Author + information
- Received December 19, 2017
- Revision received April 2, 2018
- Accepted April 16, 2018
- Published online July 2, 2018.
- Anum Saeed, MDa,b,
- Elena V. Feofanova, MSc,
- Bing Yu, PhDc,
- Wensheng Sun, MPH, MSa,b,
- Salim S. Virani, MD, PhDa,b,d,e,
- Vijay Nambi, MD, PhDa,b,e,
- Josef Coresh, MD, PhDf,
- Cameron S. Guild, MDg,
- Eric Boerwinkle, PhDc,
- Christie M. Ballantyne, MDa,b,h and
- Ron C. Hoogeveen, PhDa,b,∗ (, )@bcmhouston
- aSection of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
- bCenter for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas
- cHuman Genetics Center, The University of Texas School of Public Health, Houston, Texas
- dSection of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
- eSection of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- fDepartment of Epidemiology, Biostatistics, and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- gDepartment of Medicine, University of Mississippi School of Medicine, Jackson, Mississippi
- hSection of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- ↵∗Address for correspondence:
Dr. Ron C. Hoogeveen, Section of Cardiovascular Research, Baylor College of Medicine, 6565 Fannin Street, MS F701, Houston, Texas 77030.
Background Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG.
Objectives The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study.
Methods Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored.
Results RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10−8).
Conclusions RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.
Although the association between elevated plasma triglycerides (TGs) and cardiovascular disease (CVD) has been known for decades (1,2), genetic studies provide new evidence that genes associated with TG-rich lipoprotein (TGRL) metabolism are related to development of atherosclerotic CVD (3,4).
Genetic variants associated with TG metabolism indicate the importance of lipases (e.g., lipoprotein lipase [LPL] and hepatic lipase), their activators (e.g., apolipoprotein [apo] CII and apoAV) and inhibitors (e.g., apoCIII and angiopoietin-like protein [ANGPTL] 4), and ligands for cellular receptors involved in clearance of TGRLs (apoB and apoE) in CVD (5). However, these variants affect multiple lipoproteins, complicating investigations into direct pathophysiology. Increased production and delayed catabolism of TGRLs lead to increased TG-enriched remnant lipoproteins, with increased levels of remnant-like particle cholesterol (RLP-C). In hypertriglyceridemia, cholesteryl ester transfer protein–mediated transfer of TGs from chylomicrons and very low-density lipoprotein (VLDL) to low-density lipoprotein (LDL) and high-density lipoprotein in exchange for cholesteryl esters from LDL and high-density lipoprotein leads to TG-enriched VLDL remnants, intermediate-density lipoprotein, and LDL and to small dense LDL. Numerous studies have focused on the atherogenic potential of remnant lipoproteins and RLP-C (6–8). However, few data describe the association between TGs in LDL (LDL-TG) and future CVD risk.
We examined these 2 lipoprotein measures linked to hypertriglyceridemia—LDL-TG and RLP-C—and their association with CVD in the ARIC (Atherosclerosis Risk in Communities) study. We hypothesized that elevated LDL-TG and RLP-C levels were associated with increased CVD risk. We also used genetic array analysis to investigate associations of genetic variants with LDL-TG and RLP-C levels.
See the Online Appendix for details.
ARIC is a prospective study of CVD in 15,792 middle-aged adults recruited from 4 U.S. communities from 1987 to 1989 (9). Figure 1 describes the selection and demographics of the 9,334 subjects included in this analysis.
Incident CVD events were a composite of incident coronary heart disease (CHD) and incident ischemic stroke after visit 4 and through December 31, 2013. Methods of assessing incident CHD events and ischemic strokes in ARIC have been described (10,11). Median follow-up for CVD, CHD, and ischemic stroke events was 15.6 years (25th percentile, 75th percentile: 10.8, 16.6 years), 15.6 years (25th percentile, 75th percentile: 11.5, 16.6 years), and 15.8 years (25th percentile, 75th percentile: 13.8, 16.7 years), respectively.
Lipoprotein and lipid assays
Lipids were measured in 12-h fasting plasma stored at −70°C with ethylenediaminetetraacetic acid. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), and TGs were measured using enzymatic measures (12). RLP-C (13) and LDL-TG (14) were determined by fully automated detergent-based homogeneous methods (Denka Seiken, Tokyo, Japan).
LDL-TG and RLP-C were modeled as continuous and categorical variables. Associations between exposure variables and outcomes were determined using Cox proportional hazards modeling. Linear terms representing quartile number were used to obtain p values for trend. Model 1 was adjusted for age, sex, and race. Model 2 included model 1 plus risk factors in the Pooled Cohort Equation (PCE). Kaplan-Meier survival curves were calculated for each outcome across RLP-C and LDL-TG quartiles.
Genetic methods and analysis
In a targeted gene approach, we investigated candidate genes and well-established variants within those genes (LPL, LIPC, LIPG, APOC3, APOA5, ANGPTL3, and ANGPTL4) and APOE haplotypes with respect to LDL-TG and RLP-C.
In an unbiased approach, genotypes were obtained from the Illumina HumanExome BeadChip. Genes with cumulative minor allele count ≥3 in both European Americans and African Americans (13,690 genes) were included.
Whole-exome sequencing for 5,847 European Americans and 1,915 African Americans was completed at Baylor College of Medicine Human Genome Sequencing Center. Exomes were captured using HGSC VCRome 2.1 reagent (15); samples were paired-end sequenced using Illumina GAII or HiSeq instruments. Variant calling was done using Atlas2 (16). Whole-exome variants were annotated using ANNOVAR (17) and dbNSFP version 2.0 (18).
Both exome-chip and whole-exome sequencing were available in 5,767 European Americans and 1,857 African Americans.
In the 9,334 participants, RLP-C levels were higher in European Americans than African Americans (median 6.7 mg/dl [25th percentile, 75th percentile: 3.4, 13.5 mg/dl] vs. 3.9 mg/dl [25th percentile, 75th percentile: 2.2, 7.2 mg/dl], p = 0.0001, Wilcoxon rank sum test). Subjects with RLP-C and LDL-TG levels in the highest quartile (Tables 1 and 2⇓⇓) had proatherogenic lipid profiles, were more likely to have diabetes and hypertension, and had higher body mass index, fasting blood glucose, and plasma levels of the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and white blood cell count. Statin use was higher in subjects with RLP-C or LDL-TG levels in the third and fourth quartiles.
Association of RLP-C and LDL-TG with other lipids
As expected, RLP-C and LDL-TG showed strong positive correlations with TGs (r = 0.85 and r = 0.65, respectively, p < 0.0001) (Table 3). RLP-C and LDL-TG were also positively associated with the cholesterol in small dense LDL and with non-HDL-C and were negatively correlated with HDL-C. RLP-C and LDL-TG were also correlated with each other (r = 0.5108, p < 0.0001).
Association of RLP-C and LDL-TG with incident CVD
In quartile analyses (Figure 2), RLP-C showed a graded association with incident CVD but no association with incident ischemic stroke. LDL-TG also showed a graded association with incident CVD, but its association with incident ischemic stroke was driven largely by LDL-TG levels in the highest quartile.
In the categorical analysis of RLP-C, risk for CHD, ischemic stroke, and CVD was significantly higher across increasing quartiles of RLP-C in model 1, but not after adjustment for PCE risk factors in model 2 (Table 4). Similarly, RLP-C analyzed as a continuous variable was significantly associated with incident CHD (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.19 to 1.34; p < 0.001) and ischemic stroke (HR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001) in model 1, but not with any outcome after adjustment for PCE risk factors (Table 5). Additional adjustment for log TGs (model 3) resulted in an inverse association of RLP-C with CVD risk (Table 5). However, given the extremely high correlation between TG and RLP-C levels (Spearman r = 0.8535), our risk prediction modeling was most likely affected by multicollinearity.
For LDL-TG, risk for CHD, ischemic stroke, and CVD was significantly higher across increasing quartiles of LDL-TG in the categorical analysis, and the associations with ischemic stroke and CVD risk persisted after adjustment for PCE risk factors (Table 6). In the continuous analysis, even after adjustment for PCE risk factors, LDL-TG was significantly associated with all outcomes: CHD (HR: 1.28; 95% CI: 1.10 to 1.50; p < 0.002), ischemic stroke (HR: 1.47; 95% CI: 1.13 to 1.92; p < 0.005), and CVD (HR: 1.35; 95% CI: 1.17 to 1.55; p < 0.001) (Table 5). Further adjustment for log TGs (model 3) did not have a significant impact on the association of LDL-TG with CVD outcomes (Table 5).
To assess the extent to which LDL-TG provides incremental value in the prediction of future CVD risk beyond circulating TG and apoB levels, we determined the area under the curve, net reclassification index, and integrated discrimination improvement (Online Table 1). Although improvements in the C-statistics were generally modest for each lipid trait added separately, LDL-TG did show greater improvement in the area under the curve (with significant effects on continuous net reclassification index and integrated discrimination improvement) compared with apoB and TGs. Furthermore, addition of LDL-TG to a PCE model including both apoB and TGs resulted in further improvement in the area under the curve for CVD risk prediction. The overall modest improvement in the C-statistic of each of these lipid measures is not surprising given the traditional CVD lipid risk factors already included in the PCE model and the well-described phenomenon of pleiotropy affecting various lipid traits.
Exome analysis: Unbiased approach
Using an unbiased approach, we assessed the association of nonsynonymous common variants by race (minor allele frequency [MAF] >1%) and performed a meta-analysis. In the meta-analysis, 11 detected single variant–trait associations with RLP-C and LDL-TG reached pre-defined significance (p < 2.5 × 10−8) (Online Table 2), all in genes previously associated with other lipid traits, including small dense LDL (19). Genetic variants associated with both RLP-C and LDL-TG tended to have the same direction of effect on both traits, except rs7412 in APOE.
We also assessed the association of nonsynonymous rare variants by race (MAF <1%) and performed a meta-analysis. A total of 13,690 genes contained ≥1 annotated nonsynonymous variant (MAF ≤1%) and cumulative minor allele count ≥3 in each race. Two aggregate gene-based tests, APOC3 for RLP-C and TARM1 for LDL-TG, reached pre-defined significance in the meta-analysis (p ≤ 2.5 × 10−6) (Online Table 3). The association with APOC3 was in a consistent direction in both races, with 3 nonsynonymous variants in APOC3 leading the association in the meta-analysis (p < 0.05) (Online Table 4). The single nonsynonymous variant (rs2361558) that was monomorphic in African Americans led to the association between the aggregated rare variants in TARM1 and LDL-TG levels. The association of LDL-TG with genetic variants in TARM1 (20) may be important because of the potential link between remnant lipoproteins and the inflammatory response in the etiology of atherosclerotic CVD.
Exome analysis: Candidate gene approach
Associations between RLP-C and LDL-TG levels and coding nonsynonymous and splicing common variants belonging to 7 candidate genes (LPL, LIPC, LIPG, APOC3, APOA5, ANGPTL3, and ANGPTL4) were evaluated using single-variant analysis of whole-exome sequencing data (Tables 7 and 8⇓⇓). These candidate genes were selected because lipases and their activators and inhibitors play a key role in remnant lipoprotein metabolism. Not surprisingly, multiethnic meta-analysis showed significant associations between 2 common variants—rs3135506 (APOA5) and rs328 (LPL)—and both RLP-C and LDL-TG levels, in a consistent direction in both races (p < 0.05 in both races), as well as between RLP-C and LDL-TG. Multiethnic meta-analysis showed relatively weak associations between a common LIPC variant (rs6078) and both RLP-C and LDL-TG levels, in a consistent direction in both races but different directions for RLP-C and LDL-TG. Because it was previously reported that rs2070895 in the promotor region of the hepatic lipase gene was the lead single-nucleotide polymorphism associated with decreased hepatic lipase activity, we imputed rs2070895 in ARIC participants using the 1000 Genomes Project reference panel (21). Multiethnic meta-analysis showed a strong association between rs2070895 and higher LDL-TG levels in both races but no significant association between rs2070895 and RLP-C levels (Tables 7 and 8).
Association of RLP-C and LDL-TG with genetic variants of APOE
Our unbiased approach showed the most significant associations with genetic variants at the APOE locus, particularly rs7412. ApoE has high affinity for the LDL (apoB/E) receptor as well as other hepatic receptors and plays an important role in clearance of remnant lipoproteins from the circulation (22). The 3 common allelic variants of APOE (APOE ε2, APOE ε3, and APOE ε4) have genotype-specific effects on TG and total cholesterol levels (23).
Because rs7412 defines APOE ε2 allele status, we assessed APOE haplotypes and found that APOE ε2/2 was associated with reduced LDL-TG and increased RLP-C (p < 0.0001 vs. any other haplotype) (Figure 3). Furthermore, rs7412 was significantly associated with increased TG and HDL-C levels and with decreased LDL-TG, LDL-C, total cholesterol, non-HDL-C, and lipoprotein(a) levels (Table 9).
Although both RLP-C and LDL-TG were strongly associated with TGs, as expected, they had different associations with incident CVD events in up to 16 years of follow-up in the ARIC study. Both RLP-C and LDL-TG were associated with incident CVD events in minimally adjusted models, but only LDL-TG remained significantly associated with incident CHD and ischemic stroke in models adjusted for traditional PCE risk factors. With further adjustment for TGs and hs-CRP, LDL-TG remained significantly associated with CVD events (HR: 1.26; 95% CI: 1.08 to 1.47; p = 0.003). In the genetic analyses, a common APOE variant had the strongest association with both RLP-C and LDL-TG, but subjects with ε2/2 had decreased LDL-TG and increased RLP-C.
RLP-C and CVD
Unlike in previous studies, RLP-C was quantified directly using a fully automated detergent-based homogenous assay. Numerous studies suggest that high RLP-C concentrations increase risk for atherosclerosis and CHD (24,25).
As in prior studies (24,26,27), in ARIC, RLP-C was significantly correlated with elevated TGs and diabetes at baseline. Although RLP-C was also significantly associated with incident CVD in a basic model adjusted for age, sex, and race, after adjustment for traditional CVD risk factors, including total cholesterol, HDL-C, diabetes, and antihypertensive medication use, RLP-C was not significantly associated with incident CVD events.
In an analysis of genetic variants affecting single lipoprotein classes, including nonfasting remnants, HDL-C, and LDL-C, the causal odds ratio for ischemic heart disease was 2.8 per 39-mg/dl increase in nonfasting remnant cholesterol levels (7). However, in contrast to our study, remnant cholesterol was calculated as total cholesterol minus HDL-C and directly measured LDL-C.
In a biracial cohort from the Jackson Heart Study and Framingham Offspring Cohort Study, RLP-C was positively associated with incident CHD in unadjusted models (8). Lipoproteins were classified by ultracentrifugation, and RLP-C was determined by the sum of cholesterol in the densest VLDL subfraction (VLDL3 cholesterol) and intermediate-density lipoprotein cholesterol. After adjustment for HDL-C and LDL-C levels, the association of RLP-C with CHD was not significant, similar to in our study, which directly quantified fasting RLP-C.
LDL-TG and CVD
To our knowledge, our study is the first to report significant associations of LDL-TG with both ischemic stroke and CHD. Few data are available on the clinical utility of LDL-TG levels in CVD risk prediction, possibly because of the complexity of measuring LDL-TG (26). In a cross-sectional study of patients with stable CHD, in which LDL-TG was measured after fractionation of LDL by equilibrium density-gradient centrifugation, altered LDL metabolism characterized by high LDL-TG was correlated with prevalent CHD and systemic low-grade inflammation independent of LDL-C (28). Our results corroborate and extend these findings in a large population without clinical CHD and demonstrate that high LDL-TG levels measured by a validated automated assay (14) are associated with incident stroke and CHD after adjustment for traditional risk factors, including total cholesterol and HDL-C. Furthermore, in our study we found that individuals with elevated LDL-TG and RLP-C levels also had increased levels of the inflammatory markers hs-CRP and white blood cell count.
In a secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial (26), LDL-TG failed to predict CVD events, including stroke. AIM-HIGH was a secondary prevention trial in 3,094 patients on statin therapy, predominantly white men, with a mean 3-year follow-up. By comparison, the ARIC cohort is larger and biracial, with a longer follow-up of up to 16 years.
Prior studies evaluating the relationship between lipids and stroke risk have shown varied associations (29–31). Interestingly, data now suggest that TG level is independently associated with the stroke risk and that this association is stronger in women than men (32). Although men have higher TG levels than women, we observed that women had higher LDL-TG levels than men, which may be one reason high TG level had a stronger association with stroke in women than in men.
Arterial disease may differ among vascular beds, particularly smaller arteries and arterioles (33). Plaque composition in the smaller cerebral arteries suggests a more fibrotic process than in the coronary arteries, which have more lipid-rich cores and typical atheromatous lesions (34). In addition, arteriolar lesions are characterized by hyalinosis instead of lipid. The associations of higher LDL-TG level with increased hs-CRP level and white blood cell count may reflect an adverse impact on inflammation, which may lead to more cerebrovascular disease.
Exome analysis: Unbiased approach
Our exome-chip survey showed 11 common (MAF >1%) nonsynonymous variant-trait associations, all detected variants of genes previously associated with lipid CVD risk factors, including TG, total cholesterol, HDL-C, LDL-C, and small dense LDL. In exome analysis of rare variants, aggregated variants of TARM1 and APOC3 were also associated with decreased levels of LDL-TG and RLP-C, respectively. The association of LDL-TG levels with genetic variants in TARM1 has not been previously reported. TARM1 encodes a novel costimulator of proinflammatory cytokine secretion by macrophages and neutrophils (20) and may provide a link between LDL-TG and chronic low-grade inflammation underlying CVD progression. ApoCIII inhibits lipolysis by LPL and can delay clearance of atherogenic lipoproteins (35). APOC3 loss-of-function variants are associated with lower TG and small dense LDL levels, higher HDL-C levels, reduced postprandial lipemia, and reduced CHD risk (36). Our findings that APOC3 loss-of-function variants are associated with decreased RLP-C and LDL-TG levels support these previous reports. Notably, a gain-of-function variant of LPL (rs328), identified by both the unbiased approach and the candidate gene approach, was strongly associated with lower RLP-C and LDL-TG levels in our study. This well-known missense variant has been associated with lower TG and increased HDL-C levels (37) and reduced CHD (38).
Exome analysis: Candidate gene approach
Our candidate gene approach showed significant associations between common variants in APOA5 and LPL and circulating RLP-C and LDL-TG levels. ApoAV is postulated to regulate plasma TG levels by enhancing TGRL catabolism by LPL (39) or by inhibiting VLDL synthesis (40). The highly statistically significant variant-trait associations for LPL variants in both unbiased and candidate gene approaches may indicate the importance of LPL as the rate-limiting enzyme for hydrolysis of circulating TGs. We found weaker associations between a common LIPC variant (rs6078) and RLP-C and LDL-TG levels. However, a strong association was found between rs2070895 and LDL-TG levels. rs2070895 is located in the promotor region of the hepatic lipase gene and was previously found to be associated with decreased hepatic lipase activity (41). Hepatic lipase plays an important role in the lipolytic conversion of VLDL to LDL, a process modulated by high-density lipoprotein composition (42). Mutations in the hepatic lipase gene were associated with increased ischemic heart disease risk in the Copenhagen City Heart Study (43). Complete deficiency of hepatic lipase has also been linked with impaired catabolism and accumulation of remnant particle RLP-C as well as increased TG content of LDL (41).
ApoE and CVD
A novel aspect of this study is the identification of genetic variants associated with RLP-C and LDL-TG, including the APOE variant rs7412. A review of epidemiological studies of APOE polymorphism and CHD estimated that about 6% of the variation in CHD risk in North Americans is attributable to this locus (44). Most genotyping assays used in population studies did not include rs7412, but the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium recently demonstrated that APOE ε2 was associated with reduced subclinical atherosclerosis assessed by carotid intima-media thickness and coronary calcium scores and also with clinical CHD (45). Previous studies also suggest a protective effect of APOE ε2 on atherosclerosis (46,47), despite the association between apoE2/2 and type III hyperlipoproteinemia (46), which is characterized by accumulated remnant lipoproteins with resulting increased blood TG and cholesterol levels.
In our cohort, the APOE variant rs7412 was significantly associated with LDL-TG and RLP-C in both races. Furthermore, APOE ε2/2 was associated with higher RLP-C and TG levels but lower LDL-TG levels. The different relationships of RLP-C and LDL-TG with APOE ε2/2 may be explained in part by the low affinity of apoE2 for the LDL (apoB/E) receptor, potentially leading to delayed clearance of VLDL and chylomicron remnants (48). The slower removal of remnant particles may lead to increased RLP-C levels in the circulation, while the reduced uptake of RLP-C via the LDL receptor may simultaneously up-regulate cellular LDL receptors, leading to increased removal of LDL and thus lower LDL-TG in these subjects. We propose a model in which defective TGRL catabolism, with subsequent increased TGRL remnants, in the presence of delayed LDL catabolism leads to increased LDL-TG levels through interaction with cholesteryl ester transfer protein. Although RLP-C and LDL-TG may both be considered markers of remnant lipoprotein metabolism (Central Illustration), our data suggest that LDL-TG may be a more important marker of atherogenic altered remnant/LDL metabolism not detected by a routine lipid profile. Indeed, although most circulating TGs are in chylomicron and VLDL remnants, the relatively short half-life of these particles compared with that of LDL may render remnant particles (or measures of their lipid content, such as cholesterol or TGs) less useful as cardiovascular risk markers. Alternatively, LDL-TG may represent a lipoprotein subfraction with specific proatherogenic properties. Therapies that lower LDL-C by enhanced LDL receptor–mediated clearance (e.g., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors) would also be expected to lower LDL-TG levels. An alternative approach suggested by the genetic observations is to use therapies that inhibit apoCIII or activate LPL to clear TGRLs more rapidly, which would also be expected to lower LDL-TG levels. Future studies are needed to determine whether the relationship between LDL-TG and cardiovascular outcomes is causal, and if so, which therapies may be most effective.
Study strengths and limitations
Strengths of the present study include a large, well-characterized, biracial population followed for up to 16 years in a study designed to examine CVD incidence and risk factors, and the use of a homogenous assay to measure RLP-C and LDL-TG directly. A limitation is measurement at only 1 time point using frozen plasma samples. Also, despite adjustments, residual confounding is possible, and the relationships are, at best, associations.
Although elevated TGs were associated with increased RLP-C and LDL-TG, only LDL-TG predicted CVD risk in models adjusted for traditional risk factors. APOE variants were associated with RLP-C and LDL-TG, but subjects with ε2/2 had decreased LDL-TG and increased RLP-C. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.
COMPETENCY IN MEDICAL KNOWLEDGE: Although both RLP-C and LDL-TG levels correlate with TG levels and incident cardiovascular events, after adjusting for traditional risk factors, only LDL-TG predicts incident CHD and ischemic stroke. Hence, for risk assessment in a primary prevention setting, measurement of LDL-TG provides additional information beyond traditional risk factors and lipid levels.
TRANSLATIONAL OUTLOOK: Prospective clinical trials should examine whether pharmacotherapies that reduce LDL-TG reduce ischemic events.
The authors thank the staff and participants of the ARIC study for their important contributions.
The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-Diseases: The U.S. CHARGE Consortium” was provided by the National Institutes of Health through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273). Dr. Hoogeveen has received a research grant from Denka Seiken; Denka Seiken had no role in the design, analysis, or data interpretation of this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiopoietin-like protein
- coronary heart disease
- confidence interval
- cardiovascular disease
- high-density lipoprotein cholesterol
- hazard ratio
- high-sensitivity C-reactive protein
- low-density lipoprotein
- low-density lipoprotein triglycerides
- lipoprotein lipase
- minor allele frequency
- Pooled Cohort Equation
- remnant-like particle cholesterol
- triglyceride-rich lipoprotein
- very low-density lipoprotein
- Received December 19, 2017.
- Revision received April 2, 2018.
- Accepted April 16, 2018.
- 2018 American College of Cardiology Foundation
- Sarwar N.,
- Danesh J.,
- Eiriksdottir G.,
- et al.
- Irvin M.R.,
- Zhi D.,
- Joehanes R.,
- et al.
- Musunuru K.,
- Kathiresan S.
- Varbo A.,
- Nordestgaard B.G.
- Varbo A.,
- Benn M.,
- Tybjaerg-Hansen A.,
- Jorgensen A.B.,
- Frikke-Schmidt R.,
- Nordestgaard B.G.
- Joshi P.H.,
- Khokhar A.A.,
- Massaro J.M.,
- et al.
- Rosamond W.D.,
- Folsom A.R.,
- Chambless L.E.,
- et al.
- Sharrett A.R.,
- Patsch W.,
- Sorlie P.D.,
- Heiss G.,
- Bond M.G.,
- Davis C.E.
- Ito Y.,
- Hirao Y.
- Ito Y.,
- Ohta M.,
- Ikezaki H.,
- et al.
- Hoogeveen R.C.,
- Gaubatz J.W.,
- Sun W.,
- et al.
- Radjabova V.,
- Mastroeni P.,
- Skjodt K.,
- et al.
- Maxwell T.J.,
- Ballantyne C.M.,
- Cheverud J.M.,
- Guild C.S.,
- Ndumele C.E.,
- Boerwinkle E.
- Albers J.J.,
- Slee A.,
- Fleg J.L.,
- O’Brien K.D.,
- Marcovina S.M.
- Schaefer E.J.,
- McNamara J.R.,
- Shah P.K.,
- et al.
- Marz W.,
- Scharnagl H.,
- Winkler K.,
- et al.
- Lindenstrom E.,
- Boysen G.,
- Nyboe J.
- Shahar E.,
- Chambless L.E.,
- Rosamond W.D.,
- et al.
- Pollin T.I.,
- Damcott C.M.,
- Shen H.,
- et al.
- Zheng C.,
- Khoo C.,
- Furtado J.,
- Sacks F.M.
- Khera A.V.,
- Won H.H.,
- Peloso G.M.,
- et al.
- Merkel M.,
- Loeffler B.,
- Kluger M.,
- et al.
- Schaap F.G.,
- Rensen P.C.,
- Voshol P.J.,
- et al.
- Deeb S.S.,
- Zambon A.,
- Carr M.C.,
- Ayyobi A.F.,
- Brunzell J.D.
- Andersen R.V.,
- Wittrup H.H.,
- Tybjaerg-Hansen A.,
- Steffensen R.,
- Schnohr P.,
- Nordestgaard B.G.
- Natarajan P.,
- Bis J.C.,
- Bielak L.F.,
- et al.
- Davignon J.,
- Gregg R.E.,
- Sing C.F.
- Pablos-Mendez A.,
- Mayeux R.,
- Ngai C.,
- Shea S.,
- Berglund L.