口服葡萄糖耐量试验中循环胰高血糖素水平的全基因组关联研究。
Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test.
机构信息
The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
出版信息
BMC Med Genomics. 2021 Jan 6;14(1):3. doi: 10.1186/s12920-020-00841-7.
BACKGROUND
In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels.
METHODS
Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis.
RESULTS
A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta - 0.210, SE 0.037, P = 1.9 × 10), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10).
CONCLUSIONS
A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.
背景
为了探索 2 型糖尿病的病理生理学基础，我们研究了与 2 型糖尿病相关的基因变异对口服葡萄糖耐量试验（OGTT）期间胰高血糖素循环水平的影响。此外，我们进行了全基因组关联研究（GWAS），旨在确定影响血浆胰高血糖素水平的新基因组位点。
方法
在两个共包含多达 1899 人的独立队列中，在 OGTT 的三个时间点（0、30 和 120 分钟）获得的样本中检测胰高血糖素的血浆水平。在两个队列中分别进行横断面分析，并对结果进行合并meta 分析。
结果
在 OGTT 期间 30 分钟时，EYA2 中的一个已知的 2 型糖尿病变异与较高的血浆胰高血糖素水平显著相关（Beta 0.145，SE 0.038，P = 1.2 × 10），对应于每个效应等位基因血浆胰高血糖素水平增加 7.4%。在 GWAS 中，我们在 MARCH1 基因座中鉴定出一个标记物，该标记物与 OGTT 前 30 分钟胰高血糖素抑制的降低呈全基因组显著相关（Beta -0.210，SE 0.037，P = 1.9 × 10），每个效应等位基因的抑制作用降低 8.2%。另外 9 个先前与 2 型糖尿病无关的独立标记物与 OGTT 前 30 分钟胰高血糖素抑制减少呈提示性关联（P < 1.0 × 10）。
结论
EYA2 基因座中的 2 型糖尿病风险变异与 30 分钟时较高的血浆胰高血糖素水平相关。另外 10 个变异与胰高血糖素抑制减少提示相关，而不会增加 2 型糖尿病风险。
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