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

• Published in: Atherosclerosis Vol. 163; no. 1; pp. 183 - 192
• Main Authors: Jamshidi, Y., Flavell, D.M., Hawe, E., MacCallum, P.K., Meade, T.W., Humphries, S.E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.07.2002; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Analysis of Variance; Apolipoprotein C-III; Apolipoprotein CIII; Apolipoproteins C - analysis; Apolipoproteins C - genetics; Arterial Occlusive Diseases - blood; Arterial Occlusive Diseases - drug therapy; Arterial Occlusive Diseases - genetics; Base Sequence; Bezafibrate; Bezafibrate - administration & dosage; Biological and medical sciences; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Fibrinogen; Fibrinogen - analysis; Fibrinogen - genetics; Follow-Up Studies; Gene polymorphism; General and cellular metabolism. Vitamins; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Hypolipidemic Agents - administration & dosage; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Peripheral Vascular Diseases - blood; Peripheral Vascular Diseases - drug therapy; Peripheral Vascular Diseases - genetics; Peroxisome proliferator activated receptor α; Pharmacology. Drug treatments; Polymerase Chain Reaction; Polymorphism, Genetic; Probability; Reference Values; Sensitivity and Specificity; Treatment Outcome; Triglycerides; Peroxisome proliferator activated receptor α; Triglycerides; Apolipoprotein CIII; Bezafibrate; Gene polymorphism; Fibrinogen; Human; Prognosis; Fibrate derivatives; Cardiovascular disease; Triglyceride; Genetic determinism; Arterial disease; Vascular disease; PPAR-α receptor; Chemotherapy; Treatment; Gene; Occlusive arterial disease; Antilipemic agent; Polymorphism
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/S0021-9150(02)00002-3

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.