{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Harder MN"],"funding":["NNF Center for Basic Metabolic Research"],"pagination":["e0120890"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4370672"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(3)"],"pubmed_abstract":["<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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."],"journal":["PloS one"],"pubmed_title":["The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes."],"pmcid":["PMC4370672"],"funding_grant_id":["Hansen Group"],"pubmed_authors":["Hansen T","Sorensen TI","Linneberg A","Brandslund I","Pedersen O","Harder MN","Grarup N","Christensen C","Jorgensen T","Ahluwalia TS","Appel EV","Gjesing AP"],"additional_accession":[]},"is_claimable":false,"name":"The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes.","description":"<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015","modification":"2024-10-18T02:50:00.7Z","creation":"2019-03-26T23:30:47Z"},"accession":"S-EPMC4370672","cross_references":{"pubmed":["25799151"],"doi":["10.1371/journal.pone.0120890"]}}