Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G
Fernando MMA., Freudenberg J., Lee A., Morris DL., Boteva L., Rhodes B., Gonzalez-Escribano MF., Lopez-Nevot MA., Navarra SV., Gregersen PK., Martin J., Vyse TJ., Rioux JD., Goyette P., Hammarström L., Green T., De Jager PL., Foisy S., Wang J., De Bakker PIW., Leslie S., McVean G., Padyukov L., Alfredsson L., Annese V., Hafler DA., Pan-Hammarström Q., Matell R., Sawcer SJ., Compston AD., Cree BAC., Mirel DB., Daly MJ., Behrens TW., Klareskog L., Oksenberg JR., Hauser SL.
Objectives: Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. Methods: A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. Results: Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. Conclusion: These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.