2016 Genetics, DNA, Gender Matters
Does X Mark the Spot? Novel research will explore if having two X chromosomes make women more susceptible to lupus than men.
The study and what it means to patients
“Our study will examine if having two X chromosomes, rather than the X and Y in men, brings along a double dose of genes that may predispose women to lupus. This insight will get us one step closer to understanding what causes this complex disease.”
Why women are significantly (90%) more likely than men to be diagnosed with lupus is not well understood. Until recently, scientists believed the disparity was due to the influence of sex hormones. However, researchers are now considering the possibility that women, with two X chromosomes, receive a double dose of X-linked genes that somehow predispose them to the disease. (Since men have XY chromosomes, they would only have one dose of X-linked genes.) Our study will research whether the double dose of genes located on the X chromosome does indeed explain the sex-bias found in lupus.
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder in which 90% of patients are women. We suggest an X-chromosome dosage effect increases susceptibility to SLE. Our published data support this theory showing that men with Klinefelter’s syndrome (XXY) and trisomy X women (XXX) are overrepresented in SLE by roughly 15- and 30–fold, respectively, compared to population and healthy controls. We hypothesize that X-linked genes escaping X-inactivation regulate immune responses. Based on lupus animal model studies, we propose X-linked genes that escape X-inactivation in both man and mice: DDX3X, KDM6A, KDM5C, EIF2S3, CXorf38, and CA5B, contribute to X-linked transcriptional dose differences. Preliminary data extracted from a publically available microarray dataset show that DDX3X and CXorf38 mRNA is increased in peripheral blood immune cells. Additionally, our group found that PBMCs had increased DDX3X protein in women compared to men. Potential connection of these genes to immune response, as well as, the preliminary data generated on DDX3X make a compelling case that these proteins are major contributors to, if not entirely responsible for, the X chromosome dosage effect and specifically the sex-bias observed in SLE.