The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes

Marie Balslev-Harder; Emil Vincent Rosenbaum Appel; Niels Grarup; Anette Marianne Prior Gjesing; Tarun Veer Singh Ahluwalia; Torben Jørgensen; Cramer Christensen; Ivan Brandslund; Allan Linneberg; Thorkild I A Sørensen; Oluf Pedersen; Torben Hansen

doi:10.1371/journal.pone.0120890

The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes

Marie Balslev-Harder, Emil Vincent Rosenbaum Appel, Niels Grarup, Anette Marianne Prior Gjesing, Tarun Veer Singh Ahluwalia, Torben Jørgensen, Cramer Christensen, Ivan Brandslund, Allan Linneberg, Thorkild I A Sørensen, Oluf Pedersen, Torben Hansen

12 Citationer (Scopus)

Abstract

OBJECTIVES: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.

METHODS: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.

RESULTS: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).

CONCLUSION: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.

Originalsprog	Engelsk
Artikelnummer	e0120890
Tidsskrift	PLOS ONE
Vol/bind	10
Udgave nummer	3
Sider (fra-til)	1-13
Antal sider	13
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0120890
Status	Udgivet - 23 mar. 2015

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10.1371/journal.pone.0120890

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Balslev-Harder, M., Appel, E. V. R., Grarup, N., Gjesing, A. M. P., Ahluwalia, T. V. S., Jørgensen, T., Christensen, C., Brandslund, I., Linneberg, A., Sørensen, T. I. A., Pedersen, O., & Hansen, T. (2015). The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes. PLOS ONE, 10(3), 1-13. [e0120890]. https://doi.org/10.1371/journal.pone.0120890

Balslev-Harder, M, Appel, EVR, Grarup, N , Gjesing, AMP , Ahluwalia, TVS, Jørgensen, T, Christensen, C, Brandslund, I, Linneberg, A , Sørensen, TIA , Pedersen, O & Hansen, T 2015, 'The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes', PLOS ONE, bind 10, nr. 3, e0120890, s. 1-13. https://doi.org/10.1371/journal.pone.0120890

@article{74688851cefd4bd4b13691e8908b65bc,

title = "The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes",

abstract = "OBJECTIVES: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.METHODS: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants na{\"i}ve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.RESULTS: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).CONCLUSION: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.",

author = "Marie Balslev-Harder and Appel, {Emil Vincent Rosenbaum} and Niels Grarup and Gjesing, {Anette Marianne Prior} and Ahluwalia, {Tarun Veer Singh} and Torben J{\o}rgensen and Cramer Christensen and Ivan Brandslund and Allan Linneberg and S{\o}rensen, {Thorkild I A} and Oluf Pedersen and Torben Hansen",

year = "2015",

month = mar,

day = "23",

doi = "10.1371/journal.pone.0120890",

language = "English",

volume = "10",

pages = "1--13",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

}

TY - JOUR

T1 - The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes

AU - Balslev-Harder, Marie

AU - Appel, Emil Vincent Rosenbaum

AU - Grarup, Niels

AU - Gjesing, Anette Marianne Prior

AU - Ahluwalia, Tarun Veer Singh

AU - Jørgensen, Torben

AU - Christensen, Cramer

AU - Brandslund, Ivan

AU - Linneberg, Allan

AU - Sørensen, Thorkild I A

AU - Pedersen, Oluf

AU - Hansen, Torben

PY - 2015/3/23

Y1 - 2015/3/23

N2 - OBJECTIVES: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.METHODS: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.RESULTS: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).CONCLUSION: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.

AB - OBJECTIVES: A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.METHODS: Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.RESULTS: We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).CONCLUSION: Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.

U2 - 10.1371/journal.pone.0120890

DO - 10.1371/journal.pone.0120890

M3 - Journal article

C2 - 25799151

SN - 1932-6203

VL - 10

SP - 1

EP - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 3

M1 - e0120890

ER -

The Type 2 Diabetes Risk Allele of TMEM154-rs6813195 Associates with Decreased Beta Cell Function in a Study of 6,486 Danes

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