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1.  New Automated Assay of Small Dense Low-Density Lipoprotein Cholesterol Identifies Risk of Coronary Heart Disease 
Coronary heart disease (CHD) is the leading cause of death in the United States, yet assessing risk of its development remains challenging. The present study evaluates a new automated assay of small dense low-density lipoprotein cholesterol content (sdLDL-C) and whether sdLDL-C is a risk factor for CHD compared with LDL-C or small LDL particle concentrations derived from nuclear magnetic resonance spectroscopy.
Approach and Results
sdLDL-C was measured using a new automated enzymatic method, and small LDL concentrations were obtained by nuclear magnetic resonance in 4387 Multi-Ethnic Study of Atherosclerosis participants. Cox regression analysis estimated hazard ratios for developing CHD for 8.5 years after adjustments for age, race, sex, systolic blood pressure, hypertension medication use, high-density lipoprotein cholesterol, and triglycerides. Elevated sdLDL-C was a risk factor for CHD in normoglycemic individuals. Those in the top sdLDL-C quartile showed higher risk of incident CHD (hazard ratio, 2.41; P=0.0037) compared with those in the bottom quartile and indicated greater CHD risk than the corresponding quartile of LDL-C (hazard ratio, 1.75; P=0.019). The association of sdLDL-C with CHD risk remained significant when LDL-C (<2.57 mmol/L) was included in a multivariate model (hazard ratio, 2.37; P=0.012). Nuclear magnetic resonance–derived small LDL concentrations did not convey a significant risk of CHD. Those with impaired fasting glucose or diabetes mellitus showed higher sdLDL-C and small LDL concentrations but neither was associated with higher CHD risk in these individuals.
This new automated method for sdLDL-C identifies risk for CHD that would remain undetected using standard lipid measures, but only in normoglycemic, nondiabetic individuals.
PMCID: PMC4211254  PMID: 24233487
coronary; disease
2.  APOE genotype modifies the association between plasma measured omega-3 fatty acids and plasma lipids in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2013;228(1):181-187.
The benefits of fish oil fatty acids eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) on plasma lipid profiles have been inconsistent but may partially depend on individual Apolipoprotein E (APOE) genotypes. We aimed to determine whether APOE genotype modifies the association of lipid profile characteristics with plasma EPA and DHA levels.
APOE genotype was determined in this cross-sectional analysis of 2340 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Relative plasma phospholipid EPA and DHA levels, plasma lipids, and lipoprotein subclass particle sizes and concentrations were measured.
Significant gene-EPA interactions were found with HDL-C, and particle concentrations of large and total HDL (pinteraction = 0.0002, 0.006, and 0.007, respectively). The above lipid targets were positively associated with EPA in the E2 groups, whereas negative trends were observed among the E4 participants. Gene-DHA interactions were noted for small LDL particle concentrations alone (pinteraction = 0.01), where a positive trend was found among E4 but not E2 or E3 participants.
These results indicate a significant contribution of the APOE genotype to the EPA-lipid profile relationship; however, the results do not explain the differences in previous findings regarding LDL-C, triglycerides or total cholesterol. Future investigators examining the effects of EPA on HDL-C or lipoprotein characteristics may consider including APOE genotype in their analyses.
PMCID: PMC3640761  PMID: 23466070
APOE genotype; eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); plasma lipids; lipoproteins
3.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
PMCID: PMC3612981  PMID: 18243217
4.  Effect of Fenofibrate Therapy and ABCA1 Polymorphisms on High Density Lipoprotein Subclasses in the Genetics of Lipid Lowering Drugs and Diet Network 
Molecular genetics and metabolism  2010;100(2):118-122.
Previous studies have shown that ATP-binding cassette transporter 1 (ABCA1) polymorphisms associated with increased ABCA1 expression result in increased small HDL (high density lipoprotein) subclass particle concentration. The present study examines the effect of treatment with fenofibrate, a drug known to bind peroxisome proliferator-activated receptor alpha (PPARα) which increases the expression of ABCA1 gene, on lipoprotein subclass profiles of individuals stratified by ABCA1 genotypes.
Participants of Genetics of Lipid-lowering Drugs and Diet Network (GOLDN) were treated with fenofibrate over a three week period. We analyzed six ABCA1 polymorphisms in 287 GOLDN participants with triglyceride concentrations ≥ 150 mg/dL and studied their associations with HDL subclass particle concentrations, as measured by nuclear magnetic resonance spectroscopy, before and after treatment.
Fenofibrate treatment did not result in significant changes in small HDL subclass particle concentration. When changes in HDL subclasses were stratified by ABCA1 polymorphism genotypes, there were no statistically significant associations between ABCA1 genotypes and small HDL subclasses before fenofibrate treatment. However, after fenofibrate treatment the KK genotype of R1587K (mean 4.40 μmol/L; p = 0.004) and the RK genotype of R219K (mean 1.60 μmol/L; p = 0.02) polymorphisms were associated with significantly increased small HDL. The R1587K KK genotype (mean 4.80 μmol/L; p = 0.0002) and the R219K KK genotype (mean 2.50 μmol/L; p = 0.02) were also associated with increased HDL particle concentrations.
There is a synergistic effect between ABCA1 polymorphisms and fenofibrate. Thus our study indirectly confirms the role of fenofibrate and genotype in increasing cholesterol efflux, as evidenced by increased small HDL particles.
PMCID: PMC3598593  PMID: 20346718
ABCA1; cardiovascular disease; fenofibrate; lipoprotein; lipoprotein particle size
5.  Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study 
Aging Cell  2014;14(1):49-59.
Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = −0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.
PMCID: PMC4324456  PMID: 25476875
apolipoprotein E; age; DNA methylation; variants; epidemiology; interaction
6.  Short-Term Fenofibrate Treatment Reduces Elevated Plasma Lp-PLA2 Mass and sVCAM-1 Levels in a Sub-Cohort of Hypertriglyceridemic GOLDN Participants 
High levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with inflammation, atherosclerosis, and CHD events. In addition, Lp-PLA2 has been linked to classical markers of endothelial activation, including soluble vascular cell adhesion molecule-1 (sVCAM-1). Though treatment with fenofibrate reduces Lp-PLA2 mass, it is unclear whether fenofibrate reduces sVCAM-1 levels or whether there is an association between any changes observed in Lp-PLA2 and sVCAM-1.
Concentrations of Lp-PLA2 mass and sVCAM-1 levels were measured in plasma at baseline and after 3 weeks of fenofibrate treatment (160 mg/d) in 96 hypertriglyceridemic participants of the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN) study.
Lp-PLA2 and sVCAM-1 were stratified by tertiles as determined by baseline levels of the respective target. Fenofibrate treatment resulted in increases of 30.1% in Lp-PLA2 mass (p=0.0003) and 14.7% in sVCAM-1 levels (p=0.0096), but only in tertile1 of either target. In contrast, Lp-PLA2 mass was reduced by 35.3 % (p<0.0001) in tertile 3. Soluble VCAM-1 levels were significantly reduced by 7.74% (p=0.0109) and 17.2% (p<0.0001) in tertiles 2 and 3, respectively. No associations were observed between Lp-PLA2 and sVCAM-1 at baseline or post-treatment.
In conclusion, fenofibrate treatment in hypertriglyceridemic subjects reduced levels of LpPLA2 mass and sVCAM-1, but only in those with elevated baseline levels of these biomarkers. The greatest reductions in LpPLA2 levels were observed in individuals with LpPLA2 concentrations indicative of increased CVD risk (>200 ng/mL).
PMCID: PMC3138503  PMID: 21757154
Fenofibrate; atherosclerosis; VCAM; Lp-PLA; triglyceride; GOLDN
7.  Genetic loci associated with circulating levels of very long-chain saturated fatty acids[S] 
Journal of Lipid Research  2015;56(1):176-184.
Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
PMCID: PMC4274065  PMID: 25378659
arachidic acid; behenic acid; lignoceric acid; sphingolipids
8.  Effects of Fenofibrate on Plasma Oxidized LDL and 8-Isoprostane In a Sub-Cohort of GOLDN Participants 
Atherosclerosis  2010;214(2):422-425.
Fenofibrate significantly reduces circulating triglyceride (TG) concentrations, particularly in individuals with elevated levels. The purpose of the current study was to determine whether fenofibrate treatment reduces markers of oxidative stress, oxidized low density lipoprotein (ox-LDL) and 8-isoprostane (8-isoP), in a manner similar to TG where those with the highest levels show the greatest reductions.
The concentrations of TG, 8-isoP, and ox-LDL were measured in plasma before and after 3 weeks of fenofibrate treatment (160 mg/d) in a sub-cohort (n=187) of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study.
Data were divided into tertiles as determined by pre-treatment values of the respective target. Fenofibrate treatment resulted in significant reductions in TG concentrations by 24.2% (p<0.0001), 41.9% (p<0.0001), and 46.6% (p<0.0001) in tertiles 1, 2, and 3, respectively. Significant reductions were also observed in ox-LDL of 7.2% (p=0.0096), 8.5% (p=0.0019) and 12.1% (p<0.0001) in tertiles 1, 2, and 3, respectively. Finally, fenofibrate treatment resulted in a 32.7% increase (p=0.0201) in 8-isoP levels in tertile 1, but a significant decrease of 34.4% (p<0.0001) in tertile 3.
This study is the largest to date to demonstrate that fenofibrate reduces oxidative stress and the first to show a suppressive effect on 8-isoP levels in individuals with a high oxidative burden following short term (3 wk) drug therapy. Those with the highest baseline levels of ox-LDL and 8-isoP showed the greatest reductions following fenofibrate treatment. Given the role of oxidative stress in atherosclerosis and coronary heart disease, our observations may partially explain the efficacy of fenofibrate in reducing cardiovascular events in select patients.
PMCID: PMC3031718  PMID: 21159339
Fenofibrate; atherosclerosis; isoprostane; ox-LDL; triglyceride; GOLDN
9.  Plasma phospholipid saturated fatty acids and heart failure risk in the Physicians’ Health Study 
Previous studies have suggested that some plasma phospholipid saturated fatty acids (SFA) are associated with an increased risk of coronary heart disease and hypertension, major risk factors for heart failure (HF). However, little is known about the association between SFA and HF. This study examines associations of individual plasma phospholipid SFA with HF risk in US male physicians.
The current ancillary study used a prospective nested matched case-control design to select 788 cases of incident HF and 788 controls. Plasma phospholipid SFAs were measured using gas chromatography. HF was self-reported on follow-up questionnaires and validated by review of medical records in a subsample. We used conditional logistic regression to estimate relative risks.
Mean age was 58.7±8.0 years. One standard deviation higher plasma phospholipid 16:0 was associated with an odds ratio (95% CI) of 1.20 (1.04, 1.38) controlling for established HF risk factors and other SFAs (p=0.042). However, this association was not significant after Bonferroni correction (p>0.008). We did not observe associations between other SFAs (14:0, 15:0, 18:0, 20:0, or 22:0) and HF risk (all p for trend > 0.05).
Our data suggested no association between plasma phospholipid SFAs and HF in US male physicians.
PMCID: PMC3703479  PMID: 23473794
Saturated fatty acids; palmitic acid; heart failure
10.  Plasma Vitamin D Binding Protein and Risk of Heart Failure in Male Physicians 
The American journal of cardiology  2013;112(6):827-830.
Previous studies suggest that vitamin D deficiency may contribute to the pathogenesis of heart failure (HF); however, limited data are available on the association of vitamin D binding protein (VDBP) – a major transport protein for vitamin D – with the development of HF. Thus, we investigated whether plasma VDBP is inversely associated with HF risk. Using a prospective nested case-control design, we selected 464 cases and 464 matched controls from the Physicians’ Health Study for current analyses. VDBP was determined using an enzyme-linked immunoassay. Self-reported HF was obtained through annual follow-up questionnaires and validated in a subsample via review of medical records. We used conditional logistic regressions to compute adjusted odds ratios. The mean age was 58.6 years and the median VDBP was 307.8 (IQR: 265.2–354.6) μg/mL. Plasma VDBP was not associated with HF in our study: OR (95% CI): 1.0 (ref), 1.05 (0.66–1.65), 1.28 (0.80–2.06), 1.07 (0.65–1.75), and 1.28 (0.76–2.15) across consecutive quintiles of VDBP, p for linear trend 0.41, after adjustment for matching factors, body mass index, diabetes, atrial fibrillation, hypertension, and high sensitivity C-reactive protein. In conclusion, our data showed no significant association between plasma levels of VDBP and HF risk in apparently healthy male physicians.
PMCID: PMC3759533  PMID: 23735647
risk factors; epidemiology; heart failure; vitamin D binding protein
11.  Long-Term Variability of Inflammatory Markers and Associated Factors in a Population-Based Cohort 
To investigate long-term variability in serum high sensitivity C-reactive protein (CRP) and interleukin-6 (IL-6) and to determine associated risk factors for high risk inflammatory profiles.
Prospective population-based cohort study.
Participants (N=1,443) of the Epidemiology of Hearing Loss Study and the Beaver Dam Eye Study, two population-based prospective studies of aging in the same cohort.
Among participants aged 43–79 years at the initial exam (1988–1990), serum high sensitivity CRP was measured from three time-points (1988–1990, 1998–2000, 2009–2010) and serum IL-6 was measured from two (1998–2000 and 2009–2010).
When IL-6 levels were categorized into tertiles, 50.8% of participants remained in the same group 10 years later (weighted Kappa(κ)=.34). When CRP was categorized into three risk groups, 53.4% of participants remained in the same group during 10 years (κ=.36), and 32.4% remained in the same group at all three examinations (κ=.27). Interleukin 6 increased from a geometric mean of 1.54 pg/L to 1.78 pg/L over 10 years, while CRP increased from a geometric mean of 1.67 mg/L to 2.25 mg/L over 10 years, and then decreased to 1.93 mg/L over the next 10 years. These 10-year decreases in CRP were not observed in those not reporting statin use. Factors associated with long-term higher levels of either IL-6 and CRP included older age (IL-6), obesity, smoking, lower physical activity (IL-6), lower HDL cholesterol (IL-6), and a history of statin (non)use (CRP).
Inflammatory marker levels tracked over the long-term into older age with within-person increases observed. Several potentially modifiable risk factors were associated with long-term higher levels of inflammatory markers.
PMCID: PMC3743937  PMID: 23889670
Inflammation; Aging; Long-term Variability
12.  Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response 
Human genetics  2014;133(7):919-930.
Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.
PMCID: PMC4112746  PMID: 24604477
13.  The Effect of Non-surgical Periodontal Therapy on Hemoglobin A1c Levels in Persons with Type 2 Diabetes and Chronic Periodontitis: A Randomized Clinical Trial 
Chronic periodontitis, a destructive inflammatory disorder of the supporting structures of the teeth, is prevalent in patients with diabetes. Limited evidence suggests that periodontal therapy may improve glycemic control.
To determine if non-surgical periodontal treatment reduces hemoglobin A1c (HbA1c) in persons with type 2 diabetes (DM) and moderate to advanced chronic periodontitis.
Design, Setting and Participants
The Diabetes and Periodontal Therapy Trial (DPTT) is a 6-month, single-masked, randomized, multi-center clinical trial. Participants had DM, were taking stable doses of medications, had HbA1c ≥7% and <9%, and untreated periodontitis. Five hundred fourteen participants were enrolled between November 2009 and March 2012 from diabetes and dental clinics and communities affiliated with five academic medical centers.
The treatment group (n=257) received scaling and root planing plus chlorhexidine oral rinse at baseline, and supportive periodontal therapy at three and six months. The control group (n=257) received no treatment for six months.
Main Outcome Measure
Difference in HbA1c change from baseline between groups at six months. Secondary outcomes included changes in probing pocket depths, clinical attachment loss, bleeding on probing, gingival index, fasting glucose, and the Homeostasis Model Assessment (HOMA2).
Enrollment was stopped early due to futility. At 6 months, the periodontal therapy group increased HbA1c 0.17% (1.0) (mean (SD)) compared to 0.11% (1.0) in the control group, with no significant difference between groups based on a linear regression model adjusting for clinical site (mean difference = -0.05%; 95% Confidence Interval (CI): -0.23%, 0.12%; p=0.55). Probing depth, clinical attachment loss, bleeding on probing and gingival index measures improved in the treatment group compared to the control group at six months with adjusted between-group differences of 0.33mm (95% CI: 0.26, 0.39), 0.31mm (95% CI: 0.23, 0.39), 16.5% (95% CI: 12.9, 20.0) and 0.28 (95% CI: 0.21, 0.35), respectively; all p values <0.0001).
Conclusions and Relevance
Non-surgical periodontal therapy did not improve glycemic control in patients with DM and moderate to advanced chronic periodontitis. These findings do not support the use of nonsurgical periodontal treatment in patients with diabetes for the purpose of lowering HbA1c.
PMCID: PMC4089989  PMID: 24346989
Diabetes; Diabetes Mellitus; Type 2; Periodontal Disease; Periodontitis; Glycated Hemoglobin; HbA1c
14.  Comparison of Postprandial Responses to a High-Fat Meal in Hypertriglyceridemic Men and Women before and after Treatment with Fenofibrate in the Genetics and Lipid Lowering Drugs and Diet Network (GOLDN) Study 
SRX pharmacology  2010;2010:485146-.
The fenofibrate effect on the subclass size distribution of lipoproteins before and after a high-fat challenge is not well studied.
To characterize the baseline and post-prandial response (PPL) to a high-fat challenge following fenofibrate therapy, on changes in LDL, HDL, and VLDL particle subclasses, number, and size in 271 hypertriglyceridemic participants.
Participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study who conducted PPL studies both before and after three weeks of fenofibrate (160 mg/d) treatment were analyzed. Particle size distributions were determined using nuclear magnetic resonance imaging, and lipid determinations were measured at fasting (0 hr), 3.5 hours, and 6 hours after ingestion of a standardized high-fat meal. Analyses were stratified by gender. Changes in particle subclass distributions were assessed using repeated measures analysis of variance adjusted for pedigree.
Before PPL, fenofibrate in men (adjusted for age, field center, smoking status, diabetes, and weight circumference) lowered fasting and postprandial VLDL primarily due to reductions in postprandial levels of large and medium VLDL particles (9 SE +/–0.7 to 4 +/–0.4 and 78 / –4 to 36 / –3 nmol/L both P < .0001, resp.). Fenofibrate also reduced fasting and postprandial total LDL particles, primarily a result of reduced small LDL particles (1497 = / – 37 to 1088 = / – 36 nmol/L, P < .0001). Directional changes were similar in men and women but the magnitude of change was different for some parameters.
Fenofibrate treatment resulted in a lower triglyceride excursion following a high-fat meal. This investigation provides new knowledge of the magnitude and time course of fenofibrate induced attenuation of Lipoprotein subclass size distribution following a postprandial lipid challenge.
PMCID: PMC4067904  PMID: 24971173
15.  n-3 and n-6 Fatty acids are independently associated with lipoprotein-associated phospholipase A2 in the Multi-Ethnic Study of Atherosclerosis 
The British journal of nutrition  2013;110(9):1664-1671.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for CVD and has been proposed as a marker of vascular inflammation. Polyunsaturated n-3 fatty acids (FA) and several n-6 FA are known to suppress inflammation and may influence Lp-PLA2 mass and activity. The associations of n-3 and n-6 plasma FA with Lp-PLA2 mass and activity were analysed using linear regression analysis in 2246 participants of the Multi-Ethnic Study of Atherosclerosis; statistical adjustments were made to control for body mass, inflammation, lipids, diabetes, and additional clinical and demographic factors. Lp-PLA2 mass and activity were significantly lower in participants with the higher n-3 FA EPA (β = −4·72, P<0·001; β = −1·53; P=0·023) and DHA levels (β = −4·47, β = −1·87; both P<0·001). Those in the highest quintiles of plasma EPA and DHA showed 12·71 and 19·15 ng/ml lower Lp-PLA2 mass and 5·7 and 8·90 nmol/min per ml lower Lp-PLA2 activity than those in the first quintiles, respectively. In addition, lower Lp-PLA2 mass and activity were associated with higher levels of n-6 arachidonic acid (β = −1·63, β = −1·30; both P<0·001), while γ-linolenic acid was negatively associated with activity (β = −27·7, P=0·027). Lp-PLA2 mass was significantly higher in participants with greater plasma levels of n-6 linoleic (β = 0·828, P=0·011) and dihomo-γ-linolenic acids (β = 4·17, P=0·002). Based on their independent associations with Lp-PLA2 mass and activity, certain n-3 and n-6 FA may have additional influences on CVD risk. Intervention studies are warranted to assess whether these macronutrients may directly influence Lp-PLA2 expression or activity.
PMCID: PMC4060439  PMID: 23551952
Fatty acids; n-3; Atherosclerosis; Lipoprotein-associated phospholipase; Lipoprotein-associated phospholipase A2
16.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
17.  Genetic variants associated with VLDL, LDL and HDL particle size differ with race/ethnicity 
Human genetics  2012;132(4):405-413.
Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial / ethnic groups on lipoprotein profile.
Methods and results
Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P<1.97 * 10−05 (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N=2430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N=1594), Chinese (N=758) and Hispanic (N=1422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only.
Our findings suggest the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race / ethnicity.
PMCID: PMC3600091  PMID: 23263444
Lipoprotein size; race / ethnicity; ApoB; Hepatic Lipase; NMR
18.  Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium 
Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease.
Methods and Results
Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8).
Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
PMCID: PMC3891054  PMID: 23362303
epidemiology; fatty acids; genome-wide association study
19.  Genetic Analysis of 16 NMR-Lipoprotein Fractions in Humans, the GOLDN Study 
Lipids  2012;48(2):155-165.
Sixteen nuclear magnetic resonance (NMR) spectroscopy lipoprotein measurements of more than 1,000 subjects of GOLDN study, at fasting and at 3.5 and 6 h after a postprandial fat (PPL) challenge at visits 2 and 4, before and after a 3 weeks Fenofibrate (FF) treatment, were included in 6 time-independent multivariate factor analyses. Their top 1,541 unique SNPs were assessed for association with GOLDN NMR-particles and classical lipids. Several SNPs with −log10 p > 7.3 and MAF ≥ 0.10, mostly intergenic associated with NMR-single traits near genes FAM84B (8q24.21), CRIPT (2p21), ACOXL (2q13), BCL2L11 (2q13), PCDH10 (4q28.3), NXPH1 (7p22), and SLC24A4 (14q32.12) in association with NMR-LDLs; HOMER1 (5q14.2), KIT (4q11–q12), VSNL1 (2p24.3), QPRT (16p11.2), SYNPR (3p14.2), NXPH1 (7p22), NELL1 (11p15.1), and RUNX3 (1p36) with NMR-HDLs; and DOK5-CBLN4-MC3R (20q13), NELL1 (11p15.1), STXBP6 (14q12), APOB (2p24-p23), GPR133 (12q24.33), FAM84B (8q24.21) and NR5A2 (1q32.1) in association with NMR-VLDLs particles. NMR single traits associations produced 75 % of 114 significant candidates, 7 % belonged to classical lipids and 18 % overlapped, and 16 % matched for time of discovery between NMR- and classical traits. Five proxy genes, (ACOXL, FAM84B, NXPH1, STK40 and VAPA) showed pleiotropic effects. While tagged for significant associations in our study and with some extra evidence from the literature, candidates as CBNL4, FAM84B, NXPH1, SLC24A4 remain unclear for their functional relation to lipid metabolism. Although GOLDN study is one of the largest in studying PPL and FF treatment effects, the relatively small samples (over 700–1,000 subjects) in association tests appeals for a replication of such a study. Thus, further investigation is needed.
PMCID: PMC3601742  PMID: 23192668
Nuclear magnetic resonance particles; Lipoproteins; Fenofibrate; Postprandial challenge; Genome-wide association
20.  Circulating and Dietary Omega‐3 and Omega‐6 Polyunsaturated Fatty Acids and Incidence of CVD in the Multi‐Ethnic Study of Atherosclerosis 
Dietary guidelines support intake of polyunsaturated fatty acids (PUFAs) in fish and vegetable oils. However, some controversy remains about benefits of PUFAs, and most prior studies have relied on self‐reported dietary assessment in relatively homogeneous populations.
Methods and Results
In a multiethnic cohort of 2837 US adults (whites, Hispanics, African Americans, Chinese Americans), plasma phospholipid PUFAs were measured at baseline (2000–2002) using gas chromatography and dietary PUFAs estimated using a food frequency questionnaire. Incident cardiovascular disease (CVD) events (including coronary heart disease and stroke; n=189) were prospectively identified through 2010 during 19 778 person‐years of follow‐up. In multivariable‐adjusted Cox models, circulating n‐3 eicosapentaenoic acid and docosahexaenoic acid were inversely associated with incident CVD, with extreme‐quartile hazard ratios (95% CIs) of 0.49 for eicosapentaenoic acid (0.30 to 0.79; Ptrend=0.01) and 0.39 for docosahexaenoic acid (0.22 to 0.67; Ptrend<0.001). n‐3 Docosapentaenoic acid (DPA) was inversely associated with CVD in whites and Chinese, but not in other race/ethnicities (P‐interaction=0.01). No significant associations with CVD were observed for circulating n‐3 alpha‐linolenic acid or n‐6 PUFA (linoleic acid, arachidonic acid). Associations with CVD of self‐reported dietary PUFA were consistent with those of the PUFA biomarkers. All associations were similar across racial‐ethnic groups, except those of docosapentaenoic acid.
Both dietary and circulating eicosapentaenoic acid and docosahexaenoic acid, but not alpha‐linolenic acid or n‐6 PUFA, were inversely associated with CVD incidence. These findings suggest that increased consumption of n‐3 PUFA from seafood may prevent CVD development in a multiethnic population.
PMCID: PMC3886748  PMID: 24351702
cardiovascular disease prevention; cardiovascular risk factors; diet; fatty acids
21.  The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions 
Journal of human genetics  2008;53(8):10.1007/s10038-008-0302-2.
The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggested that the SCARB1 gene may contribute to variation in plasma lipid levels at the fasting; however, the results have been inconsistent and it is unclear if SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with post-fenofibrate change for triglyceride (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response as well as response to fenofibrate intervention.
PMCID: PMC3836273  PMID: 18542840
Scavenger receptor class B type 1; lipid; genetics; fenofibrate; postprandial
22.  Plasma Phospholipid Concentration of Cis Palmitoleic Acid and Risk of Heart Failure 
Circulation. Heart failure  2012;5(6):703-709.
While plasma palmitoleic acid has been positively associated with blood pressure, inflammation, and insulin resistance, its association with heart failure has not been investigated. We assessed whether plasma phospholipid cis palmitoleic acid was associated with heart failure risk.
Methods and Results
This ancillary study of the Physicians’ Health Study used a risk set sampling method to select 788 matched pairs. For each case of incident heart failure, we randomly selected a control among subjects that were free of heart failure and alive at the time of index case diagnosis and matched on age, year of birth, race, and time of blood collection. Plasma phospholipid fatty acids were measured using gas chromatography. Heart failure was ascertained using annual follow-up questionnaire and validated in a subsample. In a multivariable conditional logistic regression, odds ratios (95% CI) for heart failure were 1.0 (ref), 1.06 (0.75-1.48), 1.20 (0.85-1.68), and 1.58 (1.11-2.25) across consecutive quartiles of cis palmitoleic acid (p for trend 0.009). Each standard deviation increase in plasma cis palmitoleic acid was associated with 17% higher odds of heart failure (95% CI: 2% to 33%) in a multivariable model. In a secondary analysis, each standard deviation increase of log-stearoyl-coA desaturase activity (16:1n-7/16:0 ratio) was positively associated with the risk of heart failure [OR: 1.14 (95% CI: 1.00-1.29)] whereas oleic acid and cis-vaccenic acid concentrations were not related to heart failure risk.
Our data showed a positive association between plasma phospholipid cis-palmitoleic acid and heart failure risk in male physicians.
PMCID: PMC3618485  PMID: 23065037
heart failure; epidemiology; fatty acids; cis-palmitoleic acids; risk factors
23.  Association between adiponectin and heart failure risk in the Physicians' Health Study 
Obesity (Silver Spring, Md.)  2013;21(4):831-834.
Limited data are available on the association between adiponectin and incident heart failure. In the current ancillary study to the Physicians' Health Study, we used a prospective nested-case control design to examine whether plasma adiponectin concentration was related to the risk of heart failure. We selected 787 incident heart failure cases and 787 matched controls for the current analysis. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Adiponectin was measured using ELISA. Heart failure occurrence was self-reported in annual follow-up questionnaire. Validation of self-reported heart failure in this cohort has been published. The mean age was 58.7 years. In a conditional logistic regression adjusting for age, race, time of blood collection, year of birth, hypertension, atrial fibrillation, smoking, alcohol intake, and exercise, estimates of the relative risk (95% confidence interval) were 1.0 (ref), 0.74 (0.53–1.04), 0.67 (0.48–0.94), 0.70 (0.50–0.99), and 0.92 (0.65–1.30) from the lowest to the highest quintile of adiponectin, respectively, p for quadratic trend 0.004. Additional adjustment for potential mediating factors including diabetes, C-reactive protein, and body mass index led to the attenuation of the estimate of effect [1.0 (ref), 0.81 (0.57–1.15), 0.75 (0.53–1.06), 0.83 (0.58–1.18), and 1.26 (0.87–1.81) across consecutive quintiles of adiponectin]. Our data are consistent with a J-shaped association between total adiponectin and the risk of heart failure among US male physicians.
PMCID: PMC3479315  PMID: 23712986
Adiponectin; epidemiology; heart failure; risk factors
24.  Association of Biomarkers for Inflammation, Endothelial Dysfunction and Oxidative Stress with Cognitive Impairment. The Epidemiology of Hearing Loss Study (EHLS) 
Individual biomarkers of inflammation, endothelial dysfunction and oxidative stress have been associated with cognitive impairment. This study explored whether a combination of biomarkers could prospectively identify those who developed cognitive decline.
Biomarkers were obtained during the baseline examination of the Beaver Dam Eye Study (1988–90), and cognitive status was assessed during the 5-year follow-up examination of the Epidemiology of Hearing Loss Study (1998–2000). Cognitive impairment was defined as a score of < 24 points on the Mini-Mental State Examination or self- or proxy report of Alzheimer Disease or dementia. Among those with cognitive data, interleukin-6, isoprostanes, protein carbonyl, soluble inter-cellular adhesion molecule-1 and vascular cell adhesion molecule-1 were available for 950 participants and 2,336 had high sensitivity C-reactive protein.
Biomarkers of inflammation and endothelial dysfunction were not associated with cognitive impairment. There was a weak inverse association between higher levels of protein carbonyl content and cognitive impairment (OR, 0.8 per quartile of protein carbonyl content, p=0.045 unadjusted for multiple comparisons). This was not significant on multiple testing and may have been a chance finding.
We found that many markers of inflammation and endothelial dysfunction were not associated with cognitive impairment. An inverse association with carbonyl protein, a marker of oxidative stress needs further confirmation.
PMCID: PMC3693393  PMID: 23814681
oxidative stress; inflammation; biomarkers; cognitive impairment
25.  A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network (GOLDN) 
Pharmacogenetics and Genomics  2012;22(3):191-197.
Despite evidence in support of anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.
Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns (hsCRP-IL6 and MCP1-TNF-α) were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.
Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the hsCRP-IL6 pattern (rs7911500, P=5×10−9 and rs12722605, P=5×10−8). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes (CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)) approached genome-wide significance (P=3×10−7, 5×10−7, 6×10−7, and 7×10−7 respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10−7). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10−7).
We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.
PMCID: PMC3275691  PMID: 22228203
fenofibrate; inflammation; genome-wide association study

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