Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans

Daniel Marks, Nathalie Boucher, Christian Marc Lanouette, Louis Pérusse, Gregor Brookhart, Anthony G. Comuzzie, Yvon C. Chagnon, Roger D. Cone

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

A role for melanocortin signaling in the regulation of body weight in humans has been clearly established. Haploinsufficiency of the type 4 melanocortin receptor is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. Agouti-related peptide (AGRP) is an endogenous antagonist of melanocortin signaling. Therefore, loss of AGRP function could lead to the expression of a lean phenotype. We investigated the potential role of AGRP in human weight regulation by examining the association between the Ala67Thr AGRP polymorphism and indices of body composition. Significant associations were found between homozygosity for this mutation (n = 8) and body composition phenotype in 874 subjects of the Quebec family study (QFS). By PCR-RFLP analysis, we have identified eight individuals who are homozygous for the 67Thr variant allele within the QFS population, where none were observed in SAFHS. The eight QFS homozygote individuals have lower weight (-16%; P = 0.02), body mass index (-17%; P=0.01), fat free mass (-9%; P=0.002), fat mass (FM) (-20%; P = 0.04), and leptin (-20%; P=0.02) when compared to those carrying at least one 67Ala allele. Individuals homozygous for the 67Thr allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the Ala67Thr AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body FM. We did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system, thus the mechanism of this effect requires further investigation.

Original languageEnglish (US)
Pages (from-to)267-271
Number of pages5
JournalAmerican Journal of Medical Genetics
Volume126 A
Issue number3
StatePublished - Apr 30 2004

Fingerprint

Thinness
Quebec
Peptides
Melanocortins
Genes
Alleles
Body Composition
Fats
Body Weight
Receptor, Melanocortin, Type 4
Phenotype
Haploinsufficiency
Weights and Measures
Homozygote
Mutant Proteins
Leptin
Restriction Fragment Length Polymorphisms
Weight Gain
Adipose Tissue
Body Mass Index

Keywords

  • Agouti-related peptide
  • Melanocortin
  • Obesity
  • Polymorphism

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Marks, D., Boucher, N., Lanouette, C. M., Pérusse, L., Brookhart, G., Comuzzie, A. G., ... Cone, R. D. (2004). Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans. American Journal of Medical Genetics, 126 A(3), 267-271.

Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans. / Marks, Daniel; Boucher, Nathalie; Lanouette, Christian Marc; Pérusse, Louis; Brookhart, Gregor; Comuzzie, Anthony G.; Chagnon, Yvon C.; Cone, Roger D.

In: American Journal of Medical Genetics, Vol. 126 A, No. 3, 30.04.2004, p. 267-271.

Research output: Contribution to journalArticle

Marks, D, Boucher, N, Lanouette, CM, Pérusse, L, Brookhart, G, Comuzzie, AG, Chagnon, YC & Cone, RD 2004, 'Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans', American Journal of Medical Genetics, vol. 126 A, no. 3, pp. 267-271.
Marks D, Boucher N, Lanouette CM, Pérusse L, Brookhart G, Comuzzie AG et al. Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans. American Journal of Medical Genetics. 2004 Apr 30;126 A(3):267-271.
Marks, Daniel ; Boucher, Nathalie ; Lanouette, Christian Marc ; Pérusse, Louis ; Brookhart, Gregor ; Comuzzie, Anthony G. ; Chagnon, Yvon C. ; Cone, Roger D. / Ala67Thr Polymorphism in the Agouti-Related Peptide Gene Is Associated with Inherited Leanness in Humans. In: American Journal of Medical Genetics. 2004 ; Vol. 126 A, No. 3. pp. 267-271.
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abstract = "A role for melanocortin signaling in the regulation of body weight in humans has been clearly established. Haploinsufficiency of the type 4 melanocortin receptor is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. Agouti-related peptide (AGRP) is an endogenous antagonist of melanocortin signaling. Therefore, loss of AGRP function could lead to the expression of a lean phenotype. We investigated the potential role of AGRP in human weight regulation by examining the association between the Ala67Thr AGRP polymorphism and indices of body composition. Significant associations were found between homozygosity for this mutation (n = 8) and body composition phenotype in 874 subjects of the Quebec family study (QFS). By PCR-RFLP analysis, we have identified eight individuals who are homozygous for the 67Thr variant allele within the QFS population, where none were observed in SAFHS. The eight QFS homozygote individuals have lower weight (-16{\%}; P = 0.02), body mass index (-17{\%}; P=0.01), fat free mass (-9{\%}; P=0.002), fat mass (FM) (-20{\%}; P = 0.04), and leptin (-20{\%}; P=0.02) when compared to those carrying at least one 67Ala allele. Individuals homozygous for the 67Thr allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the Ala67Thr AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body FM. We did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system, thus the mechanism of this effect requires further investigation.",
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