FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease
FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease
Year: 2008
Authors: Martinelli, N. Girelli, D. Malerba, G. Guarini, P. Illig, T. Trabetti, E. Sandri, M. et.al.
Publication Name: Am. J. Clin. Nutr.
Publication Details: Volume 88; Pages 941 – 949.
Abstract:
The delta-5 and delta -6 desaturases, encoded by FADS1 and FADS2 genes, are key enzymes in polyunsaturated fatty acid (PUFA) metabolism that catalyze the conversion of linoleic acid (LA) into arachidonic acid (AA) and that of alpha-linolenic acid (ALA) into eicosapentaenoic acid (EPA). Single-nucleotide polymorphisms (SNPs) in FADS1 and FADS2 have been associated with different concentrations of AA and LA, and those associations have possible functional consequences for desaturase activity. We aimed to evaluate the possible association among FADS genotypes, desaturase activity, inflammation, and coronary artery disease (CAD). Thirteen FADS SNPs and the ratio of AA to LA (AA/LA) on red blood cell (RBC) membranes, a marker of desaturase activity, were evaluated in 876 subjects with (n=610) or without (n= 266) angiographically documented CAD. Both AA/LA and the ratio of EPA to ALA (EPA/ALA) were higher in patients with CAD than in those without CAD, but, in a multiple logistic regression model, only a higher AA/LA resulted an independent risk factor for CAD (odds ratio: 2.55; 95% CI: 1.61, 4.05 for higher compared with lower ratio tertile; P for trend <0.001). Furthermore, concentrations of high-sensitivity C-reactive protein increased progressively across tertiles of AA/LA. Graded increases in high-sensitivity C-reactive protein concentrations and CAD risk were related to the carriership of FADS haplotypes, including the alleles associated with a higher ratio. In populations following a Western diet, subjects carrying FADS haplotypes that are associated with higher desaturase activity may be prone to a proinflammatory response favoring atherosclerotic vascular damage. (Authors abstract)
The delta-5 (D5D) and delta-6 (D6D) desaturases are key enzymes of the PUFA pathway. D6D catalyzes the conversion from LA to alpha-linolenic acid (18:3n6), which is elongated to dihomo-gamma-linolenic acid (20:3n6), which is in turn desaturated to AA by D5D. D5D and D6D are also involved in the n-3 FA pathway, which favors the conversion of alpha-linolenic acid (ALA) into eicosapentaenoic acid (EPA). D5D and D6D are encoded by FADS1 and FADS2 genes. Several polymorphisms of the FADS1-FADS2 gene cluster are associated with serum phospholipid PUFA concentrations. Various FADS alleles were associated with high concentrations of AA and low concentrations of LA. Desaturase activity is assayed in vitro or in animals by measurement of the rate of conversion of radiolabeled precursor Fas to their respective products. In humans, the use of a product-to-precursor ratio (eg, AA/LA or EPA/ALA) as a surrogate measure to estimate desaturase activity is well established. The present study was aimed to establish whether differences in desaturase activity may affect the availability of eicosanoid precursor, which may result in inflammatory damage. Subjects with greater desaturase activity may have a greater risk of vascular disease. In this study, using the framework of an ongoing case-control study in an Italian population with or without angiographically confirmed coronary artery disease (CAD), an analysis of RBC membrane FA composition and genotyping of 13 single-nucleotide polymorphisms (SNPs) in the FADS region was conducted. The relationships between desaturase activity [estimated as the ratio of RBC-AA to RBC-LA (RBC-AA/RBC-LA)] to the highly sensitive inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and CAD risk were assessed. The first major result of the present study was that a greater proportion of the C20-chain FAs (both the n-3 and n-6 families) per unit of precursor essential FA (18:0) was present in RBC membranes and serum phospholipids of patients with CAD, suggesting that elongation and the D5D-D6D desaturation process are accelerated in these patients. The second significant result is that a continuous gradient of both higher hs-CRP and a greater risk of CAD was observed across AA/LA tertiles in the whole study population. Inappropriately high elongase or desaturase activity (as reflected by the higher ratio of 20:0 FA to precursor) may indicate susceptibility to inflammation. A third major result is that haplotypes of the FADS gene cluster, including variants associated with an elevated AA/LA ,were also related to both a higher hs-CRP concentration and greater risk of CAD. These observations all suggest that apparently distinct phenotypic features (elevated AA/LA, increase in hs-CRP, and greater CAD risk) link together functionally and with specific variants on the FADS gene complex, which in turn affected desaturase activity in this population. The authors hypothesized: 1) carriers of specific FADS haplotypes are constitutively able to form more AA from dietary LA; 2) greater AA availability at the membrane and cellular levels facilitates the synthesis of AA-derived inflammatory mediators such as leukotrienes and prostaglandins; 3) vascular inflammatory responses involved in the atherosclerotic process are greatly amplified by the cascade (with multiple effects) of AA-derived mediators; and 4) carriers of unfavourable haplotypes are at a greater risk of developing clinically significant CAD. Patients in the highest tertile of AA/LA had concentrations of hs-CRP nearly double those in patients in the lowest tertile. This difference suggests a difference of>20% in desaturase activity (the cutoff was 1.90 and 2.26 for the lowest and highest tertile, respectively) accounted for a 100% increase in the concentration of the inflammatory marker. The present results show that the proinflammatory, detrimental effects are predominant in a population assumed to be following a Western diet that is abundant in n-6 FAs and somewhat deficient in n-3 Fas. This study shows an association between greater desaturase activity, FADS genotypes, an increase in inflammatory markers, and a greater risk of CAD and support a role of PUFA metabolism in CVD. The data implies that a greater desaturase activity, in the context of a Western diet characterized by an unbalanced ratio of n-6 to n-3, may contribute to the atherosclerotic process by favoring inflammation. The speculate that therapeutic strategies aimed at reducing cell AA availability (eg, by n-3 PUFA supplementation) would be particularly advisable in patients with a genetically determined increase in desaturase activity. (Editors comments)
The delta-5 (D5D) and delta-6 (D6D) desaturases are key enzymes of the PUFA pathway. D6D catalyzes the conversion from LA to alpha-linolenic acid (18:3n6), which is elongated to dihomo-gamma-linolenic acid (20:3n6), which is in turn desaturated to AA by D5D. D5D and D6D are also involved in the n-3 FA pathway, which favors the conversion of alpha-linolenic acid (ALA) into eicosapentaenoic acid (EPA). D5D and D6D are encoded by FADS1 and FADS2 genes. Several polymorphisms of the FADS1-FADS2 gene cluster are associated with serum phospholipid PUFA concentrations. Various FADS alleles were associated with high concentrations of AA and low concentrations of LA. Desaturase activity is assayed in vitro or in animals by measurement of the rate of conversion of radiolabeled precursor Fas to their respective products. In humans, the use of a product-to-precursor ratio (eg, AA/LA or EPA/ALA) as a surrogate measure to estimate desaturase activity is well established. The present study was aimed to establish whether differences in desaturase activity may affect the availability of eicosanoid precursor, which may result in inflammatory damage. Subjects with greater desaturase activity may have a greater risk of vascular disease. In this study, using the framework of an ongoing case-control study in an Italian population with or without angiographically confirmed coronary artery disease (CAD), an analysis of RBC membrane FA composition and genotyping of 13 single-nucleotide polymorphisms (SNPs) in the FADS region was conducted. The relationships between desaturase activity [estimated as the ratio of RBC-AA to RBC-LA (RBC-AA/RBC-LA)] to the highly sensitive inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and CAD risk were assessed. The first major result of the present study was that a greater proportion of the C20-chain FAs (both the n-3 and n-6 families) per unit of precursor essential FA (18:0) was present in RBC membranes and serum phospholipids of patients with CAD, suggesting that elongation and the D5D-D6D desaturation process are accelerated in these patients. The second significant result is that a continuous gradient of both higher hs-CRP and a greater risk of CAD was observed across AA/LA tertiles in the whole study population. Inappropriately high elongase or desaturase activity (as reflected by the higher ratio of 20:0 FA to precursor) may indicate susceptibility to inflammation. A third major result is that haplotypes of the FADS gene cluster, including variants associated with an elevated AA/LA ,were also related to both a higher hs-CRP concentration and greater risk of CAD. These observations all suggest that apparently distinct phenotypic features (elevated AA/LA, increase in hs-CRP, and greater CAD risk) link together functionally and with specific variants on the FADS gene complex, which in turn affected desaturase activity in this population. The authors hypothesized: 1) carriers of specific FADS haplotypes are constitutively able to form more AA from dietary LA; 2) greater AA availability at the membrane and cellular levels facilitates the synthesis of AA-derived inflammatory mediators such as leukotrienes and prostaglandins; 3) vascular inflammatory responses involved in the atherosclerotic process are greatly amplified by the cascade (with multiple effects) of AA-derived mediators; and 4) carriers of unfavourable haplotypes are at a greater risk of developing clinically significant CAD. Patients in the highest tertile of AA/LA had concentrations of hs-CRP nearly double those in patients in the lowest tertile. This difference suggests a difference of>20% in desaturase activity (the cutoff was 1.90 and 2.26 for the lowest and highest tertile, respectively) accounted for a 100% increase in the concentration of the inflammatory marker. The present results show that the proinflammatory, detrimental effects are predominant in a population assumed to be following a Western diet that is abundant in n-6 FAs and somewhat deficient in n-3 Fas. This study shows an association between greater desaturase activity, FADS genotypes, an increase in inflammatory markers, and a greater risk of CAD and support a role of PUFA metabolism in CVD. The data implies that a greater desaturase activity, in the context of a Western diet characterized by an unbalanced ratio of n-6 to n-3, may contribute to the atherosclerotic process by favoring inflammation. The speculate that therapeutic strategies aimed at reducing cell AA availability (eg, by n-3 PUFA supplementation) would be particularly advisable in patients with a genetically determined increase in desaturase activity. (Editors comments)
