title: Novel obesity risk loci do not determine distribution of body fat depots: a whole-body MRI/MRS study.
abstract: A recent meta-analysis of genome-wide association studies has identified six new risk-loci for common obesity. We studied whether these risk loci influence the distribution of body fat depots. We genotyped 1,469 nondiabetic subjects for the single-nucleotide polymorphisms (SNPs) TMEM18 rs6548238, KCTD15 rs11084753, GNPDA2 rs10938397, SH2B1 rs7498665, MTCH2 rs10838738, and NEGR1 rs2815752. We assessed BMI, waist circumference, total body fat, and lean body mass (bioimpedance). All subjects underwent an oral glucose tolerance test (OGTT) for estimation of insulin sensitivity. In 332 subjects, we measured total adipose tissue (TAT), visceral adipose tissue (VAT), nonvisceral adipose tissue (NVAT), liver fat content, and intramyocellular lipids (IMCLs) using whole-body magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In the dominant inheritance model, the risk alleles of TMEM18 rs6548238 and MTCH2 rs10838738 were nominally associated with higher BMI (P = 0.04, both). The risk allele of TMEM18 rs6548238 was additionally associated with higher waist circumference and total body fat (P <or= 0.03), the risk allele of NEGR1 rs2815752 with higher waist circumference (P = 0.05) and unexpectedly with lower BMI (P = 0.01). In the MR cohort, we found an association of the risk allele of SH2B1 rs7498665 with higher VAT (P = 0.009) and of GNPDA2 rs10938397 with increased IMCLs (P = 0.03). After Bonferroni correction for multiple comparisons (corrected alpha-level: P = 0.0085), none of the SNPs was significantly associated with measures of adiposity or body fat distribution (all P > 0.009, dominant inheritance model). Therefore, our results suggest that these new obesity SNPs, despite their influence on BMI, are neither associated with a metabolically unfavorable nor with a favorable body composition.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Haupt
authors.forename: Claus
authors.initials: C
authors.lastname: Thamer
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D050218:Body Fat Distribution; D015992:Body Mass Index; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D058851:GPI-Linked Proteins; D056426:Genetic Loci / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics; D012307:Risk Factors; D051598:Whole Body Imaging / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; C552182:KCTD15 protein, human; C502207:MTCH2 protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C485559:NEGR1 protein, human; D015221:Potassium Channels; C518910:SH2B1 protein, human; C530715:TMEM18 protein, human