BACKGROUND: 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. METHODS: 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. RESULTS: 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/m2) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1). CONCLUSIONS: 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.

Center for Human Genetics Cliniques universitaires Saint Luc Brussels Belgium

Clinical Genetics Unit University of Brescia and Spedali Civili Brescia Italy

Department of Biological Sciences Molecular Medicine Research Center University of Cyprus Nicosia Cyprus

Department of Nephrology and Transplantation Beaumont Hospital Dublin Ireland

Department of Nephrology Evangelismos Hospital Paphos Cyprus

Department of Paediatrics and Inherited Metabolic Disorders Research Unit of Rare Diseases 1st Faculty of Medicine Charles University Prague Czech Republic

DNA Data Solutions LLC St Petersburg FL USA

Genespector Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics General University Hospital and the 1st Faculty of Medicine of Charles University Prague Czech Republic

Medirex Group Academy Trnava Slovakia

Newcastle Biomedical Research Centre NIHR Newcastle upon Tyne UK

Renal Services The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Royal College of Surgeons in Ireland Dublin Ireland

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK

Wake Forest School of Medicine Section on Nephrology Winston Salem NC 27157 USA

medRxiv. 2024 Jul 04:2024.07.03.24309887. doi: 10.1101/2024.07.03.24309887. PubMed

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