Xq28 and lupus: IRAK1 or MECP2?

IRAK1 and MECP2 are in the same haplotype block on chromosome Xq28, and we previously reported the association between this genetic locus and lupus (1). Due to high linkage disequilibrium (LD) in this locus, both IRAK1 and MECP2 should be considered candidate associations, as a polymorphism in either IRAK1 or MECP2 could explain the genetic effect observed by Jacob et al. (2). We disagree that abrogation of lupus manifestations in an IRAK1-deficient lupus mouse model localizes the lupus susceptibility gene in the Xq28 locus to IRAK1. Thorough implementation of “reverse genetics” in this setting requires a study on the effect of the disease-causing polymorphism in human disease by using an animal model. Jacob et al. (2) did not identify the disease-causing polymorphism in Xq28, whether it is in IRAK1 or MECP2, whether it affects IRAK1 or MECP2 function or expression or both, or whether it is a gain-of-function or a loss-of-function polymorphism. Their studies (2) in an IRAK1-deficient mouse revealed that IRAK1 is involved in autoimmunity. However, this gives no indication that the lupus-associated genetic effect in Xq28 in human disease is in IRAK1, as the authors propose. Indeed, IRAK1 expression is regulated by MECP2 (3, 4). We caution against applying the term “reverse genetics” within the context of the paper published (2). Until resequencing of this locus identifies the lupus-causing polymorphism in Xq28, or proper functional studies of the disease-associated haplotype in humans demonstrate dysfunction of IRAK1 or MECP2, either of the 2 genes or possibly both remain candidates.