The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1-3, DK-2100, Copenhagen, Denmark,
Diabetologia. 2015 May;58(5):1006-12. doi: 10.1007/s00125-015-3516-9. Epub 2015 Feb 9.
AIMS/HYPOTHESIS: We examined the extent to which surrogate measures of insulin release have shared genetic causes.
Genetic and phenotypic correlations were calculated in a family cohort (n = 315) in which beta cell indices were estimated based on fasting and oral glucose-stimulated plasma glucose, serum C-peptide and serum insulin levels. Furthermore, we genotyped a large population-based cohort (n = 6,269) for common genetic variants known to associate with type 2 diabetes, fasting plasma glucose levels or fasting serum insulin levels to examine their association with various indices.
We found a notable difference between the phenotypic and genetic correlations for the traits, emphasising that the phenotypic correlation is an insufficient measure of the magnitude of shared genetic impact. In addition, we found that corrected insulin response, insulinogenic index and incAUC for insulin after an oral glucose challenge shared the majority of their genetic backgrounds, with genetic correlations of 0.80-0.99. The BIGTT index for acute insulin response differed slightly more from the latter with genetic correlations of 0.78-0.87. The HOMA for beta cell function was genetically closely related to fasting insulin with a genetic correlation of 0.85. The effects of 82 selected susceptibility single nucleotide polymorphisms on these insulin secretion indices supported our interpretation of the data and added insight into the biological differences between the examined traits.
CONCLUSIONS/INTERPRETATION: The level of shared genetic background varies between surrogate measures of insulin release, and this should be considered when designing a genetic association study to best obtain information on various mechanisms of insulin release.
目的/假设：我们研究了替代胰岛素释放的测量指标在多大程度上具有共同的遗传原因。
在一个基于家族的队列（n=315）中，我们计算了遗传和表型相关性，该队列中根据空腹和口服葡萄糖刺激的血浆葡萄糖、血清 C 肽和血清胰岛素水平来估计β细胞指数。此外，我们对一个基于人群的大型队列（n=6269）进行了常见的遗传变异基因分型，这些变异与 2 型糖尿病、空腹血浆葡萄糖水平或空腹血清胰岛素水平相关，以研究它们与各种指数的关联。
我们发现这些特征的表型相关性和遗传相关性之间存在显著差异，这强调了表型相关性是衡量共同遗传影响程度的一个不充分的指标。此外，我们发现口服葡萄糖挑战后校正的胰岛素反应、胰岛素原指数和胰岛素增量 AUC 共享了大部分遗传背景，遗传相关性为 0.80-0.99。BIGTT 急性胰岛素反应指数与后两者略有不同，遗传相关性为 0.78-0.87。B 细胞功能的 HOMA 与空腹胰岛素密切相关，遗传相关性为 0.85。82 个选定的易感性单核苷酸多态性对这些胰岛素分泌指数的影响支持了我们对数据的解释，并深入了解了所检查特征之间的生物学差异。
结论/解释：替代胰岛素释放的测量指标之间的遗传背景共享程度不同，在设计遗传关联研究时应考虑这一点，以最佳获取各种胰岛素释放机制的信息。
