The nuclear receptor PPAR-alpha (Peroxisome proliferator-activated receptor-alpha) regulates the transcription of genes involved in fatty acid and bile acid metabolism and transport. PPAR-alpha is activated following binding with natural (fatty acids) or exogenous (fibrates) ligands. A common polymorphism in the PPAR-alpha gene (PPARA) is a functional missense mutation which causes a leucine to valine substitution (L162V). Another frequent polymorphism is a G to C transversion in intron 7. In order to test the etiopathogenic relevance of PPARA polymorphisms in gallstone disease, we investigated the prevalence of exon 5 and intron 7 variants, either isolated or in combination, in gallstone patients and in a control population. One hundred and twenty seven gallstone patients (56 males, 71 females) admitted to the hospital for either elective cholecystectomy or endoscopic treatment of choledocolithiasis, were screened for the presence of PPARA polymorphisms. Control population was composed of 110 age matched hospital workers and university students (53 males, 57 females). After DNA extraction from peripheral blood leukocytes, PCR amplification of exon 5 and intron 7 was performed. Denaturing-high performance liquid chromatography (D-HPLC) was then used to screen the PCR products for the presence of polymorphisms. Automated sequencing was employed to confirm and characterize the polymorphisms. Statistical analysis was performed by the chi-square test. The overall carrier frequency of exon 5 L162V polymorphism was 11% in the control population and 13.4% in the gallstone group (p=NS). The total carrier frequency for intron 7 polymorphism was 25% in the control population, while in male and female lithiasic patients it was 43% and 37%, respectively (p= 0.03). The haplotype characterized by exon 5 L162V, in the absence of intron 7 polymorphism, was not found in males with gallstones, while a 11% frequency was observed in male controls (p=0.02). These data demonstrate a significant higher prevalence of PPARA intron 7 polymorphism in gallstone patients, mainly due to its frequency in the male subgroup. Furthermore, the haplotype characterized by exon 5 L162V, in the absence of an associated intron 7 polymorphism, seems to confer protection from gallstones in males but not in females, supporting an hormone modulation on PPAR-alpha polymorphic variants.
Prevalence of different PPAR-alpha gene polymorphisms and haplotypes in gallstone patients. Dig Liv Dis 2005;Vol. 37 Suppl.1:S36.
MONTAGNANI, MARCO;ALDINI, RITA;BACCHI REGGIANI, MARIA LETIZIA;FESTI, DAVIDE;AZZAROLI, FRANCESCO;MAZZELLA, GIUSEPPE;MINNI, FRANCESCO;RODA, ENRICO
2005
Abstract
The nuclear receptor PPAR-alpha (Peroxisome proliferator-activated receptor-alpha) regulates the transcription of genes involved in fatty acid and bile acid metabolism and transport. PPAR-alpha is activated following binding with natural (fatty acids) or exogenous (fibrates) ligands. A common polymorphism in the PPAR-alpha gene (PPARA) is a functional missense mutation which causes a leucine to valine substitution (L162V). Another frequent polymorphism is a G to C transversion in intron 7. In order to test the etiopathogenic relevance of PPARA polymorphisms in gallstone disease, we investigated the prevalence of exon 5 and intron 7 variants, either isolated or in combination, in gallstone patients and in a control population. One hundred and twenty seven gallstone patients (56 males, 71 females) admitted to the hospital for either elective cholecystectomy or endoscopic treatment of choledocolithiasis, were screened for the presence of PPARA polymorphisms. Control population was composed of 110 age matched hospital workers and university students (53 males, 57 females). After DNA extraction from peripheral blood leukocytes, PCR amplification of exon 5 and intron 7 was performed. Denaturing-high performance liquid chromatography (D-HPLC) was then used to screen the PCR products for the presence of polymorphisms. Automated sequencing was employed to confirm and characterize the polymorphisms. Statistical analysis was performed by the chi-square test. The overall carrier frequency of exon 5 L162V polymorphism was 11% in the control population and 13.4% in the gallstone group (p=NS). The total carrier frequency for intron 7 polymorphism was 25% in the control population, while in male and female lithiasic patients it was 43% and 37%, respectively (p= 0.03). The haplotype characterized by exon 5 L162V, in the absence of intron 7 polymorphism, was not found in males with gallstones, while a 11% frequency was observed in male controls (p=0.02). These data demonstrate a significant higher prevalence of PPARA intron 7 polymorphism in gallstone patients, mainly due to its frequency in the male subgroup. Furthermore, the haplotype characterized by exon 5 L162V, in the absence of an associated intron 7 polymorphism, seems to confer protection from gallstones in males but not in females, supporting an hormone modulation on PPAR-alpha polymorphic variants.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
