title: Effect of genetic variation in the human fatty acid synthase gene (FASN) on obesity and fat depot-specific mRNA expression.
abstract: Inhibition of fatty acid synthase (FASN) induces a rapid decline in fat stores in mice, suggesting a role for this enzyme in energy homeostasis. To investigate the potential role of FASN in the pathophysiology of human obesity, the FASN gene was sequenced in 48 German whites. Thirty-five single-nucleotide polymorphisms (SNPs) were identified. Eight SNPs representative for their linkage disequilibrium groups and the Val1483Ile (rs2228305) substitution were genotyped for subsequent association analyses in 1,311 adults from Germany. Further, the tagging SNPs were genotyped also in German childhood cohorts (738 schoolchildren, 205 obese children). Effects of genetic variation on FASN mRNA expression in visceral and subcutaneous adipose tissue from a subgroup of 172 subjects were analyzed. Several polymorphisms in the FASN (rs62078748, rs2229422, rs2229425, and rs17848939) were nominally associated with obesity in case-control studies including 446 obese subjects (BMI >or=30 kg/m(2)) and 389 lean controls (BMI <or=25 kg/m(2)) (adjusted P < 0.05). The strongest significant effect was found for rs2229422 (P = 1.3 x 10(-5) adjusted for age, sex, type 2 diabetes status), which was supported by associations with BMI, waist-to-hip ratio (WHR), fasting plasma insulin and glucose infusion rate (adjusted P < 0.05). Subjects with the Val1483Ile substitution appeared to be protected against obesity. In addition, rs17848939 was nominally significantly associated with the ratio of visceral/subcutaneous FASN mRNA expression (adjusted P = 0.04). No effect of genetic variation in FASN on obesity was found in children. In conclusion, our data indicate a role of FASN genetic variation in susceptibility to obesity in adults.
authors.affiliation: Interdisciplinary Centre for Clinical Research, Leipzig, Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Schleinitz
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.forename: Janin
authors.initials: J
authors.lastname: Berndt
authors.forename: Marlene
authors.initials: M
authors.lastname: Reichenbächer
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Karen
authors.initials: K
authors.lastname: Ruschke
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.forename: Kerstin
authors.initials: K
authors.lastname: Dietrich
authors.forename: Beate
authors.initials: B
authors.lastname: Enigk
authors.forename: Matthias
authors.initials: M
authors.lastname: Filz
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schön
authors.forename: Jost
authors.initials: J
authors.lastname: Jenkner
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D064429:Fatty Acid Synthases