Analysis of Glucocorticoid-Related Genes Reveal CCHCR1 as a New Candidate Gene for Type 2 Diabetes.
Analysis of Glucocorticoid-Related Genes Reveal CCHCR1 as a New Candidate Gene for Type 2 Diabetes.
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DOI：
10.1210/jendso/bvaa121
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发表时间：
2020-11-01
影响因子：
4.1
通讯作者：
Florez JC
中科院分区：
文献类型：
--
作者：
Brenner LN;Mercader JM;Robertson CC;Cole J;Chen L;Jacobs SBR;Rich SS;Florez JC
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。尽管糖皮质激素有好处，但其使用通常会导致高血糖。由于糖皮质激素诱发的高血糖 (GIH) 和 2 型糖尿病 (T2D) 的病理生理学重叠，我们假设糖皮质激素途径的遗传变异会导致 T2D 风险。为了确定糖皮质激素作用对 T2D 风险的遗传贡献，我们进行了多项遗传研究。首先，我们使用公开的全基因组关联和全外显子组数据对 3 个整理的糖皮质激素相关基因集进行基因集富集分析，并证明糖皮质激素相关基因的遗传变异与 T2D 和相关血糖特征相关。为了确定哪些基因驱动了这种关联，我们使用全外显子组序列数据进行了基因负荷测试。我们在糖皮质激素相关基因集中鉴定了 20 个基因，这些基因名义上富含 T2D 相关蛋白编码变体。最显着的关联发现于 HLA 区域的卷曲螺旋 α-螺旋杆蛋白 1 (CCHCR1) 的编码变异中 (P = .001)。进一步分析显示，CCHCR1 附近的非编码变异也与全基因组显着性的 T2D 相关（P = 7.70 × 10–14），与 1 型糖尿病 HLA 风险无关。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 CCHCR1 表达降低相关，表明该基因是该位点的潜在效应转录物。我们发现糖皮质激素与 T2D 之间存在遗传联系，这支持了 T2D 和 GIH 可能具有共同的潜在机制的假设。
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 (CCHCR1) in the HLA region (P = .001). Further analyses revealed that noncoding variants near CCHCR1 are also associated with T2D at genome-wide significance (P = 7.70 × 10–14), 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 CCHCR1 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.
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影响因子：
64.8
作者：
Elliott LT;Sharp K;Alfaro-Almagro F;Shi S;Miller KL;Douaud G;Marchini J;Smith SM
通讯作者：
Smith SM
影响因子：
15.9
作者：
Heine, Vivi M.;Rowitch, David H.
通讯作者：
Rowitch, David H.
影响因子：
3.5
作者：
Asumalahti, K;Veal, C;Kere, J
通讯作者：
Kere, J
影响因子：
4.6
作者：
Liu, Ching-Ti;Merino, Jordi;Bouatia-Naji, Nabila
通讯作者：
Bouatia-Naji, Nabila
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium