, P = 0.002), NMR (small LDL, P = 0.001), and ion mobility (LDL IIb, P = 0.04; LDLIIIa, P = 0.002; LDLIIIb, P = 0.0007; LDLIVa, P = 0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P = 10−5) and LDLIVa (P = 0.04); NMR-estimated small LDL (P = 0.03); or ion mobility estimated large VLDL (P = 0.02), LDLIIIa (P = 0.04) or LDLIIIb (P = 0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods. ConclusionFour methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements.Clinical Trial Registration: clinicaltrials.gov/ct2/show/NCT00000553.

Influence of Apolipoproteins on the Association Between Lipids and Insulin Sensitivity

OBJECTIVEWe evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence.RESEARCH DESIGN AND METHODSThis study included a cross-sectional analysis of the RISC Study, a multicenter European clinical investigation in 1,017 healthy volunteers balanced in sex (women 54%) and age strata (range 30–60 years). Insulin sensitivity (M/I in µmol ⋅ min−1 ⋅ kgFFM−1 ⋅ nM−1) was measured by the clamp technique and apolipoproteins (ApoB, -C3, -A1, and -E) by Multiplex Technology.RESULTSThe center-, sex-, and age-adjusted standardized regression coefficients (STDβ) with M/I were similar for HDL and triglycerides (+19.9 ± 1.9 vs. −20.0 ± 2.0, P < 0.0001). Further adjustment for triglycerides (or HDL), BMI, and adiponectin (or nonesterified fatty acid) attenuated the strength of the association of M/I with both HDL (STDβ +6.4 ± 2.3, P < 0.01) and triglycerides (−9.5 ± 2.1, P < 0.001). Neither ApoA1 nor ApoE and ApoB showed any association with M/I independent from plasma HDL cholesterol and triglycerides. ApoC3, in contrast, in both men and women, was positively associated with M/I independently of plasma lipids. A relative enrichment of plasma lipids with ApoC3 is associated with lower body fat percentage and lower plasma alanine amino transferase.CONCLUSIONSOur results suggest that HDL cholesterol modulates insulin sensitivity through a mechanism that is partially mediated by BMI and adiponectin but not by ApoA1. Similarly, the influence of triglycerides on insulin sensitivity is in part mediated by BMI and is unrelated to ApoE or ApoB, but it is significantly modulated by ApoC3, which appears to protect from the negative effect of plasma lipids.

Apolipoprotein C‐III as a Potential Modulator of the Association Between HDL‐Cholesterol and Incident Coronary Heart Disease

BackgroundHigh-density lipoproteins (HDL) are structurally and metabolically heterogeneous and subclasses with differential effects on coronary heart disease (CHD) might exist. Apolipoprotein (apo) C-III, a small proinflammatory protein that resides on the surface of lipoproteins, enhances the atherogenicity of VLDL and LDL particles, but little is known about the role apoC-III on HDL. We investigated whether the presence or absence of apoC-III differentiates HDL into subtypes with nonprotective or protective associations with risk of future CHD.Methods and ResultsHigh-density lipoprotein cholesterol (HDL-C) levels were measured in plasma separated according to apoC-III (by immunoaffinity chromatography) in two prospective case-control studies nested within the Nurses’ Health and the Health Professionals Follow-Up Studies. Baseline was in 1990 and 1994, and 634 incident CHD cases were documented through 10 to 14 years of follow-up. The relative risk of CHD per each standard deviation of total HDL-C was 0.78 (95% confidence intervals, 0.63–0.96). The HDL-C subtypes were differentially associated with risk of CHD, HDL-C without apoC-III inversely and HDL-C with apoC-III directly (P=0.02 for a difference between the HDL types). The relative risk per standard deviation of HDL-C without apoC-III was 0.66 (0.53 to 0.93) and 1.18 (1.03 to 1.34) for HDL-C with apoC-III. HDL-C with apoC-III comprised ∼13% of the total HDL-C. Adjustment for triglycerides and apoB attenuated the risks; however, the two HDL-C subgroups remained differentially associated with risk of CHD (P=0.05).ConclusionSeparating HDL-C according to apoC-III identified two types of HDL with opposing associations with risk of CHD. The proatherogenic effects of apoC-III, as a component of VLDL and LDL, may extend to HDL. (J Am Heart Assoc. 2012;1:jah3-e000232 doi: 10.1161/JAHA.111.000232.)

HIV, HAART, and lipoprotein particle concentrations in the Women's Interagency HIV Study

Changes in lipoprotein particle concentrations, especially greater small low-density lipoprotein particle (LDL-p) and lower small high-density lipoprotein particle (HDL-p) may provide information regarding cardiovascular disease (CVD) risk above and beyond that which is provided by standard lipids. We quantified the association HIV and HAART use had with LDL-p and HDL-p. Cross-sectional study of 1077 individuals classified by HIV/HAART status (361 HIV-uninfected, 128 HIV-infected/HAART naive, 588 HIV-infected/on HAART) enrolled in the Women's Interagency HIV Study. Nuclear magnetic resonance spectroscopy estimated total and subclass lipoprotein particle concentrations. Quantile regression models were used to estimate differences in the 10th, 25th, 50th, 75th, and 90th percentiles of the distributions of lipoprotein particle concentrations between the two HIV-infected exposure groups and HIV-uninfected controls after adjustment for demographic, nonlipid metabolic factors, and standard lipids. Compared with HIV-uninfected women, those on HAART had greater 75th and 90th percentiles of small LDL-p; there was little difference between HIV-infected/HAART naive and HIV-uninfected women. After adjustment for triglycerides, the association of HAART with greater 75th and 90th percentiles of small LDL-p was attenuated and no longer significant. In contrast, after adjustment for triglycerides, HIV infection irrespective of HAART status remained associated with significantly lower 10th, 25th, 50th, 75th, and 90th percentiles of small HDL-p. Our findings suggest that testing for LDL-p confers little additional information beyond triglycerides levels when assessing CVD risk. Further investigation is needed to examine the role of HDL-p in the link between HIV and CVD in women.

Strong association of the APOA5-1131T>C gene variant and early-onset acute myocardial infarction

BackgroundEpidemiological studies support the role for a strong genetic component in the occurrence of early-onset myocardial infarction (MI), although the specific genetic variants responsible for familial clustering remain largely unknown. MethodsThe Italian study of early-onset MI is a nationwide case-control study involving 1864 case patients <45 years old who were hospitalized for a first MI, and age/sex/place of origin-matched controls (n=1864). We investigated the association between early-onset MI, lipid levels and 20 single nucleotide polymorphisms (SNPs) in the candidate genes ADIPOQ, APOA5, ALOX5AP, CYBA, IL6, LPL, PECAM1, PLA2G2A and PLA2G7, chosen because of previously reported associations with Coronary Heart Disease (CHD) or with CHD risk factors. ResultsOf all the SNPs investigated, APOA5-1131T>C [(rs662799), minor allele frequency 0.084 (95% confidence interval (CI) 0.07–0.09)] alone showed a statistically significant association with risk of early-onset MI (p=6.7×10−5), after Bonferroni correction, with a per C allele odds ratio of 1.44 (95% CI 1.23–1.69). In controls, APOA5-1131T>C was significantly associated with raised plasma triglyceride levels (p=0.001), compared with non-carriers, the per C allele increase being 11.4% (95% CI 4–19%), equivalent to 0.15mmol/L (95% CI 0.11–0.20mmol/L). In cases, the association with early MI risk remained statistically significant after adjustment for triglycerides (p=0.006). ConclusionsThe APOA5-1131C allele, associated with higher fasting triglyceride levels, strongly affects the risk for early-onset MI, even after adjusting for triglycerides. This raises the possibility that APOA5-1131T>C may affect the risk of early MI over and above effects mediated by triglycerides.

Genetic variation in the GCKR gene is associated with non-alcoholic fatty liver disease in Chinese people

Recent genome-wide association studies reported that GCKR rs780094 polymorphism is associated with elevated fasting serum triglyceride levels and elevated levels of C-reactive protein (CRP). There are a ample of data on the association between circulating triglyceride, CRP concentrations and risk of non-alcoholic fatty liver (NAFLD). To determine whether the GCKR rs780094 polymorphism contributes to the development of non-alcoholic fatty liver, a case-control study was performed in 903 Chinese subjects. Among study population, 436 patients with B-mode ultrasound-proven NAFLD (318 with steatosis hepatis I°, 90 with steatosis hepatis II° and 28 with steatosis hepatis III°) and 467 controls were genotyped by using TaqMan allelic discrimination assays. We confirmed the association of GCKR rs780094 with NAFLD in Chinese people (OR = 1.607, 95% CI 1.139-2.271, P[dom] = 7.2 × 10(-3)). In this study, polymorphism in GCKR rs780094 was not significantly associated with the degree of fatty infiltration of the liver. In addition, the T-allele of GCKR rs780094 was significantly associated with increasing fasting triglyceride (P[add] = 3.8 × 10(-4)) and CRP (P[add] = 2.9 × 10(-4)) concentrations after adjusting for age, gender, and BMI. The association with NAFLD remained significant after adjustment for triglyceride, while adjustment for CRP abolished the association. Genetic variation in GCKR gene rs780094 polymorphism contributes to the risk of NAFLD in Chinese people. The effect of genotype on NAFLD is probably mediated through chronic low-grade systemic inflammation rather than through dislipidemia.

Abstract 3705: Pioglitazone Augments Niacin-Induced Increases in Adiponectin in Non-Diabetics with Metabolic Syndrome and Low HDL

Background Niacin and pioglitazone (PIO) increase HDL by uncertain mechanisms. Both increase adiponectin, whose effects on carbohydrate and fatty acid metabolism may benefit HDL indirectly. Little is known of the combined effects of the drugs on adiponectin and other adipokines. We hypothesized that PIO would complement changes in adipokines from niacin, and in turn, augment HDL. Methods In an open-label run-in, non-diabetics with low HDL titrated from 0 to 2 g extended-release niacin over 4 weeks, and were randomized to add PIO 30 mg or placebo in a double-blind manner. After 6 weeks, PIO was increased to 45 mg for another 6 weeks. We assessed changes in fasting adiponectin, resistin, complement C3 (the serum-detectable precursor of acylation stimulating protein), free fatty acids (FFA), hydroxy-butyrate (HBA), and triglycerides (TG), and their relationship to changes in HDL. Results Of 72 completers, 34 took niacin and placebo and 38 took niacin and PIO. The table shows absolute and relative change of each analyte from baseline to 16 weeks. Relative change in adiponectin was strongly correlated with change in HDL (Spearman’s rho +0.49, p&lt;0.0001), as was change in TG (rho −0.50, p&lt;0.0001); the other analytes had little influence. On multivariable regression, change in HDL was predicted by change in adiponectin (p=0.0001) and TG (p&lt;0.0001), which remained significant on adjustment for changes in glucose and insulin. Conclusion Pioglitazone augments niacin-induced changes in adiponectin and complement C3 thought to be favorable, and neutralizes niacin’s unfavorable increase in FFA. Adiponectin strongly predicted HDL after adjustment for TG. Since PIO had no independent effect on TG, we speculate that additional HDL-raising from PIO is mediated by the large increase in adiponectin. In summary, PIO enhances HDL-raising from niacin in proportion to increased adiponectin.

Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study

Genetic variation at the apolipoprotein A5 gene (APOA5) is associated with increased triglyceride concentrations, a risk factor for atherosclerosis. Carotid intimal medial thickness (IMT) is a surrogate measure of atherosclerosis burden. We sought to determine the association of common APOA5 genetic variants with carotid IMT and stenosis. A total of 2,273 Framingham Offspring Study participants underwent carotid ultrasound and had data on at least one of the five APOA5 variants (-1131T>C, -3A>G, 56C>G, IVS3+476G >A, and 1259T>C). Although none of the individual variants was significantly associated with carotid measures, the haplotype defined by the presence of the rare allele of the 56C>G variant was associated with a higher common carotid artery (CCA) IMT compared with the wild-type haplotype (0.75 vs. 0.73 mm; P < 0.05). The rare allele of each of the -1131T >C, -3A>G, IVS3+476G>A, and 1259T>C variants and the haplotype defined by the presence of the rare alleles in these four variants were each significantly associated with CCA IMT in obese participants. These associations remained significant even after adjustment for triglycerides. APOA5 variants were associated with CCA IMT, particularly in obese participants. The mechanism of these associations and the effect modification by obesity are independent of fasting triglyceride levels.

Association of Apolipoproteins C3 and E with Metabolic Changes in HIV-Infected Adults Treated with a Protease-Inhibitor-Containing Antiretroviral Therapy

To examine the relationship between plasma levels of apolipoproteins C3 (APOC3) and E (APOE) and the presence of lipid and carbohydrate metabolism abnormalities or clinical signs of lipodystrophy in HIV-1-infected patients started with a protease-inhibitor-containing antiretroviral therapy. The Aproco (Antiproteases Cohort) Study enrolled 1,181 HIV-1-infected adults in 47 French healthcare centres from May 1997 to June 1998. From December 1998 through July 1999, the APROCO-Metabolic Complications (APROCO-MC) cross-sectional study was performed at the month 20 visit for those patients enrolled in 1997 and at the month 12 visit for those enrolled in 1998. The current analysis presents results from a subset of patients who had undergone additional tests to measure APOC3 and APOE in order to study their relationship with metabolic syndrome (n=157) and abnormal results in an oral glucose tolerance test (n=135). Increases in triglycerides and non-high-density lipoprotein (HDL) cholesterol were associated with significantly higher levels of APOC3, in both Lp B (lipoproteins containing apolipoprotein B) and Lp non-B (lipoproteins free of apolipoprotein B), and a significant higher level of APOE Lp B. APOC3 and APOC3 Lp non-B were increased when glucose metabolism abnormalities were more severe. The presence of a metabolic syndrome was associated with increased plasma APOC3, APOC3 Lp B and APOC3 Lp non-B levels. In a multiple regression analysis, high levels of APOC3 in Lp B and APOC3 Lp non-B were associated with the presence of clinical signs of lipodystrophy, even after adjustment for triglycerides and HDL-cholesterol levels. Lipid and/or glucose metabolism abnormalities in treated HIV-1-infected patients are associated with increased levels of APOC3 and, to a lesser extent, APOE plasma concentrations. Increased values are also related to clinical signs of insulin resistance and lipodystrophy.