Please cite this article in press as: Fava C, et al. The functional variant V433M of the CYP4F2 and the metabolic syndrome in Swedes. Prostaglandins Other Lipid Mediat (2012), http://dx.doi.org/10.1016/j.prostaglandins.2012.03.001 ARTICLE IN PRESS G Model PRO 5983 1–6 Prostaglandins & other Lipid Mediators xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Prostaglandins and Other Lipid Mediators The functional variant V433M of the CYP4F2 and the metabolic syndrome in Swedes 1 2 Cristiano Fava a,b,∗ , Martina Montagnana a,c,1 , Elisa Danese a,b,c,1 , Marketa Sjögren a , Peter Almgren a , Q1 Gian Cesare Guidi c , Bo Hedblad a , Gunnar Engström a , Pietro Minuz b , Olle Melander a 3 4 a Department of Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden 5 b Department of Medicine, Italy 6 c Department of Life and Reproduction Sciences, University Hospital of Verona, Italy 7 8 a r t i c l e i n f o 9 10 Article history: 11 Received 10 January 2012 12 Received in revised form 20 February 2012 13 Accepted 22 March 2012 14 Available online xxx 15 Keywords: 16 Cytochrome P450 17 20-HETE 18 Genetics 19 Metabolic syndrome 20 CYP4F2 21 Triglycerides 22 a b s t r a c t Background and aim: The genetic basis of Metabolic syndrome (MetS) is largely unknown but a link with salt sensitivity is recognized. The cytochrome P450 isoform 4F2 (CYP4F2) is involved in renal production of 20-hydroxyeicosatethraenoic acid (20-HETE), a natriuretic substance associated with salt sensitivity. The same enzyme is implicated in -hydroxylation of very long and medium chain fatty acids in the liver suggesting its possible influence on gluco-metabolic components of MetS. The aim of the present study was to evaluate the effect of CYP4F2 V433M, a functional polymorphism previously associated with hypertension via renal salt reabsorption, on the individual components of MetS and MetS itself. Methods: The polymorphism was genotyped in the cardiovascular cohort of the Malmö Diet and Cancer (MDC-CVA) study and successively in the Malmö Preventive Project (MPP) cohort. Different definitions of the MetS were applied. Results: In the MDC-CVA, male, but not female, CYP4F2 M433 carriers had significantly higher levels of waist, triglycerides, BP and a composite sum of MetS phenotypes (MetS score) beside lower HDL- cholesterol respect to V-homozygotes. MetS, as defined in the ATPIII and the AHA/NHLBI definitions, was more prevalent in M-carriers with respect to V-homozygotes. In the MPP cohort, significant association was detectable only for triglycerides at baseline and for Diastolic BP at reinvestigation in male M-carriers. Conclusion: The initial positive association of the CYP4F2 V433M polymorphism with components of MetS and MetS itself, found in MDC-CVA, was partially denied in another large cohort. The first association either could be due to a false positive result or alternatively, different genetic background or population stratification could have hidden the effect of the polymorphism in the replication cohort. © 2012 Published by Elsevier Inc. 1. Introduction 23 20-HETE is a vasoconstrictor and natriuretic substance, derived 24 by metabolism of arachidonic acid by cytochrome p450 (CYP). 25 Since the 1980s its role in hypertension development in different 26 rats and mice strains has been established [1] and more recently 27 has been proposed also in humans [2]. CYP4F2 is the enzyme 28 responsible for most of 20-HETE production at renal level whereas 29 a common, functional polymorphism, CYP4F2 V433M, was asso- 30 ciated with hypertension development and other cardiovascular 31 outcomes in different studies [3–5]. The functional significance of 32 ∗ Corresponding author at: Department of Medicine, Division of Internal Medicine C, Piazzale LA Scuro 10, 37134 Verona, Italy. Tel.: +39 45 8124414; fax: +39 45 8027465. E-mail addresses: cristiano.fava@med.lu.se, cristiano.fava@univr.it (C. Fava). 1 Contributed equally to this work. these mutations on the ability of the CYP4F2 enzyme to metabo- 33 lize arachidonic acid was previously demonstrated in recombinant 34 baculoviruses, where the presence of the M433 allele, decreased 35 20-HETE production to more than 50% of control [6]. 36 Other authors found that a haplotype construct of the CYP4F2 is 37 involved in hypertension development and cardiovascular disease 38 [7,8]. 39 A link between salt sensitivity and other gluco-metabolic traits 40 has long been recognized and is partially demonstrated by the clus- 41 tering of all these features in the metabolic syndrome (MetS). The 42 genetic basis of this clustering is largely unknown and most of the 43 studies converge about the relation between insulin resistance and 44 salt sensitivity [9]. 45 Since the CYP4F2 is expressed also at liver level and is implicated 46 in -hydroxylation of very long and medium chain fatty acids, a 47 process that is increased in different metabolic diseases and differ- 48 ently influenced by starvation, excess lipid and alcohol intake [10], 49 we were interested in exploring a possible role of the functional 50 1098-8823/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.prostaglandins.2012.03.001