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Articles by N Wareham
Total Records ( 2 ) for N Wareham
  B Hoeft , J Linseisen , L Beckmann , K Muller Decker , F Canzian , A Husing , R Kaaks , U Vogel , M. U Jakobsen , K Overvad , R. D Hansen , S Knuppel , H Boeing , A Trichopoulou , Y Koumantaki , D Trichopoulos , F Berrino , D Palli , S Panico , R Tumino , H.B Bueno de Mesquita , F. J.B van Duijnhoven , C. H van Gils , P. H Peeters , V Dumeaux , E Lund , J. M Huerta Castano , X Munoz , L Rodriguez , A Barricarte , J Manjer , K Jirstrom , B Van Guelpen , G Hallmans , E. A Spencer , F. L Crowe , K. T Khaw , N Wareham , S Morois , M. C Boutron Ruault , F Clavel Chapelon , V Chajes , M Jenab , P Boffetta , P Vineis , T Mouw , T Norat , E Riboli and A. Nieters
 

Colorectal cancer (CRC) is the third most common malignant tumor and the fourth leading cause of cancer death worldwide. The crucial role of fatty acids for a number of important biological processes suggests a more in-depth analysis of inter-individual differences in fatty acid metabolizing genes as contributing factor to colon carcinogenesis. We examined the association between genetic variability in 43 fatty acid metabolism-related genes and colorectal risk in 1225 CRC cases and 2032 controls participating in the European Prospective Investigation into Cancer and Nutrition study. Three hundred and ninety two single-nucleotide polymorphisms were selected using pairwise tagging with an r2 cutoff of 0.8 and a minor allele frequency of >5%. Conditional logistic regression models were used to estimate odds ratios and corresponding 95% confidence intervals. Haplotype analysis was performed using a generalized linear model framework. On the genotype level, hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), phospholipase A2 group VI (PLA2G6) and transient receptor potential vanilloid 3 were associated with higher risk for CRC, whereas prostaglandin E receptor 2 (PTGER2) was associated with lower CRC risk. A significant inverse association (P < 0.006) was found for PTGER2 GGG haplotype, whereas HPGD AGGAG and PLA2G3 CT haplotypes were significantly (P < 0.001 and P = 0.003, respectively) associated with higher risk of CRC. Based on these data, we present for the first time the association of HPGD variants with CRC risk. Our results support the key role of prostanoid signaling in colon carcinogenesis and suggest a relevance of genetic variation in fatty acid metabolism-related genes and CRC risk.

  R Sofat , A. D Hingorani , L Smeeth , S. E Humphries , P. J Talmud , J Cooper , T Shah , M. S Sandhu , S. L Ricketts , S. M Boekholdt , N Wareham , K. T Khaw , M Kumari , M Kivimaki , M Marmot , F. W Asselbergs , P van der Harst , R. P.F Dullaart , G Navis , D. J van Veldhuisen , W. H Van Gilst , J. F Thompson , P McCaskie , L. J Palmer , M Arca , F Quagliarini , C Gaudio , F Cambien , V Nicaud , O Poirer , V Gudnason , A Isaacs , J. C.M Witteman , C. M van Duijn , M Pencina , R. S Vasan , R. B D'Agostino , J Ordovas , T. Y Li , S Kakko , H Kauma , M. J Savolainen , Y. A Kesaniemi , A Sandhofer , B Paulweber , J. V Sorli , A Goto , S Yokoyama , K Okumura , B. D Horne , C Packard , D Freeman , I Ford , N Sattar , V McCormack , D. A Lawlor , S Ebrahim , G. D Smith , J. J.P Kastelein , J Deanfield and J. P. Casas
 

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.

Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.

Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

 
 
 
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