Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial
Introduction
Atherosclerosis is the most common cause of chronic arterial occlusive disease of the lower extremities. During the atherosclerotic process, arteries become obstructed thereby reducing blood flow to the lower limbs during exercise or at rest. A common symptom is intermittent claudication, cramping or fatigue in the legs and buttocks during activity, which subsides with rest. Risk factors for lower extremity disease (LEAD) are similar to those for cardiovascular disease and include advanced age [1], [2], [3], [4], male sex [1], [4], diabetes mellitus [4], [5], cigarette smoking [3], [4], [6], [7], [8], hypertension [4] and elevated lipid levels, particularly in diabetic subjects [8], [9], [10]. There is a long established association between increased plasma fibrinogen levels and the onset and progression of arterial disease [11], [12], [13], [14], [15], [16], [17], [18], and there is evidence that this is particularly important in the progression of LEAD [1], [19], [20], [21]. Patients with either asymptomatic or symptomatic LEAD have widespread arterial disease and have a significantly increased risk of stroke, MI and cardiovascular death [7], [22], [23], [24], [25], [26], [27].
The fibrate class of hypolipidemic drugs is used in the treatment of lipid disorders such as primary hypertriglyceridemia and combined hyperlipidemia. Their lipid-lowering effects are mediated by an increase in triglyceride-rich lipoprotein catabolism and the resulting inhibition of hepatic VLDL triglyceride secretion as well as affecting intracellular hydrolysis of triglycerides and HDL production. Peroxisome proliferator activated receptor α (PPARα) is a ligand-induced transcription factor belonging to the nuclear hormone receptor superfamily [28]. PPARα is expressed mainly in tissues exhibiting high rates of β-oxidation such as liver, kidney, heart and muscle [29], but also in arterial wall cell types [30], [31], [32]. PPARα mediates the hypolipidemic action of fibrates and is an important regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPARα down-regulates hepatic apolipoprotein C-III [33] and increases lipoprotein lipase gene expression [34]. PPARα activation also increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I [35] and apolipoprotein A-II [36] expression in humans. Several of the fibric acid derivatives also lower the fibrinogen levels [37], [38], [39], [40]. Bezafibrate in particular, decreases plasma fibrinogen levels by approximately 20% [41]. The main aim of the lower extremity arterial disease event reduction (LEADER) trial is to reduce the incidence of combined end-points of major IHD and stroke by 30% using a randomised placebo-controlled trial of bezafibrate in 1500 men with LEAD followed for a minimum of 4 years.
The aim of this present study is to investigate whether polymorphisms in the PPARα gene affect an individual's baseline lipid and fibrinogen levels as well as their biochemical response to bezafibrate treatment. We investigated the association between the L162V, intron 2 and intron 7 polymorphisms in the PPARα gene on the magnitude of change in both triglyceride and fibrinogen levels in response to bezafibrate treatment. Genotype association was examined with respect to baseline levels, and change at 3 months. As PPARα is a transcription factor, of additional interest are interactions with promoter variants in other fibrate-responsive genes. Thus, promoter variation in APOC3 and β-fibrinogen (FIBB) were investigated, as fibrates have been shown to modulate the expression of these genes through PPARα [42], [43], [44], [45], [46], [47], [48].
Section snippets
Subjects
One thousand five hundred and sixty-eight patients were recruited through 85 practices in the British Medical Research Council's General Practice Research Framework and through nine hospital vascular clinics. There was no age restriction. The trial was approved by the 69 Local Research Ethics Committees responsible for the participating practices and hospitals. Methods have been described in detail elsewhere [49]. Briefly, men were ineligible if they: had previous history of unstable angina,
Physical and biochemical characteristics of the sample
The baseline physical and biochemical characteristics of the subjects who made up this sample of men in the LEADER trial are presented in Table 1. The mean age was 68 years ranging from 42 to 90. Almost 40% were current smokers and 34% had previously had a cardiovascular event. Approximately, 20% of the group had diabetes, and baseline lipid and fibrinogen levels were within accepted ranges for this age group.
Allelic frequencies of the polymorphisms
The number of individuals genotyped and their allele frequencies for all polymorphisms
Discussion
Overall, in this group of male patients with LEAD, bezafibrate treatment for 3 months led to a 26% fall in triglyceride levels and a 12% fall in plasma fibrinogen levels, effects similar to that observed in other studies [56], [57], [58]. The degree of compliance in these subjects was high, as estimated by the fall in AP on treatment, and as expected, the fall in triglyceride and fibrinogen levels was positively correlated with degree of compliance and with baseline levels, and for
Acknowledgements
This study was supported by grants from the British Heart Foundation (RG95007, PG/99153 and FS98058) and the Medical Research Council. Active and placebo bezafibrate tablets were provided by Boehringer–Mannheim. We would like to thank Clare Turner and Bhavesh Patel for excellent technical assistance. We gratefully acknowledge contribution of the participating practices in the General Practice Research Framework and the hospital vascular clinics.
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Cited by (21)
Triglyceride Treatment in the Age of Cholesterol Reduction
2016, Progress in Cardiovascular DiseasesFinding chemical drugs for genetic diseases
2014, Drug Discovery TodayCitation Excerpt :In addition, a L162V mutation (LOF) in the peroxisome proliferator-activated receptor alpha (PPARα) was found to be responsible for the low transcriptional activity of various genes, which could lead to numerous diseases, such as hyperlipidemia, hyperlipoproteinemia and dysbetalipoproteinemia [23]. Interestingly, the PPARα agonists, bezafibrate and ciprofibrate, which are drugs approved to treat hyperlipidemia and hyperlipoproteinemia by targeting the wild type PPARα, are effective for the treatment of inheritable hyperlipidemia derived from the L162V mutation [24,25]. These successful examples suggest that using existing drugs with the same indications as the disease traits is possible to treat genetic diseases [26].
Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: A study in Brazilian patients
2013, GeneCitation Excerpt :There was no documented association between the Leu162Val SNP and body fat (Verdi et al., 2005; Silbernagel et al., 2009), steatosis (Silbernagel et al., 2009) and blood lipid profile (Verdi et al., 2005). The Leu162Val SNP may be associated with some specific blood lipid alterations in diabetic patients (Flavell et al., 2000; Robitaille et al., 2004; Vohl et al., 2000) as well as in healthy subjects (Jamshidi et al., 2002; Nielsen et al., 2003; Robitaille et al., 2004). In this study, we observed an association between fibrosis stage with the presence of Leu162Val, but not of Pro12Ala.
Different effects of PPARA, PPARG and ApoE SNPs on serum lipids in patients with coronary heart disease based on the presence of diabetes
2013, GeneCitation Excerpt :To further this association, they screened another sample of 193 non-diabetic subjects recruited in the greater Quebec City area and they showed that the carriers of the V162 allele had significantly higher concentrations of plasma total and LDL-C (p = 0.02). Furthermore, Jamshidi et al. (2002) found that in subjects without diabetes the presence of this polymorphism was associated with approximately 9% higher baseline TG levels (p = 0.022), contrary to their diabetic group in which the presence of the polymorphism was associated with a trend (p = 0.077) towards lower triglycerides. Robitaille et al., 2004 found that the group of subjects carrying the V162 allele had higher plasma TG levels than L162/L162 homozygous (p = 0.004) and the frequency of the V162 allele was higher in men having simultaneously abdominal obesity and low HDL-C concentrations (p = 0.05).
The role of fibrinogen and fibrinolysis in peripheral arterial disease
2008, Thrombosis ResearchCitation Excerpt :Carriers of the A allele of the beta fibrinogen -455G/A polymorphism are also at an increased risk for lacunar stroke [123]. The LEADER trial examined genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment in 853 men with PAD [124]. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) 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 beta-fibrinogen (FIBB) gene (-455G>A).