Background Of those with systemic lupus erythematosus (SLE), about 90% are women. We have reported that the female bias of the disease is related to not phenotypic sex, but instead to the complement of X chromosomes. Turners women and 46,XY men have low incidence of SLE, while 46,XX women and 47,XXY men have incidences about 10 times higher than individuals with one X chromosome. In addition, 47,XXX women (1 in ~1000 live female births) are over-represented among SLE patients. We undertook the present study to study the segregation of 47,XXX with SLE within SLE families.
Methods Women with SLE along with their sisters and mothers were enrolled in the Lupus Family Registry and Repository. Subjects were assessed by questionnaire, interview, medical records abstraction and serological examination. All patients met the revised ACR classification criteria, while unaffected family members were shown not to meet these criteria. The number of X chromosomes was assessed by examination of single nucleotide polymorphism typing of the X and Y chromosomes.
Results We studied 2948 women with SLE along with 2116 SLE-unaffected family members, almost entirely sisters and mothers of the SLE patients. Among the total of 5064, we found 7 individuals with 47,XXX, or 1 in 723 (or 0.00138), which was not significantly different from the known 47,XXX population rate (0.0006 to 0.0028 (1/1667 to 1/357 by binominal 95% confidence intervals). All seven 47,XXY subjects had SLE.
Conclusions Among SLE families there was the expected number of women with 47,XXX, approximately 1 in 1000. However, all 47,XXX subjects had SLE. Thus, a 47,XXX karyotype segregated exclusively with SLE within these families. We conclude that carriage of 47,XXX is a powerful risk factor for SLE.
Funding Source(s): Lupus Research Alliance; US Department of Veterans Affairs; National Institutes of Health
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