A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes

超过10万加拿大人和38万英国人患有1型糖尿病。1型糖尿病患者需要终生注射胰岛素，以取代胰腺中因免疫过程而死亡的特殊细胞合成的胰岛素。目前，几乎没有什么治疗方法可以防止或延缓对胰岛素产生细胞的潜在破坏。然而，最近的研究表明，许多1型糖尿病患者实际上仍然会产生少量的胰岛素。这一点很重要，因为这些人的糖尿病不那么严重：他们需要较低剂量的胰岛素；他们对血糖水平有更好的控制；发生低血糖的风险较低；而且重要的是，他们患糖尿病长期并发症的风险较低，包括眼睛、肾脏和心脏病，这些都是主要的健康问题。然而，我们对导致1型糖尿病患者胰岛素生产能力差异的因素知之甚少。遗传学提供了一个独特的机会来确定重要的生物医学措施的因果因素，例如1型糖尿病患者胰岛素产生的变化。我们已经进行了一项初步研究，我们确定了基因组中与胰岛素产生相关的不同位置的遗传变异，并表明剩余的胰岛素产生非常强烈地由基因决定。然而，我们发现，只有一小部分遗传贡献来自已知基因，因此仍有重要的基因有待发现。此外，我们还表明，糖尿病发病年龄是残余胰岛素产生的一个决定因素，但决定发病年龄的基因只占残余胰岛素产生的遗传决定的一小部分。在这个项目中，我们将使用来自10个不同研究的数据和样本，总计约12,200名1型糖尿病患者，以使我们能够识别影响残余胰岛素产生的遗传因素、发病年龄以及将影响这些特征的基因与对每个特征具有特定影响的基因分开的血糖控制。重要的是将合作结合在一起，以使研究的规模最大化，使其尽可能强大，并确保标准化的方法，因为这也增加了发现的力量。这将是迄今为止对这一主题进行的规模最大、最全面的研究。识别遗传因素是了解机制的第一步，最终可能被用来开发新的方法，帮助1型糖尿病患者保持胰岛素的产生。这项工作还将导致如何确定哪些糖尿病患者是最合适的参与者，哪些临床试验将加快药物开发计划。由于许多2型糖尿病患者的胰岛素分泌也是异常的，这影响了200多万加拿大人和400多万英国人，我们将对胰腺细胞功能的发现也将带来重要的见解，并加速开发一些2型糖尿病患者的新疗法。

Over 100,000 Canadians and 380,000 in the UK overall have type 1 diabetes. People with type 1 diabetes require lifelong insulin injections to replace insulin synthesized by specialized cells in their pancreas that have died due to an immune process. Currently there are few treatments to prevent or delay the underlying destruction of insulin producing cells. However recent studies have shown that many people with type 1 diabetes do in fact still produce small amounts of insulin. This is important because these people have less severe diabetes: they require lower doses of insulin; have better control of their blood sugar levels; are at lower risk for the development of low blood sugar; and also importantly at lower risk for long-term complications of diabetes, including eye, kidney and heart diseases which are major health problems. However, we have little understanding of the factors that result in differences in insulin production capacity between people with type 1 diabetes. Genetics provides a unique opportunity to identify causal factors for important biomedical measures, such as varying insulin production in people with type 1 diabetes. We already conducted a pilot study where we identified genetic variations different locations in the genome that are related to insulin production and have shown that residual insulin production is very strongly genetically determined. However we showed that only a small percentage of the genetic contribution is from known genes so that there are important genes still to discover. Furthermore we showed that age at onset of diabetes is one determinant of residual insulin production but that the genes determining age at onset only capture a small percentage of the genetic determination of residual insulin production. In this project we will use data and samples from ten different studies, with a total of ~12,200 people with type 1 diabetes, to allow us to identify the genetic factors that influence residual insulin production, age at onset and also glycaemic control separating those genes that influence these traits together from those that have specific effects on each trait. It is important to bring the collaboration together in order to maximise the size of the study to make it as powerful as possible and also to ensure standardised approach as that also increases the power for discovery. This would be the largest and most comprehensive study of this topic to date.Identifying the genetic factors is the first step to understanding the mechanisms, which could ultimately be used to develop new approaches to help preserve insulin production in people with type 1 diabetes. The work will also lead to ways to identify which people with diabetes are most appropriate participants for which clinical trials which will accelerate drug development programmes. Since insulin production is also abnormal in many people with type 2 diabetes, which affects over 2 million Canadians and over 4 million in the UK overall, the discoveries about pancreatic cell function that we will make will also lead to important insights and accelerate development of new treatments for some people with type 2 diabetes.