Melanocortin-4 Receptor Gene Variants Research Articles

Association of leptin–melanocortin gene polymorphisms with the risk of obesity in northwest Indian population

BackgroundObesity, a multifaceted endocrine issue, is adversely affecting all age groups and is posing a significant public health challenge. The genetic polymorphisms of the melanocortin 4 receptor (MC4R) and leptin (LEP) genes likely contribute to the development of obesity. The present study aimed to explore the effects of MC4R and LEP gene polymorphisms on obesity among the northwest Indian population.MethodsThe present study was conducted among 333 obese cases and 338 non-obese controls (aged 18–50 years). All subjects underwent measurements for anthropometric, physiometric, as well as biochemical parameters. Genotyping for MC4R and LEP gene variants was performed using the polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. However, 10% of the samples for each variant were confirmed using the Sanger sequencing method.ResultsThe polymorphisms of leptin–melanocortin pathway genes (MC4R-LEP) were found to be significantly associated with various obesity-related parameters like waist circumference: p = 0.017, waist-to-height ratio: p = 0.009, total cholesterol: p = 0.0001 and triglycerides: p = 0.0001. Both the LEP gene variants rs2167270 and rs7799039 conferred 2.4- and 2.2-fold risk toward obesity under the recessive genetic model [OR (95% CI) 2.42 (1.44–4.07), p = 0.001; OR (95% CI) 2.26 (1.41–3.60), p = 0.0001, respectively]. All four polymorphisms of the MC4R and LEP genes demonstrated a strong interaction of 82.1% with the lifestyle factor (p = 0.001). The haplotype combinations A–A for rs571312 and rs12970134 conferred twofold risk [OR (95% CI) 2.61 (1.10–6.20), p = 0.028]. However, the combination A–G for rs2167270 and rs7799039 predicted sixfold risk [OR (95% CI) 6.02 (3.39–10.68), p = 0.0001] toward the obesity development in this population.ConclusionOur study revealed a connection between MC4R (rs571312, rs12970134) and LEP (rs2167270, rs7799039) gene variants with obesity, highlighting their prominent role in assessing the risk of obesity among the northwest Indian population.

Identification of MC4R and VCP Genetic Variants in Two Pakistani Families Showing Symptoms of Diabetes, Hyperphagia, Seizures, and Obesity

Variations in the melanocortin 4 receptor (MC4R) are most commonly associated with serious early-stage monogenic obesity. The valosin-containing protein (VCP) gene, also referred to as p97, produces the ubiquitous, crucial, and multifunctional protein VCP, involved in a wide range of cellular processes, including endoplasmic reticulum-associated degradation (ERAD), degradation of lysosomal protein, and degradation of the proteasome-mediated protein. In the present study, we investigated two Pakistani families enrolled from Sibi, Pakistan, for variation in MC4R and VCP genes. Clinical symptoms involved obesity, hyperphagia, and diabetes in Family 1. Obesity with autism spectrum disorder (ASD), hyperphagia, diabetes, seizure, gastrointestinal, and sleep disorders were found in Family 2. Additionally, blood samples were collected and DNA extraction was performed. Subsequent molecular analysis was conducted to identify mutations. Clinical and genetic results were analyzed, and the segregation of MC4R and VCP gene variants in the families helped to make the diagnosis of the disease. For the identification of variations, we conducted whole exome sequencing (WES) and confirmed the findings through target sequencing. We divulged two previously reported heterozygous missense variations. Notably, WES revealed variants (c.307G>A, rs2229616) in the MC4R and (c.1360-35A>G, rs2258240) in the VCP genes in both families separately. The chromatogram illustrated homozygous unaffected siblings and parents, as well as heterozygous individuals with the disease. Both families segregate with the obesity disorder in an autosomal dominant manner. In Family 1, the change from ‘G’ to ‘A’ in the MC4R gene depicts the mutant allele ‘A’ segregating dominantly from one generation to another. Similarly, the change from ‘A’ to ‘G’ in the VCP gene illustrates the mutant allele ‘G’ segregating dominantly in Family 2.

Long-Term Weight Outcome After Bariatric Surgery in Patients with Melanocortin-4 Receptor Gene Variants: a Case–Control Study of 105 Patients

Pathogenic heterozygous MC4R variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after bariatric surgery in a few patients with MC4R variants, but lack of longer-term data prevents evidence-based clinical decision-making. Bariatric surgery patients with heterozygous (likely) pathogenic MC4R variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without MC4R mutations). Weight loss and regain outcomes up to 6years of follow-up were compared. At 60months of follow-up after RYGB, cases with MC4R variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (p = 0.062). Among patients receiving SG, the cases with MC4R variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (p = 0.010). This multicenter study reveals inferior mid-term weight outcomes of cases with MC4R variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with MC4R variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management.

Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R).

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics.

Melanocortin 4 receptor gene plays an important role in food intake, energy balance, and weight control. The autosomal dominantly inherited MC4R variants cause obesity by causing hyperphagia and decreased sense of satiety. Homozygous variants are rarely reported, and they cause earlier/severe obesity. Our objective is to determine the MC4R gene variant frequency in children and adolescents with familial early-onset obesity. One hundred thirty-nine children and adolescents (57 girls/82 boys) whose weight increase started before the age of 5 years and who had early-onset obesity in at least one of their first-degree relatives were included in the study. Obesity is defined as body mass index (BMI) of ≥ 95th percentile, and as extreme obesity is defined if the BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m2. Children having genetic syndromes associated with obesity and mental retardation or taking drugs that promote changes in eating behavior or weight were excluded from the study. Coding region of the MC4R gene was sequenced by using the Illumina MiSeq Next Generation Sequencing System. The mean age of the patients was 7.3 ± 3.7 years, and the mean BMI SDS was 3.7 ± 0.7. While 118 patients (85%) were prepubertal, 21 patients (15%) were pubertal. Seven different variants were identified in 12 patients by giving a variant detection rate of 8.6%, of these five were previously identified missense variants p.N274S, p.S136F, p.V166I, p.R165W, and p.I291SfsX10. One homozygous variant p.I291SfsX10 (c.870delG) was detected in a severely obese 2-year-old boy, and other variants were heterozygous. Two novel variants were found: p.M200del and p.S188L. By using the in silico analysis software, these novel variants were predicted to be disease causing.Conclusion: MC4R gene variants are quite common in childhood obesity in Turkish population. Screening the variants in MC4R gene is necessary in patients with severe childhood-onset obesity. In such patients, comorbidities of obesity can be seen from early years.What is known• The frequency of MC4R mutations in obese patients was approximately 0–6.3%.What is new• In obese Turkish pediatric population, unlike other European countries, MC4R gene variants are quite common as we found a variant rate of 8.6%• We believe it is necessary to screen the variants in MC4R gene in patients with severe childhood-onset obesity and who had early-onset obesity in at least one of their first-degree relatives in Turkish population.

Association of the melanocortin 4 receptor gene rs17782313 polymorphism with rewarding value of food and eating behavior in Chilean children.

Studies conducted in monozygotic and dizygotic twins have established a strong genetic component in eating behavior. Rare mutations and common variants of the melanocortin 4 receptor (MC4R) gene have been linked to obesity and eating behavior scores. However, few studies have assessed common variants in MC4R gene with the rewarding value of food in children. The objective of the study was to evaluate the association between the MC4R rs17782313 polymorphism with homeostatic and non-homeostatic eating behavior patterns in Chileans children. This is a cross-sectional study in 258 Chilean children (44% female, 8-14years old) showing a wide variation in BMI. Anthropometric measurements (weight, height, Z-score of BMI and waist circumference) were performed by standard procedures. Eating behavior was assessed using the Eating in Absence of Hunger Questionnaire (EAHQ), the Child Eating Behavior Questionnaire (CEBQ), the Three-Factor Eating Questionnaire (TFEQ), and the Food Reinforcement Value Questionnaire (FRVQ). Genotype of the rs17782313 nearby MC4R was determined by a Taqman assay. Association of the rs17782313 C allele with eating behavior was assessed using non-parametric tests. We found that children carrying the CC genotype have higher scores of food responsiveness (p value=0.02). In obese girls, carriers of the C allele showed lower scores of satiety responsiveness (p value=0.02) and higher scores of uncontrolled eating (p value=0.01). Obese boys carrying the C allele showed lower rewarding value of food in relation to non-carriers. The rs17782313 C allele is associated with eating behavior traits that may predispose obese children to increased energy intake and obesity.

Melanocortin-4 receptor gene variants are not associated with binge-eating behavior in nonobese patients with eating disorders.

We aimed to determine whether variability in the melanocortin-4 receptor (MC4R) gene, predisposing to hyperphagia and obesity, may also be present in nonobese patients with binge-eating behavior or be related to anthropometric or psychopathological parameters in these patients. The coding region of the MC4R gene was sequenced in nonobese patients with binge-eating behavior diagnosed with bulimia nervosa or binge-eating disorder (n=77); individuals with severe early-onset obesity (n=170); and lean women with anorexia nervosa (n=20). A psychometric evaluation (Eating Disorders Inventory-2 and Symptom Checklist 90 Revised inventories) was carried out for all the patients with eating disorders. In the obesity group, 10 different variants were identified, whereas in the binge-eating patients, only two individuals with bulimia nervosa were found to carry the I251L polymorphism, which did not correlate with weight, BMI, or psychopathological features. We found no evidence that mutations in the MC4R gene are associated with binge-eating behavior in nonobese eating disorder patients.

Melanocortin-4 receptor gene variants in Chilean families: association with childhood obesity and eating behavior

Objective: To screen for mutations in the coding region of the melanocortin-4 receptor (MC4R) gene and to assess the association between the rs17782313 variant near MC4R with childhood obesity and eating behavior.Subjects and methods: A cross-sectional sample of 221 obese Chilean children and 268 parents were incorporated in the study to assemble 134 case–parent trios. We performed direct sequencing of the MC4R coding region while the rs17782313 variant was genotyped by a Taqman assay. Eating behavior scores were calculated using the Child Eating Behavior and Three Factor Eating Questionnaires adapted for Chilean families.Results: A low frequency of genetic variation in the coding region of MC4R was found in Chilean obese children (Thr150Ile mutation and polymorphisms Ile251Leu and Val103Ile). The rs17782313 variant is possibly associated with satiety responsiveness (P = 0.01) and enjoyment of food scores (P = 0.03).Conclusion: The rs17782313 variant may influence eating behavior in obese children.

Endoscopic Findings in Patients with Melanocortin-4 Receptor Gene Variants

Background: Melanocortin-4 receptor gene (MC4R) variants, common in monogenic obesity, are associated with binge eating disorder (BED), which in turn may be associated with esophagogastric pathology. Adjustable gastric banding (AGB) may also affect foregut physiology. The effects of BED and/or MC4R variants on the foregut before and after AGB are not known. Methods: The complete coding region of MC4R was comparatively sequenced in 300 patients (233 women; age 42±1 years [mean±SEM]; BMI 43.5±0.3 kg/m2) having AGB. BED was determined in a semi-structured interview using the Spitzer Questionnaire. Findings on endoscopy and esophagram were compared in patients with and without gene variants and with and without BED before and a mean 36+3 months after AGB. Results: 6.3% of patients carried MC4R variants. All MC4R variant carriers had BED, compared to 18.1% of non-carriers (P<0.001). BED was associated with more oesophageal erosions before surgery (53.8% vs. 28.2%, p=0.015) and higher rate of persistence of oesophagitis (34.6% vs. 13.3%, p=0.017) and more gastritis after 3 years (15.4% vs. 3.9%, p=0.048). In contrast, postoperatively MC4R variant carriers had dilated oesophagi (2.5cm vs. 1.3cm, P<0.001), more vomiting (vomiting score 1.47±0.21 vs. 1.12±0.06, P<0.05 and five-fold more gastric complications (P<0.001) than non-carriers. Conclusion: BED is associated with esophagogastric lesions in obese patients, whereas MC4R may independently influence gastrointestinal motility.