Kidd Kendrah O, Williams Adrienne H, Taylor Abbigail, Martin Lauren, Robins Victoria, Sayer John A, Olinger Eric, Mabillard Holly R, Papagregoriou Gregory, Deltas Constantinos, Stavrou Christoforos, Conlon Peter J, Hogan Richard Edmund, Elhassan Elhussein A E, Springer Drahomíra, Zima Tomáš, Izzi Claudia, Vrbacká Alena, Piherová Lenka, Pohludka Michal, Radina Martin, Vylet'al Petr, Hodanova Katerina, Zivna Martina, Kmoch Stanislav, Bleyer Anthony J
Wake Forest School of Medicine, Section on Nephrology, Winston-Salem, NC, 27157, USA.
Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czech Republic.
BMC Nephrol. 2024 Dec 18;25(1):449. doi: 10.1186/s12882-024-03896-1.
MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1 patients produce approximately 50% of normal mucin-1.
To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths.
Surveys were emailed to 637 individuals, with responses from 89 ADTKD-MUC1 and 132 ADTKD-UMOD individuals. 19/83 (23%) ADTKD-MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1 individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD-UMOD individuals (0.6%) (P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC1 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1).
Individuals with ADTKD-MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible.
MUC1和UMOD致病变异可导致常染色体显性遗传性肾小管间质性肾病（ADTKD）。MUC1在肾脏、鼻黏膜和呼吸道表达，而UMOD仅在肾脏表达。由于单倍体不足，ADTKD-MUC1患者产生的粘蛋白-1约为正常水平的50%。
为了确定粘蛋白-1产生减少是否与新冠病毒疾病（COVID-19）风险增加相关，在2021年9月，即COVID-19最初的严重浪潮过后，我们向一个ADTKD登记处的成员发送了一份调查问卷。我们将结果与之前获得的ADTKD基因型和血浆CA15-3（粘蛋白-1）水平相关联，并创建了一个与COVID-19相关死亡的纵向登记册。
调查问卷通过电子邮件发送给了637人，其中89名ADTKD-MUC1患者和132名ADTKD-UMOD患者回复。83名ADTKD-MUC1调查问卷受访者中有19人（23%）报告曾感染COVID-19，而125名ADTKD-UMOD受访者中有14人（11%）（比值比（OR）为2.35（95%置信区间1.60-3.11，P = 0.0260）。包括调查问卷受访者报告的其他家族病例，41名ADTKD-MUC1患者中有10人（24%）死于COVID-19，而30名ADTKD-UMOD患者中有1人（3%），OR为9.21（95%置信区间1.22-69.32），P = 0.03。14名感染和27名未感染的ADTKD-MUC1患者感染前的平均血浆粘蛋白-1水平分别为7.06±4.12与10.21±4.02 U/mL（P = 0.035）。在三年时间里，我们的纵向登记册在360名ADTKD-MUC1患者中确定了19例COVID-19死亡（5%），而在478名ADTKD-UMOD患者中有3例死亡（0.6%）（P = 0.0007）。多因素逻辑回归显示COVID-19死亡的以下比值比（95%置信区间）：ADTKD-MUC1为8.4（2.9-29.5），肾移植为5.5（1.6-9.1），体重指数（kg/m）为1.1（1.0-1.2），年龄（岁）为1.04（1.0-1.1）。
与ADTKD-UMOD患者相比，ADTKD-MUC1患者的COVID-19死亡风险增加了八倍。粘蛋白-1的单倍体不足产生可能是原因所在。
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