Hyperlipidemias: Ordovas JM

Ordovas JM. · No affiliation provided · Nutr Metab Cardiovasc Dis. · Pubmed #12669677 No free full text.

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Ordovas JM. · No affiliation provided · Rev Esp Cardiol. · Pubmed #11591293 links to  free full text

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Ordovas JM. · Nutrition and Genomics Laboratory, JM-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · Gend Med. · Pubmed #18156097 No free full text.

Abstract: BACKGROUND: Although men and women share most genetic information, they have significantly different disease susceptibilities that go well beyond the expected gender-specific diseases. Sex influences the risk of nearly all common diseases that affect both men and women, including atherosclerosis and diabetes and their preceding risk factors (eg, hyperlipidemia, insulin resistance, and obesity). OBJECTIVE: The goal of this article was to examine the interplay between genes, gender, and disease susceptibility, and assess it in the context of the added complexity of environmental factors (ie, dietary habits, smoking, alcohol consumption) in the modulation of the balance between health and disease. METHODS: Original and review articles published by the author were reexamined for evidence of gene-gender interactions. RESULTS: Evidence from some key factors in lipid metabolism (apolipoprotein E [APOE])and obesity (perilipin [PLIN]) indicates that the interplay between genes, gender, and environmental factors modulates disease susceptibility. In the Framingham Heart Study, complex interactions have been shown between a promoter polymorphism at the apolipoprotein A1 gene, gender, and dietary poly-unsaturated fatty acid intake that modulate plasma concentrations of high-density lipoprotein cholesterol. Likewise, highly and clinically relevant interactions have been observed between the APOE gene common alleles APOE2 , APOE3, and APOE4 , gender, and smoking that determine cardiovascular disease risk. Most interesting is the gender-dependent association between common polymorphisms at the PLIN locus and obesity risk that has been replicated in several populations around the world. CONCLUSIONS: These data support the idea that gender-specific differences in morbidity and mortality may be mediated in part by genetic factors and by their differential response to the environment. The new knowledge generated by a more careful and complete elucidation of the complex interactions predisposing to common diseases will result in an increased ability to provide successful personalized behavioral recommendations to prevent chronic disorders.

Corella D, Ordovas JM. · Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. · Annu Rev Nutr. · Pubmed #16011471 No free full text.

Abstract: Cardiovascular disease (CVD) risk is the result of complex interactions between genetic and environmental factors. During the past few decades, much attention has focused on plasma lipoproteins as CVD risk factors. The current evidence supports the concept that gene-environment interactions modulate plasma lipid concentrations and potentially CVD risk. The findings from studies examining gene-diet interactions and lipid metabolism have been highly promising. Several loci (i.e., APOA1, APOA4, APOE, and LIPC) are providing proof-of-concept for the potential application of genetics in the context of personalized nutritional recommendations for CVD prevention. However, the incorporation of these findings to the clinical environment is not ready for prime time. There is a compelling need for replication using a higher level of scientific evidence. Moreover, we need to evolve from the simple scenarios examined nowadays (i.e., one single dietary component, single nucleotide polymorphism, and risk factor) to more realistic situations involving interactions between multiple genes, dietary components, and risk factors. In summary, there is need for both large population studies and well-standardized intervention studies.

Ordovas JM. · Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · Hum Genomics. · Pubmed #15601539 No free full text.

Abstract: The genetic basis for most of the rare lipid monogenic disorders have been elucidated, but the challenge remains in determining the combination of genes that contribute to the genetic variability in lipid levels in the general population; this has been estimated to be in the range of 40-60 per cent of the total variability. Therefore, the effect of common polymorphisms on lipid phenotypes will be greatly modulated by gene-gene and gene-environment interactions. This approach can also be used to characterise the individuality of the response to lipid-lowering therapies, whether using drugs (pharmacogenetics) or dietary interventions (nutrigenetics). In this regard, multiple studies have already described significant interactions between candidate genes for lipid and drug metabolism that modulate therapeutic response-although the outcomes of these studies have been controversial and call for more rigorous experimental design and analytical approaches. Once solid evidence about the predictive value of genetic panels is obtained, risk and therapeutic algorithms can begin to be generated that should provide an accurate measure of genetic predisposition, as well as targeted behavioural modifications or drugs of choice and personalized dosages of these drugs.

Ordovas JM, Shen H. · Nutrition and Genomics Laboratory, JM USDA HNRCA at Tufts University, 711 Washington Street, Boston, MA 02111, USA. · Curr Atheroscler Rep. · Pubmed #11931715 No free full text.

Abstract: Cardiovascular disease is associated with nonmodifiable risk factors such as age, gender, and genetic background, and with modifiable risk factors such as lipid concentrations. Lowering serum lipid levels has been demonstrated to slow the progression of, or even induce regression in, atherosclerosis. However, like any other drug treatment, the magnitude of plasma lipid responses to drug therapies varies considerably among individuals. Pharmacogenetics provides the experimental basis to understand the variability in response to drugs as a function of the individual genetic makeup. Information from small clinical trials reveals that several candidate genes may hold some promise in our quest to predict individual success to hypolipemic drug treatment. However, the current clinical relevance of this knowledge is quite limited due to the small effects observed for each of the genetic markers examined. Future progress in this area will be driven by studying gene-gene and gene-treatment interactions in much larger patient populations.

Ordovas JM, Tai ES. · Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · Nutr Rev. · Pubmed #11843001 No free full text.

Abstract: Hypercholesterolaemia is a major risk factor for coronary heart disease (CHD). Therefore, the reduction of low-density lipoprotein (LDL) cholesterol is one of the primary targets of the current recommendations to decrease CHD risk in the population. Whereas, the mechanisms involved in de novo cholesterol synthesis and its uptake by cells via the LDL receptor are well known, we still need better understanding about the mechanisms involved in intestinal cholesterol absorption and excretion. The recent discovery of ABCG5 and ABCG8 transporters will significantly improve our understanding of cholesterol trafficking and it will lead to better and new therapeutic strategies to maintain cholesterol homeostasis.

Ordovas JM, Schaefer EJ. · Lipid Metabolism Laboratory, JM-USDA-Human Nutrition Research Centre on Ageing, Tufts University, Boston, Massachusetts 02111, USA. · Curr Opin Lipidol. · Pubmed #10095985 No free full text.

Abstract: Several studies have examined gene-diet interactions in the response of plasma lipid concentrations to changes in dietary fat and/or cholesterol. Among the gene loci examined, APOE has been the most studied, and the current evidence suggests that this locus might be responsible for some of the interindividual variability in dietary response. Other loci, including APOA4, APOA1 and APOB have also been found to account for some of the variability in the fasting and fed states.

Lai CQ, Arnett DK, Corella D, Straka RJ, Tsai MY, Peacock JM, Adiconis X, Parnell LD, Hixson JE, Province MA, Ordovas JM. · Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #17431185 links to  free full text

Abstract: OBJECTIVE: Apolipoprotein A5 (APOA5) is a key determinant of plasma triglyceride (TG) concentrations. Genetic variation at the APOA5 locus could be responsible for some of the observed differences in response to fenofibrate therapy. METHODS AND RESULTS: We examined the association between tag SNPs (-1131T>C and 56C>G) at APOA5 and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG (P=0.006), and increase in HDL-C (P=0.002) levels relative to their basal values in the fasting state when compared with noncarriers (a TG reduction of -35.8+/-2.8% versus -27.9+/-0.9% and a HDL-C increase of 11.8+/-1.3% versus 6.9+/-0.5%, respectively). In the postprandial lipemia after a fat load, the 56G carriers showed a significant decrease in the area under curve for TG and increase for HDL-C than the noncarriers. These diverse beneficial responses of 56G carriers to fenofibrate were further characterized by a higher increase in large LDL-C concentrations and LDL size. On the other hand, subjects with different APOA5-1131T>C genotypes showed no significant response to fenofibrate intervention. CONCLUSION: This study suggests that the APOA5 56G carriers benefited more from the fenofibrate treatment than noncarriers in lowering plasma TG and increasing HDL-C levels.

Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. · Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, Tufts-New England Medical Center, Boston, USA. · Atherosclerosis. · Pubmed #15910869 No free full text.

Abstract: Bile-acid biosynthesis is a key determinant of intracellular cholesterol and, in turn, cholesterol synthesis rate in hepatocytes. This suggests that variation in the cholesterol 7alpha-hydroxylase gene (CYP7A1), a key enzyme in bile-acid biosynthesis, may influence the statin response. To test this hypothesis, a promoter polymorphism (A-204C) in CYP7A1 was examined in 324 hypercholesterolemic patients treated with atorvastatin 10mg. The variant C allele was significantly and independently associated with poor LDL cholesterol reductions; -39% in wild type allele homozygotes, -37% in variant allele heterozygotes, and -34% in variant allele homozygotes (p<0.0001 for trend). Differences were more striking in men, and were enhanced by the coexistence of common variants of apolipoprotein E gene (APOE), epsilon2 or epsilon4. In subjects having wild type alleles at both loci, the mean reduction in LDL cholesterol was -40%, while the value in subjects having two CYP7A1 variant alleles and at least one variant APOE allele was -31% (p<0.0001). Combination analysis of these two loci more accurately predicted the achievement of goal LDL cholesterol, than did both single locus analysis. We concluded that the CYP7A1 A-204C promoter variant was associated with poor response to atorvastatin, which were additively enhanced by common variants in another locus, APOE.

Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, Black DM, Stein EM, Corella D, Ordovas JM. · Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, New England Medical Center, Boston, MA, USA. · Atherosclerosis. · Pubmed #11500190 No free full text.

Abstract: The response to therapy with hypolipidemic agents shows considerable individual variation. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure. Our objective was to assess the effect of apolipoprotein (apo) E genotype and gender on lipid-lowering response to the HMG CoA reductase inhibitor, atorvastatin. Genotyping was carried out on DNA from 328 male and female subjects who participated in a multicentric, double-blind clinical trial, and received 10 mg/day of atorvastatin. Our data demonstrate no significant gender differences for LDL cholesterol levels at baseline. Moreover, mean LDL-C lowering was similar in men (-36.2%, range -2.7 to -57.8%) and in women (-38.1%, range -9.5 to -58.5%) as compared to baseline. However, men carrying the epsilon2 allele had a significantly higher mean LDL-C response (-44%) than epsilon3 homozygotes (-37%) and epsilon4 carriers (-34%); P=0.01 for apoE group by treatment interaction. No such gene/treatment interactions were noted in women, with those carrying the epsilon2 allele showing a similar mean response (-34%) as epsilon3 homozygotes (-39%) and epsilon4 carriers (-34%). Mean plasma triglyceride lowering with atorvastatin was 17%. A significant apoE group by treatment interaction (P=0.010) was also observed in men, with epsilon2 carriers being more responsive (-27%) than epsilon3/3 (-13%) and epsilon4 (-22%). This interaction was not observed in women. In summary, atorvastatin treatment had similar effects on plasma lipid levels in both men and women; however, the apoE gene locus was a significant predictor of LDL-C and TG responses to atorvastatin therapy in men, but not in women.

Schwab US, Ausman LM, Vogel S, Li Z, Lammi-Keefe CJ, Goldin BR, Ordovas JM, Schaefer EJ, Lichtenstein AH. · Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston 02111, USA. · Atherosclerosis. · Pubmed #10704618 No free full text.

Abstract: Evidence suggests that oxidative modification of low density lipoprotein (LDL) occurs in vivo, increasing the atherogenecity of the particle. A total of 13 subjects (age range 46-78 years) with an LDL cholesterol concentration >3.36 mmol/l consumed each of four diets for 32-day periods. The diets contained 30% energy as fat of which 2/3 was either corn oil or beef tallow with and without 115 mg/4.2 MJ of supplemental cholesterol in the form of cooked egg yolk. The susceptibility of LDL to oxidation was assessed during a challenge with hemin and hydrogen peroxide, and results are expressed as lag time to oxidation in minutes. Addition of moderate amounts of cholesterol to either the corn oil or beef tallow enriched diet resulted in increased susceptibility of LDL to oxidation (decreased lag time): 69+/-22 min versus 96+/-24 min in the corn oil diet with versus without supplemental cholesterol, respectively, P = 0.006; 82+/-20 min versus 96+/-26 min in the beef tallow diet with versus without supplemental cholesterol, respectively, P = 0.025. A stepwise equation indicated that as plasma oleic acid concentrations increased and/or linoleic acid concentrations decreased, lag time increased (decreased susceptibility to oxidation), whereas as dietary cholesterol concentrations increased, lag time decreased (increased susceptibility to oxidation). In conclusion, these data suggest that addition of a moderate amount of dietary cholesterol to a reduced fat diet rich in polyunsaturated or saturated fatty acids increased the in vitro susceptibility of LDL to oxidation.

Aguilar CA, Talavera G, Ordovas JM, Barriguete JA, Guillén LE, Leco ME, Pedro-Botet J, Gonzalez-Barranco J, Gómez-Pérez FJ, Rull JA. · Departamento de Diabetes y Metabolismo de Lípidos, Instituto Nacional de la Nutrición, Tlalpan, Mexico City, Mexico. · Atherosclerosis. · Pubmed #10030393 No free full text.

Abstract: The apolipoprotein E4 allele is associated in industrialized countries with an elevated LDL cholesterol concentration and an increased cardiovascular risk. Our purpose in this study was to assess the influence of the genetic variation at the APOE gene locus on the lipid profile of a Native American rural population. We examined plasma lipid levels and the common apo E alleles in 142 healthy randomly selected adults living in their native communities in western Mexico. Their age was 38+/-17 years and the BMI 25.7+/-4.5 kg/m2. Plasma cholesterol, triglycerides, LDL C and HDL C were 165+/-29.6, 126+/-83, 98+/-26 and 42+/-12.7 mg/dl respectively. Ninety-one per cent of the subjects had Lp(a) concentrations below 20 mg/dl and 30% had levels lower than 2 mg/dl. The most common APOE genotype was E3/3 (63%), followed by E3/4 (30.1%). The prevalence of the E2 allele was very low (2.3%). No difference was observed in LDL C concentrations between the E3/E3 and E3/E4 subjects; however carriers of the E2/3 genotype had lower LDL C levels. Similar results were obtained for cholesterol and apo B levels. In summary, the increased LDL C levels associated with the E4 allele in previous studies were not observed in a population with non-westernized habits. Environmental factors, such as diet and lifestyle, could outweigh the hypercholesterolemic predisposition resulting from the presence of the apo E4 allele.

Warodomwichit D, Arnett DK, Kabagambe EK, Tsai MY, Hixson JE, Straka RJ, Province M, An P, Lai CQ, Borecki I, Ordovas JM. · Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · J Nutr. · Pubmed #19141698 No free full text.

Abstract: The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.

Liu Y, Ordovas JM, Gao G, Province M, Straka RJ, Tsai MY, Lai CQ, Zhang K, Borecki I, Hixson JE, Allison DB, Arnett DK. · Departments of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Pharmacogenet Genomics. · Pubmed #19057464 No free full text.

Abstract: BACKGROUND: The apolipoproteins (APOA1/C3/A4/A5) are key components in modulating lipoprotein metabolism. It is unknown whether variants at the APOA1/C3/A4/A5 gene cluster are associated with lipid response to pharmacologic intervention. METHODS AND RESULTS: Plasma triglycerides (TGs) and high-density lipoprotein (HDL) levels were measured in 861 Genetics of Lipid-Lowering Drugs and Diet Network study participants who underwent a 3-week fenofibrate trial. We examined 18 common single nucleotide polymorphisms (SNPs) spanning the APOA1/C3/A4/A5 genes to investigate the effects of variants at the gene cluster on lipid response to fenofibrate treatment. We found that the minor alleles of the SNPs rs3135506 (APOA5_S19W), rs5104 (APOA4_N147S), rs4520 (APOC3_G34G), and rs5128 (APOC3_3U386) were associated with enhanced TG response to fenofibrate treatment (P= 0.0004-0.018). The minor allele of SNP rs2854117 (APOC3_M482) was associated with reduced rather than enhanced TG response (P= 0.026). The SNP rs3135506 (APOA5_S19W) was associated with HDL response, with minor allele related to reduced HDL response to fenofibrate (P= 0.002). Association analyses on haplotype provided corroborative evidence to single SNP association analyses. The common haplotypes H2, H3, and H5 were significantly associated with reduced TG response to fenofibrate. CONCLUSION: The genetic variants at APOA1/C3/A4/A5 gene cluster may be useful markers to predict response of lipid-lowering therapy with fenofibrate. Further studies to replicate/confirm our findings are warranted.

Perez-Martinez P, Corella D, Shen J, Arnett DK, Yiannakouris N, Tai ES, Orho-Melander M, Tucker KL, Tsai M, Straka RJ, Province M, Kai CS, Perez-Jimenez F, Lai CQ, Lopez-Miranda J, Guillen M, Parnell LD, Borecki I, Kathiresan S, Ordovas JM. · Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Am J Clin Nutr. · Pubmed #19056598 No free full text.

Abstract: BACKGROUND: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. OBJECTIVE: We investigated the combined effects of the GCKR rs780094C-->T, APOA5 -1131T-->C, and APOA5 56C-->G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. DESIGN: We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7,730 men and women) and 2 intervention studies in US whites (n = 1,061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). RESULTS: Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001). CONCLUSIONS: SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment.

Tanaka T, Ordovas JM, Delgado-Lista J, Perez-Jimenez F, Marin C, Perez-Martinez P, Gomez P, Lopez-Miranda J. · Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · J Lipid Res. · Pubmed #17363837 links to  free full text

Abstract: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-dependent transcription factor that plays a key role in lipid and glucose homeostasis. This study evaluated whether variants of PPARalpha are associated with postprandial lipemia. Subjects were given a single fat load composed of 60% calories as fat, 15% as protein, and 25% as carbohydrate. Blood was drawn every hour from baseline to 6 h, then every 2.5 h to 11 h to determine triglyceride (TG) levels. The minor allele of the nonsynonymous p.Leu162Val variant was associated with higher fasting total cholesterol, LDL-cholesterol, and apolipoprotein B. There were no significant associations with all of the postprandial parameters examined. Conversely, the noncoding variant c.140+5435T>C was not associated with fasting lipid concentrations but was significantly associated with decreased postprandial TG and cholesterol in the small TG-rich lipoprotein particle. Although the minor allele carriers displayed lower mean concentrations of TG and cholesterol throughout the postprandial period, the differences were most pronounced in the latter period. These data suggest that PPARalpha variants may modulate the risk of cardiovascular disease by influencing both fasting and postprandial lipid concentrations.

Kim JY, Kim OY, Koh SJ, Jang Y, Yun SS, Ordovas JM, Lee JH. · Yonsei University Research Institute of Science for Aging,, Yonsei University, Shinchon-Ding, Sudaemun-Gu, Seoul, Korea. · J Am Coll Nutr. · Pubmed #16943456 links to  free full text

Abstract: OBJECTIVE: The purpose of this study was to compare low-fat (LF) meal and high-fat (HF) meal on the postprandial lipemic responses according to the -1131T>C polymorphism of the APOA5 gene in a population usually consuming a LF diet and having a high frequency of the variant allele at the APOA5 -1131T>C SNP. METHODS: This study was conducted using a cross-over design and 49 non-obese healthy men (42.8 +/- 0.7 yrs, 23.9 +/- 0.25 kg/m(2)) participated in the meal tolerance test. They were randomly assigned to consume one of two types of experimental enteral formulae (LF vs HF) with a seven-day interval. Blood samples were collected at 0, 2, 3, 4 and 6h after ingestion and analyzed for total and chylomicron TG, glucose, insulin and free fatty acid. RESULTS: No differences were found in anthropometic parameter, calorie and macronutrient intakes and total energy expenditure between TT (n = 23) and TC + CC (n = 26) men. Fasting total TG were higher in TC + CC men than TT men, but fasting chylomicron TG were not significantly different between TT men and C carriers, TT subjects had no significant differences in postprandial responses of total TG and chylomicron TG and postprandial mean changes of chylomicron TG between LF and HF meal. On the other hand, C carriers had delayed peak time of total TG compared to TT subject and higher postprandial response and mean changes of chylomicron TG at HF meal compared to LF meal. CONCLUSION: The capacity to clear chylomicron-TG or hydrolyze TG might become a rate-limiting factor on HF diet in TC + CC men resulting in higher postprandial triglyceridemia. Therefore, HF diet for C carriers of the APOA5 gene may be one of important CVD risk factors.

Jang Y, Kim JY, Kim OY, Lee JE, Cho H, Ordovas JM, Lee JH. · Division of Cardiology, Cardiovascular Genome Center, Yonsei Medical Institute, Yonsei University, Seoul, Korea. · Am J Clin Nutr. · Pubmed #15447887 links to  free full text

Abstract: BACKGROUND: Apolipoprotein A5 plays an important role in modulating triacylglycerol metabolism in experimental animal models. OBJECTIVE: The objective was to determine associations of the common apolipoprotein A5 gene (APOA5) -1131T-->C polymorphism with postprandial lipemic response and other cardiovascular disease risk factors in humans. DESIGN: Healthy, nonobese subjects [n = 158; mean (+/-SEM) age: 33.8 +/- 1.2 y; body mass index (in kg/m(2)): 23.3 +/- 0.3] were subdivided into 3 genotype groups: TT (n = 85), TC (n = 56), and CC (n = 17). We measured fasting and postprandial lipid concentrations, lipid peroxidation, C-reactive protein concentrations, and DNA damage. RESULTS: Fasting triacylglycerol concentrations in carriers of the C allele were higher (P < 0.05) than in carriers of the TT genotype. No other significant genotype-related differences were observed for any of the other baseline measures. After consumption of a mixed meal, carriers of the C allele had significantly greater increases in total chylomicron and VLDL triacylglycerol than did subjects with the TT genotype. Moreover, carriers of the C allele had higher dense LDL, serum C-reactive protein, and urinary 8-epi-prostaglandin F(2alpha) concentrations and more lymphocyte DNA damage. Conversely, we did not find significant genotype-related differences in postprandial glucose, insulin, or free fatty acid measures. CONCLUSIONS: Our data confirm the genetic modulation of serum fasting triacylglycerol concentrations by the APOA5 gene polymorphism and extend this observation to postprandial triacylglycerol concentrations and to markers of oxidation and inflammation. The presence of the C allele in the APOA5 promoter region at position 1131 could be a significant factor contributing to higher cardiovascular disease risk in Koreans independently of common environmental factors.

Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. · Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, Tufts-New England Medical Center, Boston, MA, USA. · Atherosclerosis. · Pubmed #15262185 No free full text.

Abstract: Cholesterol excretion by ATP binding cassette transporters G5 and G8 (ABCG5/G8) and bile acid biosynthesis by cholesterol 7alpha-hydroxylase (CYP7A1) are major pathways for the removal of cholesterol into bile. To investigate the interactions between common polymorphisms in ABCG5/G8 and CYP7A1 and statin response, we examined the relationships between five non-synonymous polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and a promoter variant in CYP7A1 (A-204C) in 337 hypercholesterolemic patients treated with atorvastatin 10mg. The ABCG8 H19 allele was significantly associated with a greater LDL cholesterol reduction relative to the wild type D19 allele (39.6% versus 36.6%, P = 0.043). This difference was enhanced in non-carriers of the CYP7A1 promoter polymorphism (42.7% versus 38.2%, P = 0.048), and was diminished in accordance with the number of CYP7A1 variant alleles (1.8% in heterozygotes and 0.2% in homozygotes). Combination analysis of these polymorphisms explained a greater percentage of LDL cholesterol response variation (8.5% difference across subgroups) than did single polymorphism analysis (4.2% in CYP7A1 and 3.0% in ABCG8 D19H). The other ABCG5/G8 polymorphisms did not show any significant interactions with the CYP7A1 polymorphism. We conclude that the ABCG8 H19 and CYP7A1 C-204 alleles appear to interact in a dose-dependent manner on atorvastatin response.

Kajinami K, Brousseau ME, Nartsupha C, Ordovas JM, Schaefer EJ. · Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, Tufts-New England Medical Center, Boston, MA, USA. · J Lipid Res. · Pubmed #14703505 links to  free full text

Abstract: The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower (P = 0.028) and greater (P = 0.036) (112 mg/dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy.

Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. · Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, Tufts-New England Medical Center, Boston, Massachusetts, USA. · Am J Cardiol. · Pubmed #14697480 No free full text.

Abstract: To test whether genetic variation in the CYP system may influence the statin response, a promoter (A-290G) and 2 nonsynonymous polymorphisms (F189S and M445T) in the CYP3A4 gene locus were examined in 340 hypercholesterolemic patients who were treated with atorvastatin 10 mg. The A-290G variant allele was significantly associated with higher levels of post-treatment low-density lipoprotein cholesterol, whereas the M445T variant was associated with lower levels of low-density lipoprotein cholesterol before and after treatment.

Li Z, Otvos JD, Lamon-Fava S, Carrasco WV, Lichtenstein AH, McNamara JR, Ordovas JM, Schaefer EJ. · Lipid Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · J Nutr. · Pubmed #14608054 links to  free full text

Abstract: A diet restricted in saturated fat and cholesterol is recommended for subjects with elevated LDL cholesterol concentrations before and during drug therapy. Gender differences in lipoprotein subspecies response to such diets have not been studied in detail. We examined the effects of a diet low in total fat, saturated fat and cholesterol (Therapeutic Lifestyle Changes, TLC, diet: 26% of energy as fat, 4% as saturated fat, and 45 mg cholesterol/4.2 MJ), compared with an average American diet (AAD: 35% of energy as fat, 14% as saturated fat, and 147 mg cholesterol/4.2 MJ), on plasma lipoprotein subspecies in men and women. Each diet period lasted 6 wk. Body weight was kept constant during each diet period. Men (n = 19) and postmenopausal women (n = 14) >40 y old with moderate hypercholesterolemia participated in this study. Plasma lipoprotein concentrations were assessed by standardized methodology, and lipoprotein sizes were determined by gradient gel electrophoresis and NMR spectroscopy. The TLC diet resulted in greater reductions in total cholesterol and plasma apolipoprotein B concentrations in men than in women (-19% vs. -12%, P < 0.05, and -18% vs. -9%, P < 0.05, respectively). Postprandial triacylglycerol and LpAI:AII concentrations were reduced in men, but not in women (-15% vs. 8%, P < 0.05, and -9% vs. -2%, respectively, P < 0.05). Similar decreases in LpAI concentrations and LDL and HDL particle size were observed in men and women. These data are consistent with the concept that middle aged/elderly men may have a more favorable lipoprotein response to a low fat, low cholesterol diet than postmenopausal women.

Tai ES, Adiconis X, Ordovas JM, Carmena-Ramon R, Real J, Corella D, Ascaso J, Carmena R. · Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · Clin Genet. · Pubmed #12519372 No free full text.

Abstract: Scavenger receptor, class B, type 1 (SRBI) is a promising candidate gene involved in the pathophysiology of atherosclerosis. We have examined the association of three common polymorphisms at the SRBI locus in 77 subjects who were heterozygous for familial hypercholesterolemia (FH). The alleles represented by polymorphisms in exon 1 and exon 8 were associated with variation in plasma concentrations of fasting triglyceride (TG). Mean plasma TG concentrations for homozygotes for the most common allele, and for heterozygotes and homozygotes for the less common allele were 85 +/- 6, 111 +/- 9 and 135 +/- 22 mg/dl (p = 0.011) for exon 1, and 96 +/- 11, 86 +/- 6 and 134 +/- 13 mg/dl (p = 0.007) for exon 8, after adjustment for age, sex and body mass index. In addition, the exon 8 polymorphism was associated with increased total cholesterol (320 +/- 15, 340 +/- 8 and 388 +/- 18 mg/dl, p = 0.015), very low density lipoprotein (VLDL) cholesterol (18 +/- 2.9, 15.7 +/- 1.6 and 33.4 +/- 3.9 mg/dl, p < 0.001) and low density lipoprotein (LDL) cholesterol (251 +/- 15, 270 +/- 8 and 312 +/- 10 mg/dl, p = 0.041) concentrations. In agreement with animal studies, our data also suggest a role for the SRBI in the metabolism of apolipoprotein B (apoB)-containing lipoproteins in humans. This pathway may constitute a backup mechanism to LDL receptor-mediated pathways for the catabolism of these lipoproteins, which could be particularly relevant in subjects with high levels of apoB-containing lipoproteins, such as those occurring in patients with FH.

Chaves FJ, Real JT, García-García AB, Puig O, Ordovas JM, Ascaso JF, Carmena R, Armengod ME. · Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain. · Eur J Clin Invest. · Pubmed #11298777 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density lipoprotein receptor (LDLR) gene. To date, there has not been a systematic survey of the frequency of gross mutations in the LDLR gene in the Spanish population. The objective of our study was to investigate large rearrangements in the Spanish FH population and the relation between the kind of large rearrangement and the phenotype in carrier families. MATERIALS AND METHODS: The LDLR gene was screened to detect major rearrangements in a sample of 89 probands. Southern blot, long polymerase chain reaction (PCR), reverse transcription (RT) -PCR and DNA sequencing were used to detect and characterize the mutations. RESULTS: Five large rearrangements were found in six probands. Two mutations were due to duplications of internal regions of the gene, whereas the rest were caused by partial deletions, which eliminated the promoter region in two cases. The internal rearrangements, two duplications and one deletion, were apparently caused by recombination between ALU sequences and the study of their mRNA indicated that the reading frame was maintained. The analysis of the lipid profile between patients with similar characteristics (age, sex, body mass index, etc.) but carrying mutations that either eliminated the promoter region or produced internal rearrangements showed significant differences (total cholesterol: 366.6 +/- 81.8 vs. 304.6 +/- 25.1 P = 0.023, and LDL cholesterol: 317.7 +/- 65.1 vs. 249.2 +/- 27.4 P = 0.003). CONCLUSIONS: The frequency of large mutations in a Spanish FH sample was close to 7% and at least four of the mutations found had not been described in other populations. Mutations that eliminate the promoter region originate more severe hypercholesterolemia than defective mutations, which suggests that the absence of the promoter region and transcription of the LDLR gene is worse compensated than the synthesis of a defective LDL receptor.