Saigi-Morgui Núria, Quteineh Lina, Bochud Pierre-Yves, Crettol Severine, Kutalik Zoltán, Mueller Nicolas J, Binet Isabelle, Van Delden Christian, Steiger Jürg, Mohacsi Paul, Dufour Jean-Francois, Soccal Paola M, Pascual Manuel, Eap Chin B
Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland.
Pharmacogenomics J. 2019 Feb;19(1):53-64. doi: 10.1038/s41397-017-0001-5. Epub 2017 Dec 27.
New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (OR: 1.60 [1.36-1.90], p = 3.72*10 and OR: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (OR:1.09 [1.04-1.15], p = 0.001 and OR:1.14 [1.01-1.29], p = 0.03) and a similar OR was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.
移植后新发糖尿病（NODAT）是实体器官移植后常见的并发症，在第一年发病率较高。一些临床和遗传因素已被描述为2型糖尿病（T2DM）的危险因素。此外，T2DM与NODAT有一些共同的遗传因素。我们研究了三个遗传风险评分（w-GRS）和临床因素是否与NODAT相关，以及它们如何预测移植后1年NODAT的发生。在主要样本（n = 725）和重复样本（n = 156）中，临床风险评分均与NODAT显著相关（OR分别为：1.60 [1.36 - 1.90]，p = 3.72×10；OR为：2.14 [1.39 - 3.41]，p = 0.0008）。在主要样本中，两个w-GRS与NODAT显著相关（OR分别为：1.09 [1.04 - 1.15]，p = 0.001；OR为：1.14 [1.01 - 1.29]，p = 0.03），在重复样本中也发现了类似的OR值，尽管可能由于检验效能问题未达到显著水平。尽管与临床协变量相比，w-GRS对NODAT的OR值较低，但将w-GRS 2和w-GRS 3纳入临床模型时，受试者操作特征曲线下面积（AUROC）、特异性、敏感性和准确性分别为0.69、0.71、0.58和0.68，似然比检验判别指数显著（p值0.0004），在NODAT判别方面比单独的临床模型表现更好。若仅使用临床协变量，需要对25名患者进行基因分型才能检测出1例移植后1年可能发生NODAT的误分类病例。据我们所知，这是第一项广泛研究有助于NODAT发生的遗传风险评分的研究。
