title: A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity.
abstract: Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single-nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight "tag-SNPs" were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 x 10(-9)) and in adults (P = 8 x 10(-5)). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist-to-hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.
authors.affiliation: Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Jerome
authors.initials: J
authors.lastname: Delplanque
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: Cecile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Jean
authors.initials: J
authors.lastname: Tichet
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Walley
mesh_terms: D000328:Adult; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics* / Q000502:physiology*; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
chemical_list: D054409:Nicotinamide Phosphoribosyltransferase