Melanocortin 4 Receptor Sequence Variations Are Seldom a Cause of Human Obesity: The Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis Cohort

Jacobson, Peter; Ukkola, Olavi; Rankinen, Tuomo; Snyder, Eric E.; Leon, Arthur S.; Rao, D. C.; Wilmore, Jack H.; Lönn, Lars; Cowan, George S M; Sjöström, Lars; Bouchard, Claude

doi:10.1210/jc.2002-020568

Cited by 108 publications

(72 citation statements)

References 32 publications

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“…Thus, the prevalence of loss-of-function MC4R mutations in our large sample set of obese subjects of European origin is 1.72%. Although our mode of recruitment of obese patients may have tended to overestimate the proportion of severe phenotypes, the prevalence is consistent with that previously published in other obese cohorts (14,18,(33)(34)(35). Our findings in the control cohort are consistent with other large, population-based cohorts (6), such as the KORA-S4 study, where the prevalence of MC4R mutations was also 0.15%.…”

Section: Discussionsupporting

confidence: 91%

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

et al. 2008

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OBJECTIVE-Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS-We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS-Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P ϭ 6.9 ϫ 10 Ϫ10 ). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged Ͼ52 years, 60% in 18-to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at Ͼ40 years).CONCLUSIONS-We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.

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Section: Discussionsupporting

confidence: 91%

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

et al. 2008

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“…Subsequently, more than 30 different mutations, including missense, nonsense, and frameshift mutations, in the MC4R gene have been reported in French, English, German, American, Italian, and Spanish individuals. [31][32][33][34][35][36][37][38][39][40][41][42][43] Functional studies showed that many of the missense mutations, and all three frameshift mutations described so far, led to a complete or partial loss of function of the MC4R gene. 31,33,40,42,44,45 In a recent study, Farooqi et al 42 found that the signaling properties of mutant MC4R receptors, as determined in cell The inactivity score is adjusted for sex, age, and BMI.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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Physical inactivity is a risk factor for numerous chronic diseases. Low compliance with interventions to increase activity suggests involvement of biological systems. OBJECTIVE: To examine whether sequence variants in genes encoding neuropeptides and receptors in the arcuate and paraventricular nucleus of the hypothalamus contribute to variations in physical activity level in the Québec Family Study. METHODS: We genotyped polymorphisms in the melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), neuropeptide-Y (NPY), neuropeptide-Y Y1 receptor (NPY Y1R), cocaine-and amphetamine-regulated transcript (CART), agoutirelated protein (AGRP), and pro-opiomelanocortin (POMC) genes in 669 subjects (age (X7s.d.): parents: 5273.4 y; offspring: 2878.7 y). Total physical activity, moderate-to-strenuous activity, and inactivity phenotypes were estimated from a three-day record. The past year's physical activity level was assessed from a questionnaire. Associations between the physical activity phenotypes and the polymorphisms were analyzed using the MIXED model (SAS). RESULTS: The MC4R-C-2745T variant showed significant associations with physical activity phenotypes. The lowest moderateto-strenuous activity scores (P ¼ 0.005) and the highest inactivity scores (P ¼ 0.01) emerged in the T/T genotype. Exclusion of obese subjects increased the association. For inactivity, the association of the MC4R-C-2745T variant was strongest in the offspring (P ¼ 0.002). The T/T offspring had both the highest inactivity score and the lowest body mass index. The CART-A1475G variant modified the associations with MC4R-C-2745T; T/T homozygotes had the lowest activity scores when they also had the A/A CART-A1475G genotype. No significant associations were observed with polymorphisms in the other neuropeptides. CONCLUSION: These findings suggest that DNA sequence variation at the MC4R gene locus may contribute to the propensity to be sedentary.

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“…The first SNP, rs34114122 (A/C), was located at the 5'-UTR of the promoter site in the MC4R gene and has been previously reported in European, American, and Asian populations (Jacobson et al, 2002;Lubrano-Berthelier et al, 2003;Stutzmann et al, 2007;Van Den Berg et al, 2011;Tan et al, 2014). This variant was not found to be associated with obesity.…”

Section: Discussionmentioning

confidence: 89%

Genetic variant screening of MC3R and MC4R genes in early-onset obese children and their relatives among a Thai population: family-based study

et al. 2015

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ABSTRACT. MC3R (melanocortin-3 receptor) and MC4R (melanocortin-4 receptor) play important roles in energy homeostasis. Severe early-onset obesity, known as monogenic obesity when it is the consequence of a mutation in a single-gene product, may result when energy homeostasis is disrupted. The purpose of our study was to screen for variations of the MC3R and MC4R genes and observe the mode of inheritance of variations in affected families. We used polymerase chain reaction and direct sequencing to analyze the 11 early-onset obese children (probands) with their 71 family members, together with DNA from 100 healthy subjects used as controls. No novel mutations were found in the MC3R gene. Two previously described polymorphisms, rs3746619 and rs3827103, were detected in the MC3R gene. It was not associated with any obesity-related phenotypes. Three heterozygous variations of the MC4R gene were detected in 3 of 11 probands. The rs34114122 and rs61741819 variations have previously been reported, but rs182455344 was novel. Moreover, each MC4R variant was also found in a number of family members, indicating that this molecular analysis of a family-based study showed an autosomal dominant pattern. Our study indicated that MC4R variations in early-onset obese Thai children were found, and transmission of these variations in each family is in the dominant pattern. These variants could possibly contribute to a genetic influence of early-onset obesity in Thais. There is no evidence of any association between MC3R variations and obesity.

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Melanocortin 4 Receptor Sequence Variations Are Seldom a Cause of Human Obesity: The Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis Cohort

Cited by 108 publications

References 32 publications

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

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

Genetic variant screening of MC3R and MC4R genes in early-onset obese children and their relatives among a Thai population: family-based study

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