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

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Kaufman, Kenneth M
Zhao, Jian
Kelly, Jennifer A
Hughes, Travis
Adler, Adam
Sanchez, Elena
Ojwang, Joshua O
Langefeld, Carl D
Ziegler, Julie T
Williams, Adrienne H



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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 and lt;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-KB 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.
Palabras clave
Immunoglobulin enhancer binding protein , Interleukin 1 receptor associated kinase 1 , systemic , single nucleotide , human , Messenger rna , Methyl cpg binding protein 2 , Amino acid substitution , Arhgap4 gene , Article , Asian , Avpr2 gene , Case control study , Chromosome xq , Chromosome xq28 , Controlled study , Ethnic difference , European american , Gene , Gene location , Gene mapping , Genetic association , Genetic risk , Genetic susceptibility , Genotype , Haplotype , Hcfc1 gene , Hispanic , Human , Irak1 gene , L1cam gene , Major clinical study , Mecp2 gene , Naa10 gene , Negro , Plesiomorphy , Priority journal , Protein function , Real time polymerase chain reaction , Renbp gene , Single nucleotide polymorphism , Systemic lupus erythematosus , Tmem187 gene , Base sequence , Chromosome mapping , Chromosomes , Continental population groups , Genetic predisposition to disease , Genotype , Haplotypes , Humans , Interleukin-1 receptor-associated kinases , Lupus erythematosus , Methyl-cpg-binding protein 2 , Molecular sequence data , Polymorphism , Real-time polymerase chain reaction , Risk factors