Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Protein coding variants in the hydroxysteroid 17-β dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 x 10^–7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

基因编码区的罕见变异可能通过破坏其编码蛋白而对疾病相关表型产生比常见变异更大的影响。我们在晚期肾病阶段的 1 型糖尿病患者中寻找与 ESKD 发病相关的罕见变异。

对 1 型糖尿病和蛋白尿患者的五个大型发病队列中的 15,449 个基因进行基于基因的外显子组阵列分析，分析了 ESKD 的生存时间，测试了第六个队列中的顶级基因（所有队列中n = 2372/1115 个事件）并复制在两项回顾性病例对照研究中（ n = 1072 例，752 例对照）。对五个队列中最重要的相关基因的深度重测序证实了这一发现。我们在人类对照和患病细胞以及小鼠缺血再灌注和马兜铃酸肾病模型中进行了免疫组织化学和基因表达实验。

羟基类固醇 17- β脱氢酶 14 基因 ( HSD17B14 ) 中的蛋白质编码变体预计会影响蛋白质结构，在全外显子组范围内对 ESKD 的发展具有净保护作用 ( n =4196； P值 =3.3 x 10 ^–7 ) 。 HSD17B14基因和编码的酶在健康人肾脏中强烈表达，最大程度地在近端肾小管细胞中表达。矛盾的是，在人类糖尿病近曲小管和小鼠肾损伤模型中，基因和蛋白质表达减弱。在小鼠缺血再灌注损伤模型中，表达的HSD17B14基因和蛋白水平在 21 天后仍然较低且没有恢复。在其他 CKD 相关肾脏病变中也发现了基因表达降低。

HSD17B14基因在机制上参与糖尿病肾病。编码的性类固醇酶是一个可药物靶标，有可能为治疗开发开辟新途径。