Endocrine Abstracts

Since the discovery of melanocortin 4 receptor (MC4R) as an important regulator of food intake it has been recognised as one of the major monogenic factors of obesity. However the mutations identified are usually very rare, not found in control subjects from the background population and can explain only a minor part of heritability (2–3%). Here we explore the role of non-synonymous mutations identified by MC4R sequencing in cohort of 380 severely obese individuals (BMI 39.3–67.9 kg/m²) selected from Genome Database of Latvian Population comparing to 380 controls with normal BMI (18.5–24.9 kg/m²). We also investigated the role of SNP rs17782313 located upstream of the MC4R that have been previously identified from GWAS in the same case-control samples. The genetic association revealed no correlation between rs17782313 and obesity or related traits. The sequencing of the MC4R coding region revealed four non-synonymous substitutions: V103I, S127L, V166I and I251L. Two subjects had double V103I and S127L mutations. Noticeably, V166I is a novel substitution that has not been reported before. S127L, V166I and double V103I/S127L mutant receptors had significantly decreased expression on cell surface compared to wt MC4R. Intriguingly, despite the low abundance in cell membrane the newly discovered V166I variant demonstrated higher cAMP response upon αMSH activation than wt receptor, while S127L mutation did not display any significant cAMP response. In opposite to MC4R we found that three SNPs in another obesity related fat mass and obesity-associated protein gene locus (FTO) are associated with obesity in our study group (the lowest P value=0.019). In conclusion, we show that non-synonymous mutations can only explain 1% of morbid obesity. Thus, neither the common SNP nor rare mutations are the major genetic cause of obesity in general population in opposite to FTO gene.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.