Brenner Laura N, Mercader Josep M, Robertson Catherine C, Cole Joanne, Chen Ling, Jacobs Suzanne B R, Rich Stephen S, Florez Jose C
Pulmonary and Critical Care Division, Massachusetts General Hospital, Boston, Massachusetts.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.
J Endocr Soc. 2020 Aug 24;4(11):bvaa121. doi: 10.1210/jendso/bvaa121. eCollection 2020 Nov 1.
Glucocorticoids have multiple therapeutic benefits and are used both for immunosuppression and treatment purposes. Notwithstanding their benefits, glucocorticoid use often leads to hyperglycemia. Owing to the pathophysiologic overlap in glucocorticoid-induced hyperglycemia (GIH) and type 2 diabetes (T2D), we hypothesized that genetic variation in glucocorticoid pathways contributes to T2D risk. To determine the genetic contribution of glucocorticoid action on T2D risk, we conducted multiple genetic studies. First, we performed gene-set enrichment analyses on 3 collated glucocorticoid-related gene sets using publicly available genome-wide association and whole-exome data and demonstrated that genetic variants in glucocorticoid-related genes are associated with T2D and related glycemic traits. To identify which genes are driving this association, we performed gene burden tests using whole-exome sequence data. We identified 20 genes within the glucocorticoid-related gene sets that are nominally enriched for T2D-associated protein-coding variants. The most significant association was found in coding variants in coiled-coil α-helical rod protein 1 () in the HLA region ( = .001). Further analyses revealed that noncoding variants near are also associated with T2D at genome-wide significance ( = 7.70 × 10), independent of type 1 diabetes HLA risk. Finally, gene expression and colocalization analyses demonstrate that variants associated with increased T2D risk are also associated with decreased expression of in multiple tissues, implicating this gene as a potential effector transcript at this locus. Our discovery of a genetic link between glucocorticoids and T2D findings support the hypothesis that T2D and GIH may have shared underlying mechanisms.
糖皮质激素具有多种治疗益处，可用于免疫抑制和治疗目的。尽管有这些益处，但使用糖皮质激素常常会导致高血糖。由于糖皮质激素诱导的高血糖（GIH）和2型糖尿病（T2D）在病理生理上存在重叠，我们推测糖皮质激素途径中的基因变异会增加T2D风险。为了确定糖皮质激素作用对T2D风险的遗传贡献，我们进行了多项基因研究。首先，我们使用公开可用的全基因组关联和全外显子数据，对3个整理好的糖皮质激素相关基因集进行了基因集富集分析，结果表明糖皮质激素相关基因中的遗传变异与T2D及相关血糖性状有关。为了确定哪些基因驱动了这种关联，我们使用全外显子序列数据进行了基因负担测试。我们在糖皮质激素相关基因集中鉴定出20个基因，这些基因在名义上富集了与T2D相关的蛋白质编码变异。在HLA区域的卷曲螺旋α螺旋杆蛋白1（）的编码变异中发现了最显著的关联（ = .001）。进一步分析表明，附近的非编码变异在全基因组水平上也与T2D相关（ = 7.70 × 10），独立于1型糖尿病HLA风险。最后，基因表达和共定位分析表明，与T2D风险增加相关的变异也与多个组织中表达的降低有关，这表明该基因是该位点的潜在效应转录本。我们发现糖皮质激素与T2D之间存在遗传联系，这一发现支持了T2D和GIH可能具有共同潜在机制的假设。
