X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

Abstract

Objective More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX , 1 in ~1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren’s syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls. Methods We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR). Results We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ~404 SLE women and ~344 SS women. 47,XXX was present in excess among SLE and SS subjects. Conclusion The estimated prevalence of SLE and SS in women with 47,XXX was respectively ~2.5 and ~2.9 times higher than in 46,XX women and ~25 and ~41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

“…Conversely, Klinefelter men were not found in our RA cohort. Other data from our group also show that SS and SLE women with three X chromosomes (47,XXX) are increased in numbers compared to healthy controls [18]. Taken together these data suggest a chromosome dosage effect in these two sex-bias autoimmune disorders; namely, Sjögren's syndrome and systemic lupus erythematosus.…”

“…Thus, difference in sex hormones induced by the presence of two X chromosomes may underlie the X chromosome dose effect. However, 47,XXX women have normal sex hormone levels when compared to 46,XX women, but are found in excess among women with either SLE or Sjögren's syndrome [18]. We propose that these data argue against a sex hormone effect.…”

“…We have not found an X chromosome effect for men with RA, nor have we found excess 47,XXX among women with either RA or primary biliary cirrhosis [18]. In addition, Turner's syndrome women (45,XO) are at increased risk for type 1 diabetes, autoimmune thyroid disease, and celiac disease, but not SLE [19].…”

Incidence and Mortality of Physician-Diagnosed Primary Sjögren Syndrome

“…It mainly affects middle-aged females, with a strong sex bias potentially explained by an X chromosome dose effect 11 . pSS occurs as a primary disorder, and secondary SS may occur with other systemic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus 12, 13 .…”

Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome

“…Klinefelter's syndrome (male 47,XXY) occurs in~1 in 500 live male births, but 80% of these men remain undiagnosed (4). We have found excess 47,XXY among men with either SLE (7,8) or SS (9), as well as excess 47,XXX among women with these diseases (10). We have found excess 47,XXY among men with either SLE (7,8) or SS (9), as well as excess 47,XXX among women with these diseases (10).…”