Associations of the Melanocortin 3 Receptor C17A + G241A haplotype with body composition and inflammation in African American adults

Recent studies examining the genetic underpinnings of obesity have suggested that the melanocortin 3 receptor (MC3R) plays a role in body composition and nutrient partitioning (Chen et al., 2000, Demidowich et al., 2017). In mice, inactivating Mc3r causes increased feeding efficiency leading to obesity with increased fat mass, but with reduced lean mass (Chen et al., 2000, Kumar et al., 2009, Butler et al., 2017, Renquist et al., 2011). The common minor human MC3R C17A+G241A haplotype, which leads to 2 amino acid substitutions Thr6Lys and Val81Ile in the protein translated from the first start site of the human gene, leads to a partially inactive protein transcript (Feng et al., 2005). In a large pediatric cohort, individuals homozygous for the MC3R C17A+G241A haplotype were reported to have greater BMI, body fat, plasma leptin, and insulin concentrations, with reduced lean mass when compared to those who were heterozygous (Het) for the C17A + G241A haplotype and homozygous for the wild-type MC3R gene (WT) (Feng et al., 2005). The greater adiposity and reduced signal transduction associated with homozygosity for the C17A+G241A haplotype has since been replicated in other pediatric cohorts (Savastano et al., 2009, Lee et al., 2007, Aris et al., 2015). Supportive data for the effects of this haplotype have also been reported in mice. When the murine Mc3r was replaced with the human MC3R C17A+G241A haplotype, homozygous knockin mice also displayed increased feeding efficiency, greater adiposity, and reduced lean mass (Lee et al., 2016). Among adult human cohorts, however, the MC3R C17A+G241A haplotype has not been associated with greater BMI (Li et al., 2000, Hani et al., 2001, Wong et al., 2002, Rutanen et al., 2007, Calton et al., 2009, Matsuoka et al., 2007) and scant data exist for its effects on other anthropometric or metabolic parameters (Hani et al., 2001, Rutanen et al., 2007). A major limitation of most of these prior studies is the low number of homozygous participants (Calton et al., 2009, Li et al., 2000, Hani et al., 2001, Wong et al., 2002, Rutanen et al., 2007); consequently, many prior conclusions were based largely on the assumption that heterozygotes and homozygotes are phenotypically identical or there would be additive effects from each minor allele/haplotype. Although labelled as a common variant, the MC3R C17A+G241A haplotype is relatively rare in most races and ethnicities, with an estimated prevalence of homozygous individuals between 0.4–3.5% (Obregon et al., 2010, Lee et al., 2007, Rutanen et al., 2007, Hani et al., 2001). Individuals of predominately African ancestry are the exception, as over half carry at least one copy of the haplotype, and 12–16% are homozygous for C17A+G241A (Li et al., 2000, Feng et al., 2005, Savastano et al., 2009). As such individuals have been underrepresented in most adult cohort studies examining MC3R polymorphisms, it remains unclear if homozygous individuals have a different anthropometric and metabolic phenotype than Het or WT adults. To our knowledge, this is the first study of a large cohort of adults that has assessed the association of the MC3R C17A+G241A haplotype with body composition data such as fat mass and lean mass. Our primary hypothesis was that homozygosity for the MC3R C17A+G241A haplotype would be associated with greater BMI and fat mass in African American adults. We additionally hypothesized that this increase in adiposity would be associated with greater insulin resistance and inflammation in homozygous individuals as compared to Het and WT.