L162V Polymorphism Research Articles

Peroxisome proliferator-activated receptor α polymorphisms and postprandial lipemia in healthy men

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.

한국인에서 peroxisome proliferator-activated receptor alpha Leu162Val 유전자 다형성과 대사증후군간의 관련성

Peroxisome proliferator activated receptor (PPAR)- of three PPAR subtypes (), which are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, plays a key role in lipoprotein and glucose homeostasis. A variation in the PPAR-a gene expression has been suggested to influence the development of metabolic syndrome through alterations in lipid concentrations. The aim of our study was to investigate the association between the PPAR-a and metabolic syndrome among South Korean. A total of 542 health screen examinees were enrolled in this study who were examined in Kosin University Gospel Hospital from December, 2004 to July, 2005. The height, weight, waist circumference, and systolic and diastolic blood pressure of the subjects were examined and fasting blood glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride were measured by-sampling in venous blood. The metabolic syndrome was defined as the presence of three or more of the following : waist circumference men , women , blood pressure , fasting glucose , HDL cholesterol men . The blood pressure, fasting glucose, HDL cholesterol, triglyceride were evaluated by using the criteria of NECP ATP III and waist circumference was assessed by using the criteria of WHO Asia-Western Pacific. And the author compared the frequency of the PPAR- mutation of L162V ( variant in exon 5) in a sample of 542 subjects with and without the metabolic syndrome by polymerase chain reaction allele-specific oligonucleotide (PCR-ASO) method. One (0.2%) hetero-isotype among high risk of metabolic syndrome was identified. The values of waist circumference, body mass index and low density lipoprotein cholesterol of the mutant were 100 cm, 28.6 and 120 mg/dL, respectively. Although the author failed to see significant association between the presence of the PPAR- L162V polymorphism and metabolic syndrome, one PPAR- L162V polymorphism in metabolic syndrome patients was found.

Peroxisome Proliferator-Activated Receptor α L162V Polymorphism in Nonalcoholic Steatohepatitis and Genotype 1 Hepatitis C Virus-Related Liver Steatosis

BackgroundPeroxisome proliferator-activated receptor α (PPARα) plays important roles in lipid metabolism. A recently discovered L162V polymorphism of the PPARα gene is associated with enhanced transcriptional activity. In this study, the...

The dependence of serum interleukin-6 level on PPAR-alpha polymorphism in men with coronary atherosclerosis

Background The association between L162V polymorphism in the gene for peroxisome proliferator activated receptor (PPAR) alpha and the development of coronary heart disease was examined. Methods PPAR-alpha polymorphism was determined in 48 men with angiographically confirmed coronary atherosclerosis and in 51 healthy men. Results The frequency of the V allele of the L162V polymorphism was four times higher in men with atherosclerosis (0.25 in studied group and 0.06 in controls). The polymorphism was not associated with changes in body mass index, lipid pattern, serum adhesion molecules, or vasoactive agents concentrations. The effect of the polymorphism on the serum interleukin-6 level (IL-6) was observed ( p < 0.01). The serum IL-6 level was higher in homozygotic than in heterozygotic subjects ( p < 0.02). Multivariate regression analysis showed the existence of a relationship between simvastatin therapy and serum IL-6 level ( r = 0.83; p < 0.05) in the homozygotic men. While in homozygotic patients with atherosclerosis a negative linear correlation between serum IL-6 and NO concentration was shown, in heterozygotic men positive correlations between IL-6 or HDL cholesterol and adhesion molecule levels were found. Conclusion L162V polymorphism in the gene for PPAR-alpha seems to be associated with atherosclerosis through a mechanism including regulation of the IL-6 level.

The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Background The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator–activator receptor α (PPARα), significantly reduced the risk of cardiovascular (CV) events in men with low HDL cholesterol (<40 mg/dl) and established coronary heart disease. Treatment was particularly beneficial in those with insulin resistance (IR) or diabetes mellitus (DM). We hypothesized that the association between a functional polymorphism at the PPARA locus (L162V) and the risk of a CV event, as well as response to fibrate therapy, might be greatest in those with either IR or DM (DM/IR) in VA-HIT. Methods and results A total of 827 men (placebo, n = 413; gemfibrozil, n = 414) from the VA-HIT were genotyped. This population included a high proportion of subjects with DM/IR. In VA-HIT, the PPARA V162 allele was associated with reduced levels of HDL cholesterol and the presence of DM/IR at baseline. It was also associated with reduced risk of CV events in those with DM/IR but not in those with neither (DM/IR * PPARA genotype, P = 0.005). Among subjects with DM/IR, treatment with gemfibrozil reduced CV events in non-carriers from 29.9 to 17.8% and carriers of the V162 allele from 14.7 to 4.8%. In contrast, carriers of the V162 allele with no DM/IR who were treated with gemfibrozil experienced significantly more CV events than did those who received placebo (20.6% versus 13.6%; P = 0.01). Conclusions The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of DM/IR. Among subjects treated with gemfibrozil, the V162 allele was associated not only with reduced CV risk in subjects with DM/IR, but also with significantly increased CV risk in the absence of these traits, identifying this genetic variant as a potential marker for predicting which subjects may have a favorable response to fibrate therapy.

The peroxisome proliferator-activated receptor delta +294T/C polymorphism in relation to lipoprotein metabolism in patients with diabetes mellitus type 2 and in non-diabetic controls

Objective Peroxisome proliferator-activated receptor δ (PPARδ) is an ubiquitously expressed transcription factor that has been implicated in the regulation of genes related to cholesterol metabolism. Conflicting results exist regarding the association of the recently described +294T/C polymorphism in the 5′-untranslated region (5′-UTR) in exon 4 of the PPARδ gene and plasma lipoprotein concentrations. Purpose of the present study was to examine for the first time in a German population and for the first time also in women the presence of a potential association between the aforementioned polymorphism and lipoprotein concentrations in patients with diabetes mellitus type 2 (DM-2) and in non-diabetic controls. Furthermore, a possible gene–gene interaction between the PPARδ +294T/C polymorphism and the PPARα L162V polymorphism was examined. Design and methods We determined by PCR the polymorphism in a total of 402 patients with DM-2 (230 men and 172 women) and in 436 healthy controls (248 men and 188 women) from the LIANCO study (lipid analytic cologne). Results The genotype distribution was not different between DM-2 and controls (+294TT 65.6% versus 66.7%, +294TC 30.5% versus 29.4%, +294CC 3.9 versus 4.0%, respectively). There was no difference in the low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) or triglyceride (TG) concentrations between carriers and non-carriers of the rare C allele in the DM-2 population. In specific, the heterozygotes for the C allele had LDL-C concentrations of 157 ± 80 mg/dl, HDL-C of 54 ± 17 mg/dl and TG of 273 ± 507 mg/dl, while the C allele homozygotes had concentrations of LDL-C 149 ± 44 mg/dl, HDL-C of 59 ± 21 mg/dl and TG of 197 ± 110 mg/dl. The LDL-C, HDL-C and TG concentrations of TT homozygotes were 156 ± 49 mg/dl, 56 ± 18 mg/dl and TG 225 ± 242 mg/dl, respectively. The same lack of association was present in the non-diabetic controls, both in men and in women. There was no association between the genotypes and body mass index. Furthermore, no gene–gene interaction between the PPARδ +294TC and the PPARα L162V polymorphism was observed regarding lipoprotein concentrations and atherosclerotic disease. Conclusions The data suggest that the PPARδ +294T/C polymorphism has no influence on plasma lipoprotein concentrations, body mass index or atherosclerotic disease either in healthy subjects or in patients with DM-2, both in males and females.

Polyunsaturated Fatty Acids Interact with the PPARA-L162V Polymorphism to Affect Plasma Triglyceride and Apolipoprotein C-III Concentrations in the Framingham Heart Study

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear transcription factor regulating multiple genes involved in lipid metabolism. It was shown that a common leucine to valine (L162V) substitution at the PPARalpha gene (PPARA) is functional and affects transactivation activity of PPARalpha ligands, such as PUFA, on a concentration-dependent basis. The current study examined this gene-nutrient interaction in relation to plasma lipid variables in a population-based study consisting of 1003 men and 1103 women participating in the Framingham cohort and consuming their habitual diets. We found significant gene-nutrient interactions between the L162V polymorphism and total PUFA intake, which modulated plasma triglycerides (TG; P < 0.05) and apolipoprotein C-III (apoC-III; P < 0.05) concentrations. The 162V allele was associated with greater TG and apoC-III concentrations only in subjects consuming a low-PUFA diet (below the population mean, 6% of energy). However, when PUFA intake was high, carriers of the 162V allele had lower apoC-III concentrations. This interaction was significant even when PUFA intake was considered as a continuous variable (P = 0.031 for TG and P < 0.001 for apoC-III), suggesting a strong dose-response effect. When PUFA intake was <4%, 162V allele carriers had approximately 28% higher plasma TG than did 162L homozygotes (P < 0.01). Conversely, when PUFA intake was >8%, plasma TG in 162V allele carriers was 4% lower than in 162L homozygotes. Similar results were obtained for (n-6) and (n-3) fatty acids. Our data show that the effect of the L162V polymorphism on plasma TG and apoC-III concentrations depends on the dietary PUFA, with a high intake triggering lower TG in carriers of the 162V allele.

Association between the PPARα L162V polymorphism, plasma lipoprotein levels, and atherosclerotic disease in patients with diabetes mellitus type 2 and in nondiabetic controls

Background Peroxisome proliferator activated receptor alpha (PPARα) regulates genes involved in lipoprotein metabolism, hemostasis, and inflammation. It thus represents a candidate gene for the risk of dyslipidemia, atherosclerosis, and coronary heart disease (CHD). Nonesterified fatty acids are PPARα ligands and their levels are increased in patients with diabetes mellitus type 2 (DM-2). The effects of the polymorphism of PPARα on plasma lipids and atherosclerosis development have been until now contradictory. The present study was performed to evaluate the association between the PPARα polymorphism L162V and the presence of dyslipidemia and/or atherosclerotic disease in patients with DM-2 in comparison with nondiabetic controls. Methods and results We determined this polymorphism in 404 subjects with DM-2 and in 438 age and sex-matched nondiabetic controls. The V allele was present in 9.4% of patients with DM-2 and in 11.4% of the control group ( P = .34). There was no significant association between the presence of the polymorphism and body mass index. There was no association between the polymorphism and lipoprotein concentrations in either group, independent of lipid-lowering therapy. In patients with DM-2, there was a trend towards a lower prevalence of atherosclerosis in carriers versus noncarriers of the V allele ( P = .0837). In the control group, the presence of the V allele was not associated with an altered prevalence of atherosclerotic disease ( P = .45). Likewise, there was a trend towards lower CHD prevalence in carriers versus noncarriers of the V allele ( P = .0622). The presence of the polymorphism was not associated with CHD in the control group ( P = .80). Conclusions The data suggest that the PPARα polymorphism L162V might protect against the development of atherosclerosis or CHD in patients with DM-2. The absence of an association between the polymorphism and plasma lipoprotein concentrations may suggest that these protective effects are exerted directly on the arterial wall.

The metabolic syndrome: a practical guide to origins and treatment: Part II.

The metabolic syndrome (MetS), a cluster of metabolic abnormalities with insulin resistance as a major characteristic, has gone by several names over the past two decades. The diagnostic criteria proposed by the Adult Treatment Program III (ATP III) of the National Cholesterol Education Program (NCEP) have led to greater awareness of the components and treatment strategies.1 Five diagnostic traits are listed in the ATP III version of the MetS (Table; referred to as the “metabolic syndrome”), and the presence of any 3 of these factors is considered sufficient for diagnosis. This practical review will consider each in turn, providing advice for cardiologists, internists, and other health care providers who are diagnosing and treating persons with the syndrome in an effort to prevent a variety of clinical outcomes. View this table: Diagnostic Criteria for the Metabolic Syndrome The major adverse consequence of the MetS is cardiovascular disease (CVD). Several of the metabolic abnormalities associated with the syndrome, in fact, are CVD risk factors. One of these abnormalities, insulin resistance, also predisposes to the development of type 2 diabetes mellitus (T2DM). In age-adjusted estimates from the National Health and Nutrition Examination Survey III in 1998 to 1994, approximately 24% of adult Americans had ≥3 of the 5 MetS criteria. Key determinants of greater prevalence were age and ethnicity. Prevalence rates were highest in Mexican Americans and were successively lower in white, African American and other racial groups.2 These published estimates included persons with diabetes mellitus who had met the 1998 fasting glucose criteria (≥126 mg/dL [8.0 mmol/L]) of the American Diabetes Association.3 This article will focus on the features of the MetS in persons without diabetes mellitus, although most persons with T2DM also have the MetS. Moreover, the therapeutic approaches to metabolic risk factors described here also can be applied to …

Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men.

The objective of this work was to explore the role of peroxisome proliferator-activated receptor delta (PPARD) in lipid metabolism in humans. PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5'-region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: -409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL-cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters. These findings suggest that PPARD plays a role in cholesterol metabolism in humans.

Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study.

Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the PPARA locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (P=0.0012 and P=0.0004, respectively) and apolipoprotein B in men (P=0.009) and women (P=0.03 after adjustment for age, body mass index, smoking, and use of beta-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the APOE locus and the G allele at the APOC3 3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase in LDL cholesterol observed with the L162V PPARA polymorphism.

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor α ( PPARα) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII ( APOC3) gene (−482C>T and −455T>C) and one in the β-fibrinogen ( FIBB) gene (−455G>A). The presence of diabetes ( n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics ( n=654) ( P<0.05). Among the diabetic group, carriers of the PPARα intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele ( P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the −482T allele had 13% lower baseline triglyceride levels compared to −482C homozygotes ( P<0.02), but no effect was observed with the −455T>C substitution. In the non-diabetic patients, the PPARα V162 allele was significantly associated with 9% higher baseline triglyceride levels ( P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the −455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l ( P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARα gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.

Association between the PPARA L162V polymorphism and plasma lipid levels. Interactions with the APOE, APOC3 and LPL Loci: the Framingham offspring study

Association between the PPARA L162V polymorphism and plasma lipid levels. Interactions with the APOE, APOC3 and LPL Loci: the Framingham offspring study

A polymorphism, L162V, in the peroxisome proliferator-activated receptor alpha (PPARalpha) gene is associated with lower body mass index in patients with non-insulin-dependent diabetes mellitus.

This study examined the effect a polymorphism (L162V) in the gene for peroxisome proliferator activated receptor (PPAR) alpha in the development of non-insulin-dependent diabetes mellitus (type 2 DM), obesity and hyperlipidaemia. The frequency of the L162V polymorphism in the PPARalpha gene was determined in 370 morbidly obese patients who underwent gastric banding surgery, 154 patients attending a type 2 DM clinic, 188 patients attending a lipid clinic and 199 healthy blood donors. The overall frequency of the V allele of the L162V polymorphism was 0.06. There were no significant differences in the allele frequency between patients with morbid obesity, hyperlipidaemia, type 2 DM and healthy controls, suggesting that it does not play a major role in the development of these conditions. The polymorphism was associated with a lower body mass index (BMI) in two independently recruited groups of patients with type 2 DM. There was no effect of the polymorphism on subjects without type 2 DM. Thus a polymorphism in PPARalpha protects type 2 DM patients from the overweight which is frequently associated with their condition.