Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Abstract

Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.

Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.

Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064).

Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Figure 1. Association of SNPs in the Xq28 region with SLE

A) The genomic structure of the Xq28 region and the location of all SNPs are indicated. B) Association signals (−log₁₀P) are plotted against the position of each SNP in EA, AS, HA and AA, respectively. Genotyped and imputed SNPs are indicated as circles and triangles, respectively. SNPs are highlighted using different colors according to their LD strength (r²) with rs1059702 (shown as a black circle). An arrowhead is used to indicate the position of rs1059702. The dashed line represents the significance level after Bonferroni correction. C) Trans-ancestry meta-analysis P value generated using fixed and random model are highlighted as red and blue, respectively. The dashed line represents the significance level of 5×10⁻⁸.

Figure 2. A SLE-risk haplotype share by all four ancestral groups

Haplotypes were constructed using 34 SNPs shown in Table 1. Haplotype H1 (highlighted in green) was consistently associated with SLE in all 4 ancestral groups. Allele conferring risk of SLE is bolded and italicized.

Figure 3. Association of rs1059702 genotype with IRAK1 and MECP2 mRNA levels

Expression levels of IRAK1 and MECP2 (total level of all isoforms) were measured in PBMCs of SLE patients and healthy controls with European ancestry using real-time quantitative PCR. The expression level of housekeeping gene RPLP0 was used as an endogenous control. Log10 value of relative mRNA levels of IRAK1 and MECP2 were compared between different genotypes of rs1059702 (G+GG vs. A+AA) in SLE and control groups, respectively, using t test. Females are highlighted as black.