This study investigated whether the combined effects of FTO and MC4R increase the risk of obesity in children and adolescents living in Northwest China.
Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the minority populations in the United States.
Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity.
MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated.
We showed that MC4Rrs17782313 and FTO rs9939609 were positively associated with zBMI, with weak and very weak effects, respectively, suggesting a very scarce contribution to childhood obesity.
The combined presence of three or more high-risk alleles of both the FTO and MC4R genes confers a 4-fold higher risk for obesity in children and adolescents of Greek origin, although these risk alleles have no impact on the metabolic alterations observed in these obese children and adolescents.
Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10(-8)) with BMI at 8 years and/or change over time.
The case emphasizes both the role of the MC4R gene in obesity as well as the importance of looking for chromosomal microdeletions/duplications as a cause of obesity in children with minor anomalies or developmental delay.
MC4R polymorphism rs17782313 may contribute to childhood obesity, affecting enjoyment of food, satiety responsiveness, and possibly eating in the absence of hunger.
Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups.
In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.
We examined serum alpha-MSH in 52 otherwise healthy children with childhood obesity (Ob; mean age, 11 years; 32 girls/20 boys), 27 normal-weight children of same age, 7 additional obese patients with reduced melanocortin-4 receptor function (MC4Rmut), and 22 patients with craniopharyngioma (CP).
The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%; CI(95), 0.9-4.8) and in patients with a later onset of the disease (2.35%; CI(95), 0.9-3.8).
This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.