Investigating X-chromosome-related Differences in Scleroderma


Erika Darrah, PhD
Johns Hopkins University

Project Overview

Dr. Darrah: Scleroderma or systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs, and marked by autoantibodies to nuclear antigens. Like most autoimmune diseases, SSc disproportionately affects women with an estimated 4:1 female to male ratio. Many factors have been implicated in rendering females more susceptible to autoimmune diseases such as SSc, including the X chromosome itself, but the specific causes of this skewed gender susceptibility remain unknown.

An individual’s susceptibility to autoimmunity appears to correlate with the number of X chromosomes that individual has. This concept is highlighted by the increased risk of autoimmune diseases among women and men with Klinefelter’s syndrome. Klinefelter’s syndrome is a rare genetic condition in which biological men have two X chromosomes. Large cohort studies have demonstrated a 14-fold increase in the prevalence of Klinefelter’s syndrome among males with either Sjogren’s syndrome or systemic lupus erythematosus compared to healthy males. In addition, there have been 9 case reports of Klinefelter’s syndrome co-occurring with SSc. This supports the hypothesis that qualities uniquely present in individuals with more than one X chromosome, rather than biological sex, may be important drivers of SSc development. We are taking a novel approach to investigating these qualities in scleroderma.

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