title: High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery.
abstract: Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI.
authors.affiliation: Geisinger Obesity Research Institute, Geisinger Clinic, Danville, Pennsylvania, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.forename: G Craig
authors.initials: GC
authors.lastname: Wood
authors.forename: Xin
authors.initials: X
authors.lastname: Chu
authors.forename: Robert
authors.initials: R
authors.lastname: Erdman
authors.forename: Christina H
authors.initials: CH
authors.lastname: Manney
authors.forename: Peter N
authors.initials: PN
authors.lastname: Benotti
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Petrick
authors.forename: William E
authors.initials: WE
authors.lastname: Strodel
authors.forename: Uyenlinh L
authors.initials: UL
authors.lastname: Mirshahi
authors.forename: Tooraj
authors.initials: T
authors.lastname: Mirshahi
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
mesh_terms: D000273:Adipose Tissue; D000328:Adult; D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D005260:Female; D015390:Gastric Bypass; D005838:Genotype; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000601:surgery; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D012044:Regression Analysis; D015431:Weight Loss / Q000235:genetics*
chemical_list: C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; C403532:PCSK1N protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human