ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: L01

Analysis of 245,388 Diverse Participants in the NIH All of Us Cohort Identifies VEXAS Resiliency in UBA1 M41L Somatic Mutation Carriers

Robert Corty1 and Alexander Bick2, 1Vanderbilt University Medical Center, Nashville, TN, 2Vanderbilt University, Nashville, TN

Meeting: ACR Convergence 2023

Date of first publication: October 24, 2023

Keywords: Autoinflammatory diseases, Bioinformatics, genetics, Late-Breaking 2023

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Date: Tuesday, November 14, 2023

Title: Late-Breaking Abstract Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: VEXAS syndrome is a recently-discovered systemic auto-inflammatory disease caused by somatic mutation at position 41 in the X-linked gene UBA1.1 First, 25 older men with M41T, M41V, or M41L with variant allele fraction (VAF) 35-80% were reported among quaternary referral populations of severely ill patients. A later study of 163,096 patients participating in a regional health system research cohort found 8 older men with the same UBA1 M41X mutations, with VAF 9-74%.2 Nearly all had severe anemia and macrocytosis, and five had a clinical diagnosis of VEXAS. This study population was >96% White and more than half of participants were >60 years old. Thus, there is a critical unmet need to define the prevalence and clinical consequences of somatic UBA1 M41L mutation in a racially and geographically diverse population.

Methods: We analyzed 245,388 individuals with clinical-grade whole genome sequencing data in the NIH All of Us cohort v7 data release.3 Somatic variants in UBA1 were identified with Mutect2 4, annotated with Annovar 5, and filtered in R version 4.2.2 6 based on published pragmatic guidelines.7 VEXAS-associated SNOMED codes, laboratory abnormalities, and medications were defined by literature search of symptoms of confirmed cases.1,2,8 Controls were identified in a 10:1 ratio based on matching age and sex.

Results: 74 participants in the NIH All of Us cohort harbor somatic mutation UBA1 M41L and none have the other well-described variants, M41V or M41T. The M41L mutation was more common among women than men (n = 62 vs 12, p < 0.001) and no effect of age (p = 0.17) or ancestry (p > 0.4) was observed. The cases are age 20 to 83 and have VAF 4.5% to 33%. Their ancestry is 51% European, 27% African, and 19% admixed/Latino. The number of VEXAS-associated diagnosis codes was similar between cases and controls (4.3 vs 3.6, p = 0.77), but cases had an increased rate of asthma (27% vs 18%, p < 0.001), Tietze’s syndrome (8% vs 2%, p < 0.001), and neutropenia (7% vs 2%, p = 0.005). The minimum observed hemoglobin was similar between cases and controls (11.5 vs 11.4 mg/dL) as was the maximum mean corpuscular volume (91.7 vs 91.4). Interestingly, cases were much more likely to be prescribed systemic steroids than matched controls (55% vs 0%, p < 0.001).

Conclusion: We describe the largest cohort of people with somatic mutation M41L in the UBA1 gene and the largest cohort of women with a VEXAS-associated mutation. The diagnosis codes and laboratory values do not comport with the severe, systemic illness that has characterized our understanding of VEXAS to date. However, these cases were prescribed systemic steroids at a much higher rate than matched controls and are enriched for a few idiopathic inflammatory diagnoses suggesting an incompletely-appreciated inflammatory syndrome. These cases are younger, healthier, have lower VAF, and much better represent the demographic and geographic diversity of the United States than previous reports. We hypothesize that many of the cases reported here will not develop VEXAS due to either somatic reversion or haplosufficiency of UBA1. Further characterization of the genetic and clinical trajectories in these individuals may permit strategies for risk stratification, monitoring, and treatment.

Supporting image 1

Table 1: Demographic characteristics of participants with somatic mutation M41L in UBA1 closely mirror their matched controls.

Supporting image 2

Figure 1: Participants with with somatic mutation M41L in UBA1 reside in geographically diverse parts of the United States.

Supporting image 3

Figure 2: Participants with with somatic mutation M41L in UBA1 have similar minimum hemoglobin concentration and maximum mean corpuscular volume (MCV) as compared to matched controls.


Disclosures: R. Corty: None; A. Bick: None.

To cite this abstract in AMA style:

Corty R, Bick A. Analysis of 245,388 Diverse Participants in the NIH All of Us Cohort Identifies VEXAS Resiliency in UBA1 M41L Somatic Mutation Carriers [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/analysis-of-245388-diverse-participants-in-the-nih-all-of-us-cohort-identifies-vexas-resiliency-in-uba1-m41l-somatic-mutation-carriers/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/analysis-of-245388-diverse-participants-in-the-nih-all-of-us-cohort-identifies-vexas-resiliency-in-uba1-m41l-somatic-mutation-carriers/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology