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Proc Natl Acad Sci U S A. Apr 14, 2009; 106(15): 6256–6261.
Published online Mar 27, 2009. doi:  10.1073/pnas.0901181106
PMCID: PMC2669395
Immunology

Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Abstract

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying ≈5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association (P values reaching 10−10, odds ratio >1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell “hyperactivity” associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.

Keywords: autoimmune disease, genetic association, SNP, inflammation, interferon

Systemic lupus erythematosus (SLE) is a debilitating multisystem autoimmune disorder affecting ≈0.1% of the North American population, mainly females, characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, associated with the production of autoantibodies to a multitude of self-antigens (1). The prevalence of SLE varies among ethnic populations (higher in non-Caucasians) and is likely attributable to ethnic differences in genetic susceptibility. Despite many advances in recent years, the pathogenesis of SLE remains largely unclear.

Genetic approaches have gained much power and popularity in identifying the component mechanism(s) underlying the pathogenesis of common human diseases. Forward genetic approaches, in which human populations are studied to identify the genes involved in disease processes, have inherent shortcomings for the analysis of common diseases involving multiple genes because each gene contributes modestly, often in interaction with environmental factors. On the other hand, reverse genetic approaches—in which a gene is characterized by perturbing it in an experimental system, and then elucidating its effect on the trait of interest—have their own significant limitations. Often, such experimental approaches take place in an oversimplified context where potential interactions between the gene of interest and the genetic background or the environment are eliminated and data interpretation may be confounded by the impact of the gene on cell and organismal development. In the present study, a combined forward and reverse genetic approach is pursued, resulting in the unequivocal identification of the gene IRAK1 as an important risk factor for SLE, with a critical role in disease pathogenesis.

Results

We have recently developed a set of programs that implement a combination of automated and manual approaches to maximize the power of gene association studies by using prior information to select and prioritize genes, to reduce the number of SNPs tested resulting in higher power, and to increase the likelihood of uncovering reproducible associations (2). We have previously used this bioinformatics-driven design for a custom-made platform incorporating ≈10,000 SNPs derived from ≈1,000 selected genes to genotype a sample of 753 subjects composed of 251 childhood-onset SLE trios (SLE patient and both parents) (3). Family-based transmission disequilibrium test (TDT) and multitest correction analyses showed a significant association between the IRAK1 gene on chromosome Xq28 and childhood-onset SLE (3).

In the present study, we have used a case-control association approach to test the hypothesis that IRAK1 is a candidate gene predisposing to SLE. To this end, we have tested an independent childhood-onset cohort of 769 childhood-onset SLE patients, 5,337 North American adult-onset SLE subjects, and 5,317 healthy controls, each group being composed of 4 ethnicities as detailed in Table S1. Childhood-onset SLE constitutes a unique subgroup of patients for genetic analysis because the earlier disease onset, the more severe disease course, the greater frequency of family history of SLE, and a lesser contribution of sex hormones in disease development (4, 5) may all translate to a higher genetic load or a more penetrant expression of this genetic load, and this may facilitate gene discovery relative to studies of the adult-onset disease. Therefore, we analyzed childhood-onset and adult-onset groups of SLE patients separately. To account for any potential confounding substructure or admixture, we performed principal component analyses (PCA) (6), as detailed in Methods. Excluding the outliers, the analyses resulted in low inflation factors in all ethnicities except Hispanic Americans, with only the latter requiring additional principal component correction.

Fig. 1 shows the association of IRAK1 SNPs in four racial groups of childhood- and adult-onset SLE. It is noteworthy that the majority of the significantly associated SNPs are within a relatively small interval of 3.3 kb between intron 10 and intron 13 of the IRAK1 gene. Most of these SNPs show significance in multiple ethnicities, as is evident from Fig. 1. The classical Bonferroni correction and similar procedures for controlling the family-wise error rate for multiple testing are both too strict and inappropriate in studies such as the present one because they assume that each test is independent, whereas in actuality a complex and unknown mutual dependence exists among SNPs on the same gene (3, 7). Therefore, for multiple test correction we calculated estimates of the false discovery rate (FDR) q values by using the Benjamini–Hochberg procedure (8) considering the total number of SNPs tested and the 4 different ethnic groups (Table 1). Combined p values were calculated from the per-ethnicity p value by using the Fisher method. Table 1 shows that 5 SNPs out of the 13 tested within the IRAK1 gene showed significant association with SLE in multiple ethnic groups after correction for multiple testing. There are a number of highly significant SNPs with combined p values reaching 10−10, and attaining 10−9 in individual ethnicities, corresponding to FDRs of 10−9 and 10−7, respectively.

Fig. 1.
Association of IRAK1 SNPs with SLE in 4 ethnic groups (EA, European Americans; AA, African Americans; AsA, Asian Americans; HA, Hispanic Americans) in childhood- and adult-onset SLE cases. The position of exons (green rectangles) and introns (connecting ...
Table 1.
IRAK1 SNPs significantly associated with SLE in multiple ethnic groups after multitest-correction analyses

Three of the 5 associated SNPs (rs2239673, rs763737, and rs7061789) overlap in both the childhood- and adult-onset SLE patients, suggesting a similar involvement of IRAK1 in both adult- and childhood-onset SLE. The odds ratio (ORs) of all significantly associated SNPs are in the same direction (>1), implying that there was no residual population stratification. It is also noteworthy that ORs for the associated SNPs, with the exception of rs5945174, are >1.5, a value that compares well with published associations in SLE and other similar complex human disorders (914).

The most significantly associated SNPs are in a linkage-disequilibrium block that extends from intron 10 to intron 13 of the IRAK1 gene. Haplotype analyses in different racial groups show that the GGGG haplotype (defined as “G” at rs2239673, “G” at rs763737, “G” at rs5945174, and “G” at rs7061789) is significantly associated with disease in 3 of the 4 racial groups in adult-onset SLE and in 3 ethnicities in childhood-onset SLE (Table 2 and Fig. S1). The p values for association reach 10−5 in children and 10−6 in adults. On the other hand, the AAAA haplotype is clearly associated with protection from disease.

Table 2.
IRAK1 haplotype block associated with SLE with P <0.05

Currently no human biological system is available that would allow one to ascertain an in vivo connection between IRAK1 and its biological relevance in SLE. To test this, we turned to the laboratory mouse, as mice lacking IRAK1 function and mice prone to spontaneous lupus have both been described on the same C57BL/6 (B6) genetic background (1517). Recent studies have succeeded in defining the genetic basis of lupus in the NZBxNZW derived NZM mouse models, and have uncovered Sle1 on chromosome 1 and Sle3 on chromosome 7 as 2 of the most critical elements for disease in these models (1620). By introgressing these intervals onto the relatively normal C57BL/6 (B6) background, the immunological properties of these 2 key loci have been elucidated (16, 17). Whereas a critical gene within the Sle1 interval, Ly108, breaches central B cell tolerance, resulting in anti-chromatin autoreactivity and lymphocytic activation (19), the Sle3 gene(s) contributes to SLE by activating myeloid cells, including dendritic cells (DCs) (20). Importantly, the combined action of these 2 loci leads to full-blown lupus and lupus nephritis, which is indistinguishable from the disease noted in the traditionally studied (NZBxNZW)F1 and NZM mouse models (18).

Because Sle1 and Sle3 represent 2 key complementary loci for SLE development, we evaluated the role of IRAK1 in mediating the contributions of these 2 loci to SLE pathogenesis. B6.Sle1z mice (that were homozygous for the Sle1z allele) were bred to B6.IRAK1−/Y mice (15), to eventually derive B6.Sle1z.IRAK−/Y mice. Because Sle1z leads to spontaneous anti-nuclear antibody formation on the B6 background, notably anti-histone/DNA antibodies, splenomegaly, and spontaneous B cell and T cell activation (16), these phenotypes were first examined. Compared to age- and sex-matched B6.Sle1z control, B6.Sle1z.IRAK1−/Y mice exhibited significantly reduced IgM and IgG autoantibodies to ssDNA, histone/DNA, and dsDNA (Fig. 2). Likewise, B6.Sle1z.IRAK1−/Y mice also exhibited reduced spleen weights, total splenocyte counts, as well as total B cell and CD4-positive T cell counts, compared with the controls with an intact IRAK gene (Fig. 3). In addition, the absence of IRAK1 also dampened the number of B cell blasts (as gauged by forward scatter analysis) (Fig. 3E) and reduced the numbers of activated CD4 T cells as assessed by surface CD69 expression (Fig. S2). No differences were, however, noted in the expression of surface CD86 or CD69 on B cells from both strains. Collectively, the above findings indicate that the absence of IRAK1 significantly attenuated the serological and cellular phenotypes attributed to the lupus susceptibility locus, Sle1.

Fig. 2.
Reduced serum IgM and IgG autoantibodies in B6.Sle1z.IRAK1−/Y mice. B6.Sle1z mice (homozygous for the z allele of Sle1) either sufficient or deficient in IRAK1 (n = 15–20) were examined at the age of 9–12 months for serum levels ...
Fig. 3.
Cellular phenotypes in B6.Sle1z.IRAK1−/Y mice. B6.Sle1z mice either sufficient or deficient in IRAK1 (n = 7–10) were examined at the age of 4–6 months for spleen weight (A) and cellularity (B–D), as well as the mean B cell ...

Next, we proceeded to examine the impact of IRAK1 in mediating the lupus contributions of the second locus, Sle3. In the B6 background, Sle3z leads to low-grade anti-nuclear serological autoreactivity, myeloid cell hyperactivity resulting in secondary activation of lymphocytes, and a modest degree of nephritis (17, 20). Compared to B6.Sle3z controls, B6.Sle3z.IRAK1−/Y mice exhibited significantly reduced IgM and IgG anti-ssDNA and anti-dsDNA Abs (Fig. 4 A and B, D and E), as well as milder or negligible renal disease, as evidenced by the reduced proteinuria and renal glomerular pathology (Fig. 4 C and F). Moreover, these mice had reduced splenocyte numbers, including total T cells and B cells (Fig. S3). A cardinal feature associated with Sle3z, namely increased CD4:CD8 ratios, were normalized by the absence of IRAK1 (Fig. 5F). Because the above phenotypes had previously been attributed to the intrinsic impact of Sle3z on myeloid cells (20), these were examined next. Although the strains did not differ in absolute numbers of splenic myeloid cell subpopulations, interesting differences in their activation and maturation status were observed. In the absence of IRAK1, Sle3z myeloid DCs and macrophages examined ex vivo from spleens showed reduced surface expression of CD80, but not CD40 or CD86 (Fig. 5 A and B and Fig. S4). These differences became more pronounced when bone marrow (BM)-derived DCs were examined. Thus Sle3z BM-DCs deficient in IRAK1 exhibited reduced levels of several activation/maturation markers both basally and after TLR ligation using poly(I·C) or CpG (Fig. 5 C and D). The IRAK1-deficient B6.Sle3z DCs also produced reduced levels of proinflammatory cytokines, such as TNF-α (Fig. 5E). Hence, all of the phenotypes previously attributed to the Sle3z lupus susceptibility locus appear to be, at least partly, dependent upon IRAK1 function.

Fig. 4.
B6.Sle3z.IRAK−/Y mice exhibit reduced serum autoantibodies and nephritis. (A, B, D, and E) B6.Sle3z mice (homozygous for the z allele of Sle3) either sufficient or deficient in IRAK1 were examined at the age of 9–12 months for serum levels ...
Fig. 5.
Cellular phenotypes in B6.Sle3z.IRAK1−/Y mice. (A–D) B6.Sle3z mice either sufficient (shown in pink) or deficient (shown in green) in IRAK1 were examined at the age of 4–6 months for the surface expression of activation/maturation ...

Discussion

IRAK1 (interleukin-1 receptor associated kinase 1) is a serine/threonine protein kinase involved in the signaling cascade of the Toll/IL-1 receptor (TIR) family (21). The TIR family comprises the IL-1 receptor subfamily, recognizing the endogenous proinflammatory cytokines IL-1 and IL-18, and members of the Toll-like receptor (TLR) subfamily, which recognize pathogen-associated molecular patterns. A hallmark of the TIR family is the cytoplasmic TIR domain, which serves as a scaffold for a series of protein–protein interactions, which result in the activation of a unique and exclusive signaling module consisting of MyD88, IRAK family members, and Tollip. Subsequently, several central signaling pathways of the innate and adaptive immune systems are activated in parallel, the activation of NFκB being the most prominent event of the inflammatory response (21). Particularly noteworthy is the observation that IRAK1 is considered to be the “on-switch” of the signaling complex by linking the receptor complex to the central adapter/activator protein TRAF6, and also the “off-switch” of the complex because of its autoinduced removal from the complex (22). The extensive involvement of IRAK1 in the regulation of the immune response renders its association with SLE a prime candidate for careful genetic and functional analysis.

We envision the potential involvement of IRAK1 in at least the following 3 immune cell functions that have been reported to be aberrant in SLE. First, IRAK1 is involved in the induction of IFN-α and IFN-γ: the production of both types of IFN has been shown to be aberrant in SLE (23, 24). Second, IRAK1 is a pivotal regulator of the NFκB pathway. Abnormal NFκB activity in T lymphocytes from patients with SLE has been amply documented (25). Finally, a growing number of studies demonstrate a role for TLR activation in the pathogenesis of SLE, including the activation of anti-nuclear B cells and the subsequent immune complex formation (26). The murine studies presented in this communication resonate well with the earlier published literature on IRAK1.

The most significantly associated SNPs are in a linkage-disequilibrium block that extends from intron 10 to intron 13 of the IRAK1 gene, encompassing exons 11–13, which correspond to the C1 domain of IRAK1 (27). It has been shown that this domain is at least partially responsible for the interaction with signal transduction factors such as TRAF6 (28). Furthermore, a naturally occurring splice variant of IRAK1, IRAK1c, lacks exon 11 and most of exon 12 (27). A previous report suggests that IRAK1c may suppress NFκB activation and inhibit innate immune activation (29) and thus suppress chronic inflammatory responses. This region contains a putative nuclear localization sequence (amino acids 503–508) as well as a nuclear exit sequence (amino acids 518–526). The absence of these sequences may explain IRAK1c's stability and cytoplasmic localization and possibly its antiinflammatory role. It is therefore tempting to hypothesize that the SLE-associated haplotype block may affect these activities of IRAK1. Clearly, these predictions warrant direct testing in future studies.

IRAK1 is located on chromosome Xq28, juxtaposed to a second gene that has also been implicated in SLE susceptibility. A recent study by Sawalha et al. (30) reported the association of the neighboring gene, MECP2, and SLE in Korean and European cohorts. Given the physical proximity of IRAK1 and MECP2 on Xq28, it is plausible that they are in linkage disequilibrium, and the 2 independent studies possibly describe the same genetic association. However, without further reverse genetic studies, it would have been impossible to ascertain whether the disease-causative polymorphism(s) exert their effect through changes in IRAK1 or MECP2. In this regard, the reverse genetic studies presented in this communication shed light on this ambiguity, allowing us to confidently establish that the IRAK1 gene has a critical role in the pathogenesis of SLE. Whether MECP2 is also a causative gene for lupus awaits support from analogous experiments with that gene. Nevertheless, the results we present herein with IRAK1 exemplify the power of combining forward genetic studies in patient cohorts with reverse genetic and functional studies in animal models to elucidate the genetic basis of complex diseases. This powerful bipronged approach can be gainfully used in studies of other genes in SLE and yet other complex genetic diseases.

Although it is too early to suggest the mechanism(s) by which the IRAK1 polymorphisms may alter the disease process in humans, the murine studies presented in this communication suggest an important role for IRAK1 at 2 key checkpoints in lupus development. The first step, which leads to benign serological and cellular autoreactivity, may be the consequence of a breach in central tolerance in the adaptive arm of the immune system, whereas the second step, which leads to pathological autoimmunity, may be mediated by increased activity in the innate arm of the immune system (19, 20, 31). It is remarkable that IRAK1 significantly impacts both checkpoints in lupus development. The likely role of IRAK1 in driving the second checkpoint, myeloid cell hyperactivity, is quite apparent given the central role of IRAK1 in mediating TLR signaling, and hence myeloid cell activation (27). In contrast, the potential role of IRAK1 and TLR signaling at various B cell checkpoints is currently unknown and warrants careful analysis to better understand how IRAK1 might operate in the first checkpoint of lupus development. Conditional deletion of IRAK1 in selected cell types is clearly necessary to address this important gap in our knowledge. Along these lines, future studies elucidating the mechanistic role that IRAK1 might play at both these checkpoints are clearly warranted. The impact of IRAK1 deficiency on other polycongenic models of severe lupus nephritis also needs to be explored.

Several autoimmune disorders are characterized by a strong sex bias, with females being afflicted by SLE almost 10 times more frequently than males. Research efforts over the past 3 decades have implicated sex hormones as being responsible for the sex difference in disease susceptibility. However, effects of sex hormones do not rule out a more direct effect of the X chromosome. Very little is known about whether genes on the sex chromosomes can directly influence SLE susceptibility. Recent reports in mouse models have indicated that genes located on X/Y chromosomes could potentially influence lupus susceptibility (3234). The present report constitutes the demonstration of a sex chromosome gene in human SLE. The data presented here provide clear evidence that the female predominance of the disease could be attributed, at least in part, to IRAK1 gene dosage by virtue of its location on the X chromosome. The challenge ahead is to fathom the degree to which the sex difference in SLE prevalence can be attributed to X chromosome genes (such as IRAK1) versus hormonal differences.

Methods

Recruitment and Biological Sample Collection.

Subjects were enrolled in the Lupus Genetic Study Groups at the University of Southern California and the Oklahoma Medical Research Foundation, in the PROFILE Study Group at the University of Alabama at Birmingham, and from B.L.M., T.J.V., G.S.G., and S.-C.B., using identical protocols. All patients met the revised 1997 American College of Rheumatology criteria for the classification of SLE (35). Ethnicity was self-reported and verified by parental and grandparental ethnicity, when known. Blood samples were collected from each participant, and genomic DNA was isolated and stored by using standard methods. Cases were defined as childhood-onset according to the criterion that the diagnosis of SLE was made before the age of 13 by at least 1 pediatric rheumatologist participating in the study. All protocols were approved by the institutional review boards at the respective institutions.

Genotyping, Statistical and Stratification Analyses, Immunophenotyping of Mice.

For more information, please see SI Text.

Establishing IRAK1-Deficient Lupus Mice.

All mice used were on the C57BL/6 (B6) background. B6.IRAK1−/Y, B6.Sle1z, and B6.Sle3z mice have been characterized previously (1518). B6.IRAK1−/Y mice were bred to B6-based Sle1z or Sle3z lupus congenics to derive F1 hybrids. The F1 hybrids were intercrossed to generate F2 progeny that were then selected for mice that genotyped as B6.Sle1z.IRAK1−/Y or B6.Sle3z.IRAK1−/Y, both strains being homozygous at the respective lupus susceptibility loci. Because IRAK1 is located on the X chromosome, male IRAK1−/Y mice were used as IRAK1-deficient mice, whereas IRAK1+/Y males were used as controls in all experiments. All mice used for this study were bred and housed in a specific pathogen-free colony at the University of Texas Southwestern Medical Center Department of Animal Resources in Dallas, TX.

Supplementary Material

Supporting Information:

Acknowledgments.

We thank Drs. Yang Liu and Yong Du for their technical assistance. This work was supported in part by National Institutes of Health Grant R01AR445650 and an Alliance for Lupus Research Grant 52104 (C.O.J.), the National Institutes of Health Grant P01 AI 039824, and the Alliance for Lupus Research (C.M.), and by the University of Southern California Federation of Clinical Immunology Societies Centers of Excellence. Work at the Oklahoma Medical Research Foundation was supported by National Institutes of Health Grants (AI063622, RR020143, AR053483, AR049084, AI24717, AR42460, AR048940, AR445650, and AR043274). Work at the University of Alabama at Birmingham was supported by National Institutes of Health Grants P01-AR49084 and P60-AR48095. S.-C.B. was supported by Republic of Korea Ministry for Health Grant A010252.

Footnotes

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0901181106/DCSupplemental.

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