Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population

Marie A Vestmar; Ehm Astrid Andersson Galijatovic; Charlotte Riis Christensen; Maria Hauge Pedersen; Charlotte Glümer; Allan Linneberg; Daniel R Witte; Marit E Jørgensen; Cramer Christensen; Ivan Brandslund; Torsten  Lauritzen; Oluf Pedersen; Birgitte Holst; Niels Grarup; Thue W Schwartz; Torben Hansen

doi:10.1136/jmedgenet-2015-103728

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population

Marie A Vestmar, Ehm Astrid Andersson Galijatovic, Charlotte Riis Christensen, Maria Hauge Pedersen, Charlotte Glümer, Allan Linneberg, Daniel R Witte, Marit E Jørgensen, Cramer Christensen, Ivan Brandslund, Torsten Lauritzen, Oluf Pedersen, Birgitte Holst, Niels Grarup, Thue W Schwartz, Torben Hansen

Institut for Klinisk Medicin

10 Citationer (Scopus)

Abstract

Background p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gaq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucoserelated traits in the Danish population. Methods Surface expression, Gq and Gi coupled signalling as well as ß-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. Results p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect ß-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population ( p>0.05). Conclusions We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

Originalsprog	Engelsk
Tidsskrift	Journal of Medical Genetics
Vol/bind	53
Udgave nummer	9
Sider (fra-til)	616-23
Antal sider	8
ISSN	0022-2593
DOI	https://doi.org/10.1136/jmedgenet-2015-103728
Status	Udgivet - 1 sep. 2016

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10.1136/jmedgenet-2015-103728

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Vestmar, M. A., Galijatovic, E. A. A., Christensen, C. R., Pedersen, M. H., Glümer, C., Linneberg, A., Witte, D. R., Jørgensen, M. E., Christensen, C., Brandslund, I., Lauritzen, T., Pedersen, O., Holst, B., Grarup, N., Schwartz, T. W., & Hansen, T. (2016). Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population. Journal of Medical Genetics, 53(9), 616-23. https://doi.org/10.1136/jmedgenet-2015-103728

Vestmar, MA, Galijatovic, EAA, Christensen, CR, Pedersen, MH, Glümer, C, Linneberg, A, Witte, DR, Jørgensen, ME, Christensen, C, Brandslund, I, Lauritzen, T, Pedersen, O , Holst, B , Grarup, N , Schwartz, TW & Hansen, T 2016, 'Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population', Journal of Medical Genetics, bind 53, nr. 9, s. 616-23. https://doi.org/10.1136/jmedgenet-2015-103728

@article{28a5ddad3f5b4c18ac60dae06cd1119f,

title = "Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population",

abstract = "Background p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gaq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucoserelated traits in the Danish population. Methods Surface expression, Gq and Gi coupled signalling as well as {\ss}-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. Results p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect {\ss}-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population ( p>0.05). Conclusions We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.",

author = "Vestmar, {Marie A} and Galijatovic, {Ehm Astrid Andersson} and Christensen, {Charlotte Riis} and Pedersen, {Maria Hauge} and Charlotte Gl{\"u}mer and Allan Linneberg and Witte, {Daniel R} and J{\o}rgensen, {Marit E} and Cramer Christensen and Ivan Brandslund and Torsten Lauritzen and Oluf Pedersen and Birgitte Holst and Niels Grarup and Schwartz, {Thue W} and Torben Hansen",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

month = sep,

day = "1",

doi = "10.1136/jmedgenet-2015-103728",

language = "English",

volume = "53",

pages = "616--23",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

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number = "9",

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TY - JOUR

T1 - Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population

AU - Vestmar, Marie A

AU - Galijatovic, Ehm Astrid Andersson

AU - Christensen, Charlotte Riis

AU - Pedersen, Maria Hauge

AU - Glümer, Charlotte

AU - Linneberg, Allan

AU - Witte, Daniel R

AU - Jørgensen, Marit E

AU - Christensen, Cramer

AU - Brandslund, Ivan

AU - Lauritzen, Torsten

AU - Pedersen, Oluf

AU - Holst, Birgitte

AU - Grarup, Niels

AU - Schwartz, Thue W

AU - Hansen, Torben

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Background p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gaq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucoserelated traits in the Danish population. Methods Surface expression, Gq and Gi coupled signalling as well as ß-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. Results p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect ß-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population ( p>0.05). Conclusions We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

AB - Background p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gaq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucoserelated traits in the Danish population. Methods Surface expression, Gq and Gi coupled signalling as well as ß-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. Results p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect ß-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population ( p>0.05). Conclusions We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

U2 - 10.1136/jmedgenet-2015-103728

DO - 10.1136/jmedgenet-2015-103728

M3 - Journal article

C2 - 27068006

SN - 0022-2593

VL - 53

SP - 616

EP - 623

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 9

ER -

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population

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