Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2009

Open Access 01-12-2009 | Research article

Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI

Authors: Ineta Kalnina, Ivo Kapa, Valdis Pirags, Vita Ignatovica, Helgi B Schiöth, Janis Klovins

Published in: BMC Medical Genetics | Issue 1/2009

Login to get access

Abstract

Background

The agouti related protein (AGRP) is an endogenous antagonist of the melanocortin 4 receptor and is one of the most potent orexigenic factors. The aim of the present study was to assess the genetic variability of AGRP gene and investigate whether the previously reported SNP rs5030980 and the rs11575892, a SNP that so far has not been studied with respect to obesity is associated with increased body mass index (BMI).

Methods

We determined the complete sequence of the AGRP gene and upstream promoter region in 95 patients with severe obesity (BMI > 35 kg/m2). Three polymorphisms were identified: silent mutation c.123G>A (rs34123523) in the second exon, non-synonymous mutation c.199G>A (rs5030980) and c.131-42C>T (rs11575892) located in the second intron. We further screened rs11575892 in a selected group of 1135 and rs5030980 in group of 789 participants from the Genome Database of Latvian Population and Latvian State Research Program Database.

Results

The CT heterozygotes of rs11575892 had significantly higher mean BMI value (p = 0.027). After adjustment for age, gender and other significant non-genetic factors (presence of diseases), the BMI levels remained significantly higher in carriers of the rs11575892 T allele (p = 0.001). The adjusted mean BMI value of CC genotype was 27.92 ± 1.01 kg/m2 (mean, SE) as compared to 30.97 ± 1.03 kg/m2 for the CT genotype. No association was found between rs5030980 and BMI.

Conclusion

This study presents an association of rare allele of AGRP polymorphism in heterozygous state with increased BMI. The possible functional effects of this polymorphism are unclear but may relate to splicing defects.
Appendix
Available only for authorised users
Literature
1.
Hillebrand JJ, Kas MJ, Adan RA: To eat or not to eat; regulation by the melanocortin system. Physiol Behav. 2006, 89 (1): 97-102. 10.1016/j.physbeh.2006.01.034.CrossRefPubMed
2.
Seeley RJ, Drazen DL, Clegg DJ: The critical role of the melanocortin system in the control of energy balance. Annu Rev Nutr. 2004, 24: 133-149. 10.1146/annurev.nutr.24.012003.132428.CrossRefPubMed
3.
Klovins J, Haitina T, Fridmanis D, Kilianova Z, Kapa I, Fredriksson R, Gallo-Payet N, Schioth HB: The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. Mol Biol Evol. 2004, 21 (3): 563-579. 10.1093/molbev/msh050.CrossRefPubMed
4.
Stutz AM, Morrison CD, Argyropoulos G: The Agouti-related protein and its role in energy homeostasis. Peptides. 2005, 26 (10): 1771-1781. 10.1016/j.peptides.2004.12.024.CrossRefPubMed
5.
Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA, et al: A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology. 1998, 139 (10): 4428-4431. 10.1210/en.139.10.4428.CrossRefPubMed
6.
Lu XY, Nicholson JR, Akil H, Watson SJ: Time course of short-term and long-term orexigenic effects of Agouti-related protein (86–132). Neuroreport. 2001, 12 (6): 1281-1284. 10.1097/00001756-200105080-00045.CrossRefPubMed
7.
Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL: Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet. 1997, 17 (3): 273-274. 10.1038/ng1197-273.CrossRefPubMed
8.
Katsuki A, Sumida Y, Gabazza EC, Murashima S, Tanaka T, Furuta M, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, et al: Plasma levels of agouti-related protein are increased in obese men. J Clin Endocrinol Metab. 2001, 86 (5): 1921-1924. 10.1210/jc.86.5.1921.CrossRefPubMed
9.
Hoggard N, Johnstone AM, Faber P, Gibney ER, Elia M, Lobley G, Rayner V, Horgan G, Hunter L, Bashir S, et al: Plasma concentrations of alpha-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance perturbation. Clin Endocrinol (Oxf). 2004, 61 (1): 31-39. 10.1111/j.1365-2265.2004.02056.x.CrossRef
10.
Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS: Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997, 278 (5335): 135-138. 10.1126/science.278.5335.135.CrossRefPubMed
11.
Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL: Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 1997, 11 (5): 593-602. 10.1101/gad.11.5.593.CrossRefPubMed
12.
Mayfield DK, Brown AM, Page GP, Garvey WT, Shriver MD, Argyropoulos G: A role for the Agouti-Related Protein promoter in obesity and type 2 diabetes. Biochem Biophys Res Commun. 2001, 287 (2): 568-573. 10.1006/bbrc.2001.5600.CrossRefPubMed
13.
Loos RJ, Rankinen T, Rice T, Rao DC, Leon AS, Skinner JS, Bouchard C, Argyropoulos G: Two ethnic-specific polymorphisms in the human Agouti-related protein gene are associated with macronutrient intake. Am J Clin Nutr. 2005, 82 (5): 1097-1101.PubMed
14.
Bonilla C, Panguluri RK, Taliaferro-Smith L, Argyropoulos G, Chen G, Adeyemo AA, Amoah A, Owusu S, Acheampong J, Agyenim-Boateng K, et al: Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans. Int J Obes (Lond). 2006, 30 (4): 715-721. 10.1038/sj.ijo.0803047.CrossRef
15.
Vink T, Hinney A, van Elburg AA, van Goozen SH, Sandkuijl LA, Sinke RJ, Herpertz-Dahlmann BM, Hebebrand J, Remschmidt H, van Engeland H, et al: Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol Psychiatry. 2001, 6 (3): 325-328. 10.1038/sj.mp.4000854.CrossRefPubMed
16.
Argyropoulos G, Rankinen T, Neufeld DR, Rice T, Province MA, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C: A polymorphism in the human agouti-related protein is associated with late-onset obesity. J Clin Endocrinol Metab. 2002, 87 (9): 4198-4202. 10.1210/jc.2002-011834.CrossRefPubMed
17.
Marks DL, Boucher N, Lanouette CM, Perusse L, Brookhart G, Comuzzie AG, Chagnon YC, Cone RD: Ala67Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans. Am J Med Genet A. 2004, 126 (3): 267-271. 10.1002/ajmg.a.20600.CrossRef
18.
19.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81 (3): 559-575. 10.1086/519795.CrossRefPubMedPubMedCentral
20.
van Rossum CT, Pijl H, Adan RA, Hoebee B, Seidell JC: Polymorphisms in the NPY and AGRP genes and body fatness in Dutch adults. Int J Obes (Lond). 2006, 30 (10): 1522-1528. 10.1038/sj.ijo.0803314.CrossRef
21.
Bai F, Rankinen T, Charbonneau C, Belsham DD, Rao DC, Bouchard C, Argyropoulos G: Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium. J Med Genet. 2004, 41 (5): 350-353. 10.1136/jmg.2003.014092.CrossRefPubMedPubMedCentral
22.
Sozen MA, de Jonge LH, Greenway F, Ravussin E, Smith SR, Argyropoulos G: A rare mutation in AgRP, +79G>A, affects promoter activity. Eur J Clin Nutr. 2007, 61 (6): 809-812. 10.1038/sj.ejcn.1602585.CrossRefPubMed
23.
de Rijke CE, Jackson PJ, Garner KM, van Rozen RJ, Douglas NR, Kas MJ, Millhauser GL, Adan RA: Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness. Biochem Pharmacol. 2005, 70 (2): 308-316. 10.1016/j.bcp.2005.04.033.CrossRefPubMed
24.
Creemers JW, Pritchard LE, Gyte A, Le Rouzic P, Meulemans S, Wardlaw SL, Zhu X, Steiner DF, Davies N, Armstrong D, et al: Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology. 2006, 147 (4): 1621-1631. 10.1210/en.2005-1373.CrossRefPubMed
25.
Goto K, Inui A, Takimoto Y, Yuzuriha H, Asakawa A, Kawamura Y, Tsuji H, Takahara Y, Takeyama C, Katsuura G, et al: Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats. Int J Mol Med. 2003, 12 (3): 379-383.PubMed
26.
Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R: MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 2008, 105 (5): 1608-1613. 10.1073/pnas.0707594105.CrossRefPubMedPubMedCentral
Metadata
Title
Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI
Authors
Ineta Kalnina
Ivo Kapa
Valdis Pirags
Vita Ignatovica
Helgi B Schiöth
Janis Klovins
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-10-63

Other articles of this Issue 1/2009

BMC Medical Genetics 1/2009 Go to the issue

Research article

Type 2 diabetes gene TCF7L2polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

Research article

Genetic variants of the promoter of the heme oxygenase-1 gene and their influence on cardiovascular disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Research article

Relationship of circulating cell-free DNA levels to cell-free fetal DNA levels, clinical characteristics and laboratory parameters in preeclampsia

Research article

A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype

Research article

Differentially expressed alternatively spliced genes in Malignant Pleural Mesothelioma identified using massively parallel transcriptome sequencing

Research article

SLC6A3and body mass index in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial