title: Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations.
abstract: We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in the genetic component of obesity.
authors.affiliation: Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia; Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Cláudia B
authors.initials: CB
authors.lastname: Angeli
authors.forename: Lilian
authors.initials: L
authors.lastname: Kimura
authors.forename: Maria T
authors.initials: MT
authors.lastname: Auricchio
authors.forename: João P
authors.initials: JP
authors.lastname: Vicente
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Mattevi
authors.forename: Verônica M
authors.initials: VM
authors.lastname: Zembrzuski
authors.forename: Mara H
authors.initials: MH
authors.lastname: Hutz
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Tiago V
authors.initials: TV
authors.lastname: Pereira
authors.forename: Regina C
authors.initials: RC
authors.lastname: Mingroni-Netto
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001837:Body Weights and Measures; D001938:Brazil; D002149:Energy Intake; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007199:Indians, South American; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D058011:Multifactor Dimensionality Reduction; D058885:Multilocus Sequence Typing; D009765:Obesity / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology*; D050177:Overweight / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D054411:Receptors, Leptin / Q000235:genetics*; D012044:Regression Analysis; D012727:Sex Characteristics; D044465:White People
chemical_list: C553443:ADRB2 protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C515448:LEPR protein, human; D008565:Membrane Proteins; D047495:PPAR gamma; D018343:Receptors, Adrenergic, beta-2; D054411:Receptors, Leptin