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1.  Lipid profiles and the risk of endometrial cancer in the Swedish AMORIS study 
While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline.
Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk.
During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2nd, 3rd, and 4th quartile, compared to the 1st, with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied.
This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease.
PMCID: PMC3376923  PMID: 22724049
Lipid profiles; risk factor; endometrial cancer; Swedish AMORIS study
2.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study.
A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities.
During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 – 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 – 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends.
The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
3.  Several genetic polymorphisms interact with overweight/obesity to influence serum lipid levels 
Information about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on serum lipid profiles is still scarce. The present study was undertaken to detect ten SNPs and their interactions with overweight/obesity on serum lipid levels.
A total of 978 normal weight and 751 overweight/obese subjects of Bai Ku Yao were randomly selected from our previous stratified randomized cluster samples. Normal weight, overweight and obesity were defined as a body mass index (BMI) < 24, 24–28, and > 28 kg/m2; respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1 and ApoB levels were measured. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions were detected by factorial design covariance analysis.
The genotypic and allelic frequencies of LIPC and PCSK9 were different between normal weight and overweight/obese subjects, the genotypic frequency of LIPG and allelic frequency of MYLIP were also different between normal weight and overweight/obese subjects (P < 0.05-0.001). The levels of TC, ApoA1 (ABCA-1); TC, LDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TG, HDL-C, and ApoA1 (LIPG); TC, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); HDL-C and ApoA1 (MYLIP) in normal weight subjects were different among the genotypes (P < 0.01-0.001). The levels of LDL-C, ApoB and ApoA1/ApoB (ABCA-1); HDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TC, HDL-C, ApoA1 and ApoB (LIPG); TC, TG, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); TC, TG and ApoB (MYLIP); TG (PCSK9); TG, ApoA1 and ApoB (PPARD); and TC, HDL-C, LDL-C, ApoA1 and ApoB (SCARB1) in overweight/obese subjects were different among the genotypes (P < 0.01-0.001). The SNPs of ABCA-1 (LDL-C and ApoA1/ApoB); LIPC (TC, LDL-C, ApoA1 and ApoB); LIPG (ApoB); MTHFR (TC, TG and LDL-C); MYLIP (TC and TG); PCSK9 (TG, HDL-C, ApoB and ApoA1/ApoB); PPARD (TG and ApoA1/ApoB); and SCARB1 (TG, ApoA1 and ApoB) interacted with overweight/obesity to influence serum lipid levels (P < 0.05-0.001).
The differences in serum lipid levels between normal weight and overweight/obese subjects might partly result from different genetic polymorphisms and the interactions between several SNPs and overweight/obesity.
PMCID: PMC3508802  PMID: 23039238
Lipid; Apolipoprotein; Genetic polymorphism; Overweight; Obesity; Interaction
4.  ATP-Binding Cassette Transporter G5 and G8 Polymorphisms and Several Environmental Factors with Serum Lipid Levels 
PLoS ONE  2012;7(5):e37972.
The association of ATP-binding cassette (ABC) transporter single nucleotide polymorphisms (SNPs) and serum lipid profiles is inconsistent. The present study was undertaken to detect the association of ABCG5/G8 SNPs and several environmental factors with serum lipid levels.
Methodology/Principal Findings
Genotyping of the ABCG5 (rs4131229 and rs6720173) and ABCG8 (rs3806471 and rs4148211) SNPs was performed in 719 unrelated subjects of Mulao nationality and 782 participants of Han nationality. There were no differences in the genotypic and allelic frequencies of four SNPs between the two ethnic groups besides the genotypic frequencies of rs4131229 SNP in Han. The levels of triglyceride (TG), apolipoprotein (Apo) A1, and ApoA1/ApoB ratio (rs4131229); low-density lipoprotein cholesterol (LDL-C) and ApoB (rs6720173); high-density lipoprotein cholesterol (HDL-C), ApoA1, ApoB, and ApoA1/ApoB ratio (rs3806471); and HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han were different among their genotypes (P<0.05–0.001). The levels of LDL-C (rs6720173) and ApoA1 (rs3806471) in Mulao were also different among their genotypes (P<0.05 for each). The levels of TC, TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4131229); LDL-C and ApoB (rs6720173); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs3806471); and TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han males; and ApoA1/ApoB ratio (rs4131229); LDL-C, ApoB, and ApoA1/ApoB ratio (rs3806471); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han females were different between the genotypes (P<0.05–0.001). The levels of LDL-C in Mulao females were also different between GG and GC/CC genotypes of rs6720173 (P<0.05). The correlation between serum lipid parameters and genotypes of four SNPs was observed in Han, especially in Han males. Serum lipid parameters were also correlated with several environmental factors.
The associations of four ABCG5/G8 SNPs and serum lipid levels are different between the Mulao and Han populations, or between males and females, suggesting that there may be a racial/ethnic- and/or sex-specific association between ABCG5/G8 SNPs and some serum lipid parameters.
PMCID: PMC3360029  PMID: 22655090
5.  The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls† 
European Heart Journal  2009;30(17):2137-2146.
Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A1, the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear.
Methods and results
Case–control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA1 than to HDL-C. The ratio apoB/apoA1 was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8–9.2)] and varied little with age. The ratio apoB/apoA1 was substantially more informative about risk (χ12 = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (χ12 = 407, 334, 204, and 105, respectively). Given apoB and apoA1, the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA1 and pre-onset HDL-C with risk in such retrospective case–control studies.
Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.
PMCID: PMC2735728  PMID: 19520708
Myocardial infarction; Lipoproteins; Lipids; Cholesterol; Risk factors
6.  Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients*  
Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman’s rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=−0.306, P=0.012), LDL-C (R=−0.283, P=0.020), and non-HDL-C (R=−0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this.
PMCID: PMC3087092  PMID: 21528490
Lipids; Lipoproteins; Paraoxonase-1 (PON-1) activity; Oxidized low-density lipoprotein (ox-LDL); High-density lipoprotein (HDL) particles; Post-renal transplant; Hemodialysis
7.  The Apolipoprotein B/Apolipoprotein A-I Ratio as a Potential Marker of Plasma Atherogenicity 
Disease Markers  2015;2015:591454.
Background. The apolipoprotein (apo) B/apoA-I ratio represents the balance between apoB-rich atherogenic particles and apoA-I-rich antiatherogenic particles, and this ratio is considered to be a marker of cardiovascular risk. Although many studies have demonstrated the importance of the apoB/apoA-I ratio in predicting the presence or absence of cardiovascular disease, less is known about apoB/apoA-I ratio as a marker of plasma atherogenicity. Methods. A total of 157 normolipidemic men aged 20–59 years were included in the study. The plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apoA-I, apoB, and apoE were determined after a 12 h fasting period. Results. The median of the apoB/apoA-I ratio in the studied normolipidemic subjects was 0.52, with values ranging from 0.19 to 2.60. The percentage of subjects with the apoB/apoA-I ratio exceeding 0.9 (the accepted risk value of cardiovascular disease) was 19.1%. The subjects with apoB/apoA-I>0.9 were characterized by higher TG levels and atherogenic index of plasma (AIP) and lower values of ratio of low-density lipoprotein cholesterol (LDL-C) to apoB (LDL-C/apoB) and apoE levels compared with men with apoB/apoA-I<0.9. Conclusion. Despite normolipidemia, the subjects with the unfavorable apoB/apoA-I ratio had more atherogenic lipid profile.
PMCID: PMC4380097  PMID: 25852220
8.  The Lipid-lowering Effects of R-bambuterol in Healthy Chinese Volunteers: A Randomized Phase I Clinical Study 
EBioMedicine  2015;2(4):356-364.
Existing treatments are inadequate for patients at high risk of coronary heart disease caused by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C). Bambuterol is a prodrug of β2-agonist commonly used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) with the advantage of once daily dosing and favorable side effect profile. The potential lipid-lowering effects of bambuterol were unclear, possibly due to the racemic bambuterol (rac-bambuterol) that was used in previous studies.
The lipid-lowering effects of R-bambuterol were examined in a randomized phase I trial in 48 healthy Chinese volunteers aged 18–45 years. Participants were randomly assigned to five groups to receive a single dose (2.5 mg, 5 mg or 10 mg) or multiple doses (5 mg) of oral medications of R-bambuterol, or a single dose of rac-bambuterol (10 mg). Plasma lipid levels were measured at baseline, time to peak concentration (Tmax) and 24 h after the treatment.
Administration of a single-dose of R-bambuterol resulted in dose-dependent reductions in the levels of plasma LDL-C, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) at Tmax. Levels of LDL-C exhibited the most reductions, which were statistically significant in all three single-dose R-bambuterol groups (all P values < 0.05). R-bambuterol was more potent in LDL-C lowering compared to rac-bambuterol at Tmax (P = 0.08). At 24 h after dosing, the significant lipid lowering effects of R-bambuterol sustained for LDL-C (P = 0.01), ApoB (P = 0.001) and ApoA1 (P = 0.03), but not for HDL-C. The ratio of ApoA1/ApoB was marginally increased (P = 0.06). In the multiple-dose group, LDL-C levels again were significantly reduced (all P values < 0.05), whereas the ratios of ApoA1/ApoB were marginally increased.
R-bambuterol can lower the plasma levels of LDL-C, and marginally raise the ratio of ApoA1/ApoB (indicator of HDL-C/LDL-C) with both a single dose and multiple doses. R-bambuterol was more potent in LDL-C lowering than rac-bambuterol.
•Oral administration of R-bambuterol, a long-acting bronchodilator, can significantly lower LDL cholesterol in healthy Chinese volunteers.•R-bambuterol was more potent than rac-bambuterol in lowering LDL-C and raising the ratio of ApoA1/ApoB.•It may provide an alternative for treating high cholesterol, especially for those also suffering from COPD.
PMCID: PMC4485901  PMID: 26137575
β2-Agonist; R-bambuterol; Cholesterol; LDL-C
9.  Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance 
To directly compare traditional lipid ratios (total cholesterol [TC]/high density lipoprotein cholesterol [HDL-C], non-HDL-C/HDL-C, low density lipoprotein cholesterol [LDL-C]/HDL-C, and triglycerides [TG]/HDL-C), apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP), and the product of TG and fasting glucose (TyG) for strength and independence as risk factors for insulin resistance (IR).
We conducted a cross-sectional analysis of 7629 Chinese adults using data from the China Health and Nutrition Survey 2009.
For all lipid ratios (traditional lipid ratios and apoB/apoA-I), among both sexes, TG/HDL-C explained the most additional percentage of variation in HOMA-IR (2.9% in men, and 2.3% in women); for all variables of interest, the variability in HOMA-IR explained by VAI and TG/HDL-C were comparable; TyG had the most significant association with HOMA-IR, which explained 9.1% for men and 7.8% for women of the variability in HOMA-IR. Logistic regression analysis showed the similar patterns. Receiver operating characteristic (ROC) curve analysis showed that, among both sexes, TG/HDL-C was a better discriminator of IR than apoB/apoA-I; the area under the ROC curve (AUC) for VAI (0.695 in men and 0.682 in women) was greater than that for TG/HDL-C (AUC 0.665 in men and 0.664 in women); TyG presented the greatest value of AUC (0.709 in men and 0.711 in women).
The apoB/apoA-I performs no better than any of the traditional lipid ratios in correlating with IR. The TG/HDL-C, VAI and TyG are better markers for early identification of IR individuals.
PMCID: PMC4209231  PMID: 25326814
Insulin resistance; Apolipoprotein B; Apolipoprotein A-I; Visceral adiposity index; Lipid accumulation product; TyG index
10.  Impact of corpulence parameters and haemoglobin A1c on metabolic control in type 2 diabetic patients: comparison of apolipoprotein B/A-I ratio with fasting and postprandial conventional lipid ratios 
The Libyan Journal of Medicine  2015;10:10.3402/ljm.v10.27400.
Background and objective
The incidence of diabetes co-morbidities could probably be better assessed by studying its associations with major corpulence parameters and glycaemic control indicators. We assessed the utility of body mass index (BMI), waist circumference (WC), and glycosylated haemoglobin (HbA1c) levels in metabolic control for type 2 diabetic patients.
Fasting and postprandial blood samples were collected from 238 type 2 diabetic patients aged 57.4±11.9 years. The sera were analysed for glucose, HbA1c, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and apolipoproteins (apoA-I and apoB). Ratios of lipids and apolipoproteins were calculated and their associations with BMI, WC, and HbA1c levels were analysed.
Our investigation showed increases in most fasting and postprandial lipid parameters according to BMI and WC. In men, postprandial HDL-c and TG levels were significantly higher (p<0.05) in overweight and obese patients, respectively, as well as in patients with abdominal obesity. Contrariwise, postprandial TC levels were significantly higher (p<0.01) in overweight and abdominal obese women. However, elevations of apoA-I and apoB levels were according to BMI and WC in both genders. There was a strong influence of BMI, WC, and HbA1c levels on the apoB/apoA-I ratio compared to traditional fasting and postprandial lipid ratios in both men and women. The apoB/apoA-I ratio was more correlated with postprandial TC/HDL and LDL-c/HDL-c ratios in men and with postprandial TG/HDL-c in women.
The apoB/apoA-I ratio is helpful in assessing metabolic risk caused by overall obesity, abdominal obesity and impaired glycaemia in type 2 diabetic patients.
PMCID: PMC4426286  PMID: 25959906
type 2 diabetes; body mass index; waist circumference; HbA1c; metabolic control
11.  Associations between smoking, components of metabolic syndrome and lipoprotein particle size 
BMC Medicine  2013;11:195.
The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.
We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.
Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).
Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.
Please see related commentary:
PMCID: PMC3766075  PMID: 24228807
Metabolic syndrome; Smoking; HDL; Cholesterol; Apolipoproteins; Triglycerides; Obesity; Cross-sectional; BMI classes
12.  Combining β-adrenergic and peroxisome proliferator—activated receptor γ stimulation improves lipoprotein composition in healthy moderately obese subjects 
Current pharmacological regimens for hypertriglyceridemia and low high-density lipoprotein (HDL) are limited to the peroxisome proliferator—activated receptor (PPAR) α activating fibrates, niacin, and statins. This pilot study examined the impact of simultaneous stimulation of cyclic adenosine monophosphate with a β-adrenergic agonist and PPARγ with pioglitazone (PIO) on lipoprotein composition in moderately obese, healthy subjects. Subjects were treated with PIO (45 mg) to stimulate PPARγ or a combination of ephedrine (25 mg TID), a β-agonist, with caffeine (200 mg TID), a phosphodiesterase inhibitor (ephedrine plus caffeine), or both for 16 weeks. Lipoproteins were separated by gradient ultracentrifugation into very low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein (LDL), and 3 HDL (L, M, and D) subfractions. Apolipoproteins were measured by high-performance liquid chromatography. PIO alone reduced the core triglyceride (TG) content relative to cholesterol ester (CE) in VLDL (−40%), IDL (−25%), and HDL-M (−38%). Ephedrine plus caffeine alone reduced LDL CE (−13%), phospholipids (−9%), and apolipoprotein (apo) B (−13%); increased HDL-M LpA-I (HDL containing apoA-I without apoA-II, 28%), CE/TG (23%), and CE/apoA-I (8%) while reducing apoA-II (−10%); and increased HDL-L LpA-I (29%). Combination therapy reduced total plasma TG (−28%), LDL cholesterol (LDL-C, −10%), apoB(−16%), apoB/apoA-I ratio(−21%), while increasing HDL cholesterol (HDL-C, 21%), total plasma apoA-I (12%), LpA-I (43%), and apoC-I (26%). It also reduced VLDL total mass (−34%) and apoC-III (−39%), LDL CE (−13%), apoB (−13%), and total mass (−11%). Combination therapy increased HDL-L CE/TG (32%), apoC-I (30%), apoA-I (56%), and LpA-I (70%), as well as HDL-M CE (35%), phospholipids (24%), total mass (19%), apoC-I (25%), apoA-I (18%), and LpA-I (56%). In conclusion, simultaneous β-adrenergic and PPARγ activation produced beneficial effects on VLDL, LDL, HDL-L, and HDL-M. Perhaps the most important impact of combination therapy was dramatic increases in LpA-I and apoC-I in HDL-L and HDL-M, which were much greater than the sum of the monotherapies. Because LpA-I appears to be the most efficient mediator of reverse-cholesterol transport and a major negative risk factor for cardiovascular disease, this combination therapy may provide very effective treatment of atherosclerosis.
PMCID: PMC2597222  PMID: 16324916
13.  Interactions of the apolipoprotein C-III 3238C>G polymorphism and alcohol consumption on serum triglyceride levels 
Both apolipoprotein (Apo) C-III gene polymorphism and alcohol consumption have been associated with increased serum triglyceride (TG) levels, but their interactions on serum TG levels are not well known. The present study was undertaken to detect the interactions of the ApoC-III 3238C>G (rs5128) polymorphism and alcohol consumption on serum TG levels.
A total of 516 unrelated nondrinkers and 514 drinkers aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoC-III 3238C>G was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Interactions of the ApoC-III 3238C>G genotype and alcohol consumption was assessed by using a cross-product term between genotypes and the aforementioned factor.
Serum total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C), ApoA-I and ApoB levels were higher in drinkers than in nondrinkers (P < 0.05-0.001). There was no significant difference in the genotypic and allelic frequencies between the two groups. Serum TG levels in nondrinkers were higher in CG genotype than in CC genotype (P < 0.01). Serum TC, TG, low-density lipoprotein cholesterol (LDL-C) and ApoB levels in drinkers were higher in GG genotype than in CC or CG genotype (P < 0.01 for all). Serum HDL-C levels in drinkers were higher in CG genotype than in CC genotype (P < 0.01). Serum TC, TG, HDL-C and ApoA-I levels in CC genotype, TC, HDL-C, ApoA-I levels and the ratio of ApoA-I to ApoB in CG genotype, and TC, TG, LDL-C, ApoA-I and ApoB levels in GG genotype were higher in drinkers than in nondrinkers (P < 0.05-0.01). But the ratio of ApoA-I to ApoB in GG genotype was lower in drinkers than in nondrinkers (P < 0.01). Multivariate logistic regression analysis showed that the levels of TC, TG and ApoB were correlated with genotype in nondrinkers (P < 0.05 for all). The levels of TC, LDL-C and ApoB were associated with genotype in drinkers (P < 0.01 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, body weight, and body mass index in both groups.
This study suggests that the ApoC-III 3238CG heterozygotes benefited more from alcohol consumption than CC and GG homozygotes in increasing serum levels of HDL-C, ApoA-I, and the ratio of ApoA-I to ApoB, and lowering serum levels of TC and TG.
PMCID: PMC2929234  PMID: 20716347
14.  Both Serum Apolipoprotein B and the Apolipoprotein B/Apolipoprotein A-I Ratio Are Associated with Carotid Intima-Media Thickness 
PLoS ONE  2013;8(1):e54628.
Previous studies indicated that apolipoprotein measurements predicted cardiovascular disease (CVD) risk; however, associations between apolipoproteins and carotid intima-media thickness (CIMT) were less explored.
Methodology and Principal Findings
The cross-sectional study included 6069 participants aged 40 years or older with NGT from Shanghai, China. Serum fasting traditional lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]), apoA-I and apoB were assessed. A high-resolution B-mode ultrasonography was performed to measure CIMT. We found CIMT increased progressively across the quartiles of serum apoB (p for trend <0.0001). In logistic regression, concentrations of apoB (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.18–1.36), TC (OR 1.23, 95% CI 1.14–1.32), LDL-C (OR 1.25, 95% CI 1.16–1.34) and TG (OR 1.11, 95% CI 1.04–1.20) were significantly related to elevated CIMT after adjusted for age and sex. Meanwhile, the apoB/apoA-I ratio (OR 1.25, 95% CI 1.17–1.34) related to elevated CIMT. ApoB (OR 1.23, 95% CI 1.00–1.51) and the apoB/apoA-I ratio (OR 1.19, 95% CI 1.04–1.36) remained significantly associated with elevated CIMT, after adjusted for the traditional CVD risk factors including traditional lipids.
Conclusions and Significance
There were significant associations between serum apoB, the apoB/apoA-I ratio and elevated CIMT. Serum apoB and the apoB/apoA-I ratio might be independent predictors of early atherosclerosis in NGT.
PMCID: PMC3554742  PMID: 23359805
15.  Is the ratio of apoB/apoA-1 the best predictor for the severity of coronary artery lesions in Chinese diabetics with stable angina pectoris? An assessment based on Gensini scores 
There is a paucity of data about the best lipid ratio predicting the severity of coronary artery disease (CAD) in patients with diabetes mellitus. We determined the relationship between five conventional lipid ratios and the extent of coronary artery lesions in Chinese Type 2 diabetics with stable angina pectoris (SAP).
A prospective cohort study within 373 type 2 diabetic patients diagnosed with stable CAD by coronary angiography was performed. All patients were classified into three groups according to the tertiles of Gensini scores (GS, low group < 8 points n = 143; intermediate group 8–28 points, n = 109; high group > 28 points, n = 121). Association between the ratios of apolipoprotein (apo) B and apoA-1, total cholesterol and high density lipoprotein cholesterol (TC/HDL-C), triglycerides and HDL-C (TG/HDL-C), low density lipoprotein cholesterol and HDL-C (LDL-C/HDL-C), Non-HDL-C/HDL-C and GS were evaluated using the receivers operating characteristic (ROC) curves and multivariate logistic regression models.
The ratio of apoB/apoA-1, TC/HDL-C, LDL-C/HDL-C, and Non-HDL-C/HDL-C were correlated with Gensini scores. Area under the ROC curves for predicting high Gensini scores in the ratios of apoB/apoA-1, TC/HDL-C, LDL-C/HDL-C and Non-HDL-C/HDL-C were 0.62, 0.60, 0.59 and 0.60, respectively (P < 0.005 for all). According to multivariate logistic regression analysis after adjusted with demographic characteristic and other lipid parameters, the ratio of apoB/apoA-1 is qualified as an independent discriminator for the severity of CAD. However, after further adjusting different baseline variables, such as left ventricular ejective fraction, hemoglobin A1c, leukocytes count and serum creatinine, none of the above lipid ratios remained.
Compared with other lipid parameters, the ratio of apoB/apoA-1 appears to be more significantly correlated with the extent of coronary artery lesions in Chinese diabetics, but it was not an independent predictor in these settings.
PMCID: PMC4554779  PMID: 26346771
Coronary artery disease; Diabetic mellitus; Gensini scores; Lipid disorder
16.  The association between the apolipoprotein A1/ high density lipoprotein -cholesterol and diabetes in Taiwan — a cross-sectional study 
Traditional lipid indices have been associated with type 2 diabetes, but it remains uncertain which lipid index is the best discriminator for diabetes. In this study, we aimed to assess lipoproteins, traditional lipid variables, and other variables to discover their association with diabetes in the Taiwanese population.
Data from a nationwide cross-sectional population-based survey of 3087 men and 3373 women in 2002 were analyzed in this study. All participants were assessed for anthropometry, glycosylated hemoglobin, fasting sugar and lipid profiles with triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) and B (ApoB). The ratio of LDL-C/HDL-C, ApoB/ApoA1, ApoB/LDL-C and ApoA1/HDL-C and other variables were analyzed to determine their potential roles in type 2 diabetes in the Taiwanese population. The Odds ratios (ORs) of the risk variables for diabetes were estimated using logistic regression and were adjusted for confounding factors.
The increased ratio of ApoA1/HDL-C was significantly associated with diabetes in men (top tertile vs. lowest: OR 2.98; 95% CI: 1.12 - 7.92; P-trend = 0.030) and women (top tertile vs. lowest: OR 2.15; 95% CI: 1.00 - 4.59; P-trend = 0.047). A modest increased diabetic risk was evident with ApoB/LDL-C in women (top tertile vs. lowest: OR 2.03; 95% CI: 1.07- 3.85; P-trend = 0.028), but not in men (top tertile v. lowest: OR 1.69; 95% CI: 0.79- 3.62; P-trend = 0.198).
ApoA1/HDL-C had a significant linear association with diabetes in both sexes and was superior to other lipid and lipoprotein variables among the general Taiwanese population.
PMCID: PMC3851878  PMID: 24093822
Apolipoprotein A1; Apolipoprotein B; High density lipoprotein-cholesterol; Low density lipoprotein-cholesterol; Diabetes
17.  Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population 
European Heart Journal  2008;30(6):710-717.
Prospective studies indicate that apolipoprotein measurements predict coronary heart disease (CHD) risk; however, evidence is conflicting, especially in the US. Our aim was to assess whether measurements of apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) can improve the ability to predict CHD death beyond what is possible based on traditional cardiovascular (CV) risk factors and clinical routine lipid measurements.
Methods and results
We analysed prospectively associations of apolipoprotein measurements, traditional CV risk factors, and clinical routine lipid measurements with CHD mortality in a multi-ethnic representative subset of 7594 US adults (mean age 45 years; 3881 men and 3713 women, median follow-up 124 person-months) from the Third National Health and Nutrition Examination Survey mortality study. Multiple Cox-proportional hazards regression was applied. There were 673 CV deaths of which 432 were from CHD. Concentrations of apoB [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.09–3.61], apoA-I (HR 0.48, 95% CI 0.27–0.85) and total cholesterol (TC) (HR 1.17, 95% CI 1.02–1.34) were significantly related to CHD death, whereas high density lipoprotein cholesterol (HDL-C) (HR 0.68, 95% CI 0.45–1.05) was borderline significant. Both the apoB/apoA-I ratio (HR 2.14, 95% CI 1.11–4.10) and the TC/HDL-C ratio (HR 1.10, 95% CI 1.04–1.16) were related to CHD death. Only apoB (HR 2.01, 95% CI 1.05–3.86) and the apoB/apoA-I ratio (HR 2.09, 95% CI 1.04–4.19) remained significantly associated with CHD death after adjusting for CV risk factors.
In the US population, apolipoprotein measurements significantly predict CHD death, independently of conventional lipids and other CV risk factors (smoking, dyslipidaemia, hypertension, obesity, diabetes and C-reactive protein). Furthermore, the predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements. Inclusion of apolipoprotein measurements in future clinical guidelines should not be discarded.
PMCID: PMC2721712  PMID: 18676970
Apolipoprotein A-I; Apolipoprotein B; ApoB/apoA-I ratio; Cardiovascular risk factors; Cardiovascular mortality; Coronary heart disease; HDL-cholesterol; Outcomes; NHANES
18.  Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth 
Biological Research  2014;47(1):4.
Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.
The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.
These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.
PMCID: PMC4060374  PMID: 25027185
Apolipoprotein; ATP-binding cassette transporter 1 gene; Gene polymorphism; High-carbohydrate/low-fat diet; Lipid ratios
19.  Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels 
PLoS ONE  2011;6(3):e17954.
Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5–1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.
Methodology/Principal Findings
A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05–0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between –1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The –1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the –1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05–0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05–0.01).
The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption.
PMCID: PMC3056790  PMID: 21423763
20.  Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels 
The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels in the general Chinese population.
A total of 1030 unrelated subjects (492 males and 538 females) aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoA1 -75 bp G>A, ApoC3 3238C>G, ApoA5 -1131T>C, ApoA5 c.553G>T and ApoA5 c.457G>A was performed by polymerse chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Pair-wise linkage disequilibria and haplotype analysis among the five SNPs were estimated.
The levels of high-density lipoprotein cholesterol (HDL-C) and ApoA1 were lower in males than in femailes (P < 0.05 for each). The allelic and genotypic frequencies of the SNPs were no significant difference between males and females except ApoC3 3238C>G. There were 11 haplotypes with a frequency >1% identified in the cluster in our population. At the global level, the haplotypes comprised of all five SNPs were significantly associated with all seven lipid traits. In particular, haplotype G-G-C-C-A (6%; in the order of ApoA5 c.553G>T, ApoA5 c.457G>A, ApoA5 -1131T>C, ApoC3 3238C>G, and ApoA1 -75bp G>A) and G-A-T-C-G (4%) showed consistent association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoA1, ApoB, and the ApoA1/ApoB ratio. In addition, carriers of haplotype G-G-T-C-G (26%) had increased serum concentration of HDL-C and ApoA1, whereas carriers of G-G-C-G-G (15%) had high concentrations of TC, triglyceride (TG) and ApoB. We also found that haplotypes with five SNPs explain much more serum lipid variation than any single SNP alone, especially for TG (4.4% for haplotype vs. 2.4% for -1131T>C max based on R-square) and HDL-C (5.1% for haplotype vs. 0.9% for c.553G>T based on R-square). Serum lipid parameters were also correlated with genotypes and several environment factors.
Several common SNPs and their haplotypes in the ApoA1/C3/A5 gene cluster are closely associated with modifications of serum lipid parameters in the general Chinese population.
PMCID: PMC3170230  PMID: 21854571
21.  Hierarchical modelling of blood lipids’ profile and 10-year (2002–2012) all cause mortality and incidence of cardiovascular disease: the ATTICA study 
The traditional view on the relationship between lipid biomarkers and CVD risk has changed during the last decade. However, it is not clear whether novel lipid biomarkers are able to confer a better predictability of CVD risk, compared to traditional ones.Under this perspective, the aim of the present work was to evaluate the predictive ability of blood lipids’ profile on all cause mortality as well as 10-year incidence of CVD, in a sample of apparently healthy adults of the ATTICA epidemiological study. 
From May 2001 to December 2002, 1514 men and 1528 women (>18 y) without any clinical evidence of any other chronic disease, at baseline, were enrolled. In 2011–12, the 10-year follow-up was performed in 2583 participants (85 % follow-up participation rate). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. Baseline serum blood lipids’ profile (Total-C, HDL-, non HDL-, LDL-cholesterol, triglycerides (TG), apolipoprotein (Apo)A1 and B, and lipoprotein–(a) levels were also measured.
The 10-year all-cause mortality rate was 5.7 % for men and 2.0 % for women (p = 0.55). The, 10-year CVD incidence was 19.7 % in men and 11.7 % in women (p < 0.001). Multi-adjusted analysis revealed that TC, non-HDL-C, TG and TG/HDL-C ratio, were independent predictors of all cause mortality (RR per 1 mg/dL or unit (95 % CI): 1.006 (1.000–1.013), 1.006 (1.000–1.013), 1.002 (1.000–1.004), 1.038 (1.001–1.077), respectively). Moreover, TC, HDL-, LDL-, non-HDL-cholesterol, TG, apoA1, TC/HDL-C and TG/HDL-C were independently associated with CVD risk. Among all lipid indices the ratio of apoB/apoA1 demonstrated the best correct reclassification ability, followed by non-HDL-C and TC/HDL-C ratio (continuous Net Reclassification Index 26.1 and 21.2 %, respectively).
Elevated levels of lipid biomarkers are independently associated with all-cause mortality, as well as CVD risk. The ratio of apoB/apoA1, followed by non-HDL-C, demonstrated the best correct classification ability of the developed CVD risk models.
PMCID: PMC4570524  PMID: 26370413
Cardiovascular disease; All cause mortality; Lipids; Lipoproteins; Apolipoproteins; Epidemiology
22.  Evaluation of Efficacy and Safety of Fixed Dose Lovastatin and NiacinER Combination in Asian Indian Dyslipidemic Patients: A Multicentric Study 
Asian Indian dyslipidemia is characterized by: borderline high low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B; high triglycerides, low high-density lipoprotein (HDL) cholesterol and apoA1; and high lipoprotein(a) (lp[a]). We performed a controlled multicentric trial in India to evaluate the efficacy and safety of a fixed dose combination of lovastatin and niacin extended release (niacinER) formulation in patients with moderate to severe dyslipidemia. Consecutive subjects that satisfied the selection criteria, agreed to an informed consent, and with no baseline presence of liver/renal disease or heart failure were enrolled in the study. After a 4-week run-in period there were 142 patients with LDL levels ≥130 mg/dL. Eleven patients were excluded because of uncontrolled hyperglycemia and 131 patients were recruited. After baseline evaluation of clinical and biochemical parameters all subjects were administered lovastatin (20 mg) and niacinER (500 mg) combination once daily. Dose escalation was done on basis of lipid parameters at 8 weeks and in 11 patients increased to lovastatin (20 mg) and niacinER (1000 mg). An intention-to-treat analysis was performed and data was analyzed using nonparametric Wilcoxon signed rank test. Thirteen patients (10%) were lost to follow-up and 4 (3%) withdrew because of dermatological adverse effects: flushing, pruritus, and rash. The mean values of various lipid parameters (mg/dL) at baseline, and at weeks 4, 12, and 24 respectively were: total cholesterol 233.9 ± 27, 206.3 ± 27, 189.8 ± 31, and 174.9 ± 27 mg/dL; LDL cholesterol 153.4 ± 22, 127.3 ± 21, 109.2 ± 27, and 95.1 ± 23 mg/dL; triglycerides 171.1 ± 72, 159.5 ± 75, 149.2 ± 45, and 135.2 ± 40 mg/dL; HDL cholesterol 45.6 ± 7, 48.9 ± 7, 51.6 ± 9, and 53.9 ± 10 mg/dL; lp(a) 48.5 ± 26, 40.1 ± 21, 35.4 ± 21, and 26.9 ± 19 mg/dL; and apoA1/apoB ratio 0.96 ± 0.7, 1.04 ± 0.4, 1.17 ± 0.5, and 1.45 ± 0.5 (p < 0.01). The percentage of decline in various lipids at 4, 12, and 24 weeks was: total cholesterol 11.8%, 18.8%, and 25.2%; LDL cholesterol 17.0%, 28.8%, and 38.0%; triglyceride 6.8%, 12.8%, and 21.0%; lp(a) 17.5%, 26.9%, and 44.5% respectively (p < 0.01). HDL cholesterol and apoA1/apoB increased by 7.2%, 13.1%, and 18.2%; and 7.9%, 21.9%, and 51.6% respectively (p < 0.01). Target LDL levels (<100 mg/dL in subjects with manifest coronary heart disease or diabetes; <130 mg/dL in subjects with >2 risk factors) were achieved in 92 (80.7%) patients. No significant changes were observed in systolic or diastolic blood pressure, blood creatinine, transaminases, or creatine kinase. A fixed dose combination of lovastatin and niacinER significantly improved cholesterol lipoprotein lipids as well as lp(a) and apoA1/apoB levels in Asian Indian dyslipidemic patients. Satisfactory safety and tolerability profile in this population was also demonstrated.
PMCID: PMC1993969  PMID: 17319473
Hypercholesterolemia; South Asians; coronary heart disease; lipid abnormalities; low HDL; lipoprotein(a)
23.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642).
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years.
We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95 % CI 1.01–1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95 % CI 1.02–1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95 % CI 1.08–1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer.
As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
24.  Intercorrelations of lipoprotein subfractions and their covariation with lifestyle factors in healthy men 
So far, little is known about the effect of nutrition and lifestyle on the composition of circulating lipoprotein subfractions. In the current study, we measured the correlations among physical activity, nutrient intake, smoking, body-mass index (BMI), and age with the concentration of triglycerides, cholesterol, phospholipids, and apolipoproteins (ApoA1, ApoA2 and ApoB) in subfractions of LDL and HDL in 265 healthy working men. Concentrations of cholesterol, phospholipids, and ApoB in small, dense atherogenic LDL particles (sdLDL) correlated negatively (p<0.001) with those of cholesterol, phospholipids, and ApoA1 in HDL2, respectively. Age correlated positively with sdLDL while increasing BMI correlated with an atherogenic shift of cholesterol, phospholipids, and ApoB from large, buoyant LDL (lbLDL) to sdLDL and decreasing concentrations of HDL2 constituents. Physical activity and alcohol intake correlated negatively with sdLDL constituents and positively with HDL2 components. Consumption of monounsaturated fatty acids (MUFA) correlated with a lower ratio of sdLDL to HDL2 cholesterol. A favorable lipoprotein subfraction profile linked to a reduced risk of cardiovascular disease in men was associated with physical activity, moderate alcohol consumption, and dietary intake of MUFA, which might be exploited in future interventions for prevention of age- and BMI-associated atherogenic shifts of lipoprotein subfractions.
PMCID: PMC4042151  PMID: 24895480
lipoprotein subfractions; small dense lipoprotein particles; atherogenic shift; nutrition; body-mass index
25.  Effect of insulin analog initiation therapy on LDL/HDL subfraction profile and HDL associated enzymes in type 2 diabetic patients 
Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase.
Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis.
Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions. CETP protein level and activity was significantly increased while apoB levels were significantly decreased following insulin analog initiation therapy. No significant difference was found in LCAT mass, LCAT activity, apoA-I and PON-1 arylesterase levels following insulin initiation therapy.
These findings indicate that insulin analog initiation therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL-large and decreasing LDL-3 and LDL-4 subfractions in a short time period.
PMCID: PMC3653690  PMID: 23617853
Diabetes mellitus; Insulin; CETP; LDL; HDL

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