title: SIRT1 genetic variation and mortality in type 2 diabetes: interaction with smoking and dietary niacin.
abstract: SIRT1 protects cells against oxidative stress and aging. Its activity may be modulated by dietary niacin (vitamin B3) intake. We studied the association of SIRT1 genetic variation with mortality in subjects with increased oxidative stress (type 2 diabetes and smokers) in relation to dietary niacin. In 4573 participants from the Rotterdam Study, including 413 subjects with prevalent and 378 with incident type 2 diabetes, three SIRT1 tagging SNPs were genotyped and all-cause mortality was studied (average follow-up 12 years). We found no association between SIRT1 variation and mortality in the total population or in smokers. In subjects with prevalent type 2 diabetes, homozygous carriers of the most common SIRT1 haplotype, 1, had 1.5 times (95%CI 1.1-2.1) increased mortality risk compared to noncarriers. This risk further increased among smokers and those with low niacin intake. In the lowest tertile of niacin intake, mortality risk was increased 2.3 (95%CI 1.1-4.9) and 5.7 (95%CI 2.5-13.1) times for heterozygous and homozygous carriers of haplotype 1. Subjects with incident diabetes showed similar findings but only when they smoked. We conclude that in subjects with type 2 diabetes, SIRT1 genetic variation influences survival in interaction with dietary niacin and smoking. Correction of niacin deficiency and SIRT1 modulators may prolong the life span of patients with diabetes.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. m.c.zillikens@erasmusmc.nl
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015331:Cohort Studies; D019610:Cytoprotection; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D019587:Dietary Supplements / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000378:metabolism*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects; D016019:Survival Analysis
chemical_list: D009525:Niacin; C447939:SIRT1 protein, human; D056564:Sirtuin 1