A preliminary candidate genotype-intermediate phenotype study of satiation and gastric motor function in obesity

Abstract

Stomach motility contributes significantly to fullness sensation while eating and cessation of food intake in humans. Genes controlling adrenergic and serotonergic mechanisms (ADRA2A, GNB3, and SLC6A4) affect gastric emptying (GE), volume (GV), and satiation. Fat mass and obesity-associated gene (FTO) is linked with satiety. Our aim was to examine the association of these candidate genes with stomach functions that signal postprandial fullness: GE, GV, and maximum tolerated volume (MTV). These biomarkers constitute a component of the intermediate phenotype of satiation. A total of 62 overweight or obese participants underwent genotyping of the candidate genes, and validated measurements of GE of solids and liquids by scintigraphy, fasting and postprandial change in GV by SPECT (single photon emission computed tomography), and MTV by nutrient drink test. These markers of satiation were compared for 38 genetic variants in ADRA2A, ADR2C, ADRB3, uncoupling protein (UCP)-2 and -3, GNB3, FTO, and SLC6A4 using a recessive model of inheritance. ADRA2A, ADR2C, UCP-3, GNB3, and FTO loci were significantly associated with the intermediate phenotype markers of satiation: ADR2C (Ins-Del322_325) with accelerated GE; GNB3 (rs1047776) with delayed GE; ADRA2A (rs491589 and rs553668) and GNB3 (rs2269355, rs10849527, and rs3759348) with decreased postprandial GV; ADRA2A (rs3750625) and GNB3 (rs4963517 and rs1129649) with increased postprandial GV; UCP-3 (rs1685356) with increased MTV, and FTO (rs9939609) decreased MTV. Genetic susceptibility to postprandial satiation can be identified through intermediate phenotype markers. With independent validation, these markers may guide patient selection of weight-loss therapies directed at gastric motor functions.

Figure 1

The proposed conceptual pathogenetic model includes the disease of obesity as the clinical endpoint, satiation as the surrogate endpoint, and gastric motor functions and gastrointestinal hormones as biomarkers or endophenotype, subject to modulation by the genotype.

Figure 2

Study flow chart. Note that the age, gender and BMI distributions of the 62 people who underwent intermediate phenotyping were similar to those of the entire cohort of people from southeastern Minnesota, USA.

Figure 3

Haploview analysis of haploblocks within the candidate genes studied. Two haploblocks were identified within GNB3 (A), three within the UCP2/UCP3 locus (B) and one within ADRA2A (C). Population frequencies are shown next to each haplotype and lines show the most common crossings from one block to the next, with thicker lines showing more common crossings than thinner lines. Shown beneath the crossing lines is multi-locus D’.