A +2138InsCAGACC Polymorphism of the Melanocortin Receptor 3 Gene is Associated in Human with Fat Level and Partitioning in Interaction with Body Corpulence

Abstract

Background: The melanocortin system includes five receptors (MC1R to MC5R), and mouse and human MC4R has been shown to be involved in the regulation of feeding, and mouse MC3R in body composition. To verify a possible similar effect of MC3R in humans, we analyzed one insertion and one single nucleotide polymorphism by restriction fragment length polymorphisms (RFLP), and a microsatellite (D20S32e) in relation to body composition and glucose metabolism. Methods: Eight hundred twelve subjects of the Québec Family Study (QFS) cohort were analyzed for body composition, food intake, and energy metabolism phenotypes. Southern Blot with the complete MC3R cDNA was used to detect a new ϩ2138InsCAGACC variant by Pst1 restriction. PCR-RFLP with BsaJ1 was used to type amino acid polymorphism V81I arising from a G241A nucleotide change. PCR and automatic DNA sequencers were used for the analysis of the TG dinucleotide repeat D20S32e located between Ϫ1933/Ϫ1892 of MC3R. In a covariance analysis among genotypes, phenotypes were adjusted for age and sex as covariates. Food intake and energy metabolism phenotypes were also adjusted for body mass index (BMI), and leptin and abdominal fat, as assessed by a computed tomography scan, for fatness using six skinfold thicknesses.

Common melanocortin-3 receptor variants are not associated with obesity, although rs3746619 does influence weight in obese individuals

“…Boucher et al reported the association of the ?2138InsCAGACC polymorphism, a 6 base pair insertion located 2138 base pairs Nominal P values are given for Pearson chi square analysis downstream of the MC3R start codon, and body composition related phenotypes, while again no association between V81I (rs3827103) and body composition was found. However, as the obesity-related variables BMI and body weight were not analyzed, it is difficult to compare their study with our results [16]. Although Schälin-Jantti et al also detected the rs6127698 (-373G[T) variant 5 0 of the MC3R gene, they did not genotype this SNP in their entire population, which makes comparison with our study impossible.…”

“…The MC3R gene, which maps to 20q13.2-q13.3, is therefore an excellent candidate gene for obesity research. Several research groups attempted to investigate association of variants in MC3R with obesity, but limited number of study subjects, ethnically diverse study populations and a variety of genotyping techniques led to contradictory results [10,[15][16][17][18]. In this study, we covered the entire variation in a 2 kb region around the MC3R gene.…”

Melanocortin-4 receptor gene and physical activity in the Québec Family Study

“…The size of the fragments was estimated using lDNA digested with EcoR1 and HindIII as standards. The PCR conditions for typing restriction fragment polymorphisms in MC4R (MC4R-C-2745T (dbSNP database: rs7242169), MC4R-Val103Ile (dbSNP database: 2229616)) 21,22 and MC3R (MC3R-Pst1) 23 have been described elsewhere. To identify the exact location of the MC4R-C-2745T polymorphism, we screened the MC4R coding region along with 3500 bp of the 5 0 flanking region in 16 subjects with known genotype.…”

Haplotypes in the phospholipid transfer protein gene are associated with obesity-related phenotypes: the Québec Family Study

“…43 The melanocortin 3 receptor and the adenosine deaminase, located approximately 10.3 and 1.3 Mb from the PLTP gene, respectively, have been significantly associated with obesity-related phenotypes. 44,45 The agouti signaling protein (ASIP) is also located within the relevant region of human chromosome 20. The ASIP is the human ortholog of the mouse agouti gene, which is a single-gene mutation model of obesity.…”