Can an Extra X Chromosome Amplify Autoimmune Disease Risk?

TOPLINE:

Extra X chromosomes significantly increase the risk for systemic lupus erythematosus (SLE) and Sjögren disease, with the prevalence of these conditions being higher among patients with Klinefelter and triple X syndromes than among men and women in the general population, respectively.

METHODOLOGY:

• Researchers conducted a multicenter, retrospective cohort study using TriNetX, a global federated health research network, to investigate the influence of extra X chromosomes on the development of SLE and Sjögren disease in patients with Klinefelter and triple X syndromes.
• International Classification of Diseases, 10th Revision, Clinical Modification codes were used to identify patients with a diagnosis of SLE or Sjögren disease in the general population and in those with Klinefelter syndrome and triple X syndrome between January 2010 and January 2024.
• Of the 113,748,373 patients identified, 1975 were men with Klinefelter syndrome and 1136 were women with triple X syndrome.

TAKEAWAY:

• The prevalences of SLE and Sjögren disease among men in the general population were 0.059% and 0.077%, respectively, while those among women in the general population were 0.381% and 0.388%, respectively; the male-to-female ratio was 1:6.4 for SLE and 1:5 for Sjögren disease.
• The prevalence of both SLE and Sjögren disease was 0.5% in patients with Klinefelter syndrome, while the prevalences of SLE and Sjögren disease were 1.3% and 0.8%, respectively, in patients with triple X syndrome.
• The prevalences of SLE and Sjögren disease were 8.5-fold and 6.6-fold higher in men with Klinefelter syndrome than in men in the general population (P
• SLE was 3.5-fold more likely (P P

IN PRACTICE:

“The extra X chromosomes in [Klinefelter syndrome] (47, XXY) and triple X syndrome (47, XXX) appear to confer a synergistic, nonproportional susceptibility to the development of SLE and [Sjögren disease] beyond what is seen in the general population,” the authors wrote. “This supports previous literature suggesting that X chromosome dose partially explains the disproportionate prevalence of some autoimmune diseases between men and women.”

SOURCE:

This study was authored by Anna-Kay Palmer, MD, and Irene J. Tan, MD, of Jefferson Einstein Hospital, Philadelphia. It was published online on January 23, 2025, in ACR Open Rheumatology.

LIMITATIONS:

Many patients with Klinefelter and triple X syndromes remain undiagnosed, which may lead to their inclusion in “normal” men and women population cohorts. The reliance on self-identification rather than karyotyping might have affected the accuracy of this study. Inaccurate diagnostic coding might have introduced errors. Due to the use of deidentified data, researchers were unable to verify if SLE or Sjögren disease was diagnosed according to the American College of Rheumatology criteria. Though the study demonstrated increased prevalence of autoimmune conditions with additional X chromosomes, it could not establish causality.

DISCLOSURES:

The authors reported being principal investigators for trials supported by Navidea Biopharmaceuticals and AbbVie.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.