Harder Marie Neergaard, Appel Emil Vincent Rosenbaum, Grarup Niels, Gjesing Anette Prior, Ahluwalia Tarunveer S, Jørgensen Torben, Christensen Cramer, Brandslund Ivan, Linneberg Allan, Sørensen Thorkild I A, Pedersen Oluf, Hansen Torben
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.
PLoS One. 2015 Mar 23;10(3):e0120890. doi: 10.1371/journal.pone.0120890. eCollection 2015.
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.
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.
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).
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.
一项2型糖尿病全基因组关联研究的跨种族荟萃分析在TMEM154、SSR1/RREB1、FAF1、POU5F1/TCF19、LPP、ARL15和ABCB9/MPHOSPH9内部或附近鉴定出7个新的易感变异。我们研究的目的是在一项基于丹麦人群的研究中调查这些新的风险变异与2型糖尿病及糖尿病前期特征之间的关联，该研究在口服葡萄糖耐量试验后测量血浆葡萄糖和血清胰岛素，以阐明这些变异的生理影响。
对多达5777例2型糖尿病患者和7956例空腹血糖水平正常的个体进行病例对照分析。对多达5744例未使用降糖药物的Inter99参与者进行数量性状分析。选择TMEM154-rs6813195与β细胞指标胰岛素生成指数和处置指数之间以及FAF1-rs17106184与2小时血清胰岛素水平之间的显著关联，在另外的丹麦研究中进行进一步调查，并将结果合并到一项荟萃分析中，该荟萃分析纳入了多达6486名丹麦人。
我们证实了7个单核苷酸多态性（SNP）中的5个与2型糖尿病有关联（TMEM154-rs6813195、FAF1-rs17106184、POU5F1/TCF19-rs3130501、ARL15-rs702634和ABCB9/MPHOSPH9-rs4275659）。TMEM154-rs6813195的2型糖尿病风险C等位基因与Inter99中处置指数降低（n=5181，β=-0.042，p=0.012）和胰岛素生成指数降低（n=5181，β=-0.032，p=0.043）相关，并且在纳入另外四项丹麦研究的荟萃分析中这些关联仍然显著（处置指数n=6486，β=-0.042，p=0.0044；胰岛素生成指数n=6486，β=-0.037，p=0.0094）。FAF1-rs17106184的2型糖尿病风险G等位基因与Inter99中2小时血清胰岛素水平升高（n=5547，β=0.055，p=0.017）相关，在与另外三项丹麦研究合并效应时也是如此（n=6260，β=0.062，p=0.0040）。
对2型糖尿病中间性状的研究表明，TMEM154-rs6813195的C等位基因的致糖尿病作用是通过β细胞功能降低介导的。然而，FAF1-rs17106184的糖尿病风险G等位基因对2小时胰岛素水平升高的影响尚无法解释。
