Locke Jonathan M, Wei Fan-Yan, Tomizawa Kazuhito, Weedon Michael N, Harries Lorna W
Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
Diabetologia. 2015 Apr;58(4):745-8. doi: 10.1007/s00125-015-3508-9. Epub 2015 Jan 30.
AIMS/HYPOTHESIS: Intronic single nucleotide polymorphisms (SNPs) in the CDKAL1 gene are associated with risk of developing type 2 diabetes. A strong correlation between risk alleles and lower levels of the non-coding RNA, CDKAL1-v1, has recently been reported in whole blood extracted from Japanese individuals. We sought to replicate this association in two independent cohorts: one using whole blood from white UK-resident individuals, and one using a collection of human pancreatic islets, a more relevant tissue type to study with respect to the aetiology of diabetes.
Levels of CDKAL1-v1 were measured by real-time PCR using RNA extracted from human whole blood (n = 70) and human pancreatic islets (n = 48). Expression with respect to genotype was then determined.
In a simple linear regression model, expression of CDKAL1-v1 was associated with the lead type 2 diabetes-associated SNP, rs7756992, in whole blood and islets. However, these associations were abolished or substantially reduced in multiple regression models taking into account rs9366357 genotype: a moderately linked SNP explaining a much larger amount of the variation in CDKAL1-v1 levels, but not strongly associated with risk of type 2 diabetes.
CONCLUSIONS/INTERPRETATION: Contrary to previous findings, we provide evidence against a role for dysregulated expression of CDKAL1-v1 in mediating the association between intronic SNPs in CDKAL1 and susceptibility to type 2 diabetes. The results of this study illustrate how caution should be exercised when inferring causality from an association between disease-risk genotype and non-coding RNA expression.
目的/假设：CDKAL1基因内含子单核苷酸多态性（SNP）与2型糖尿病发生风险相关。最近有报道称，在从日本个体提取的全血中，风险等位基因与非编码RNA CDKAL1-v1水平较低之间存在强相关性。我们试图在两个独立队列中重复这一关联：一个队列使用来自英国白人居民的全血，另一个队列使用人类胰岛集合，胰岛是在糖尿病病因学研究方面更相关的组织类型。
使用从人类全血（n = 70）和人类胰岛（n = 48）中提取的RNA，通过实时PCR测量CDKAL1-v1的水平。然后确定其与基因型的表达关系。
在简单线性回归模型中，CDKAL1-v1的表达与全血和胰岛中与2型糖尿病相关的主要SNP rs7756992相关。然而，在考虑rs9366357基因型的多元回归模型中，这些关联被消除或大幅降低：rs9366357是一个中度连锁的SNP，可解释CDKAL1-v1水平中更大比例的变异，但与2型糖尿病风险无强关联。
结论/解读：与先前的研究结果相反，我们提供证据表明CDKAL1-v1表达失调在介导CDKAL1内含子SNP与2型糖尿病易感性之间的关联中不起作用。本研究结果说明了在从疾病风险基因型与非编码RNA表达之间的关联推断因果关系时应如何谨慎行事。
