Investigating the genetic association between ERAP1 and ankylosing spondylitis
| Autor: | David Harvey, B P Wordsworth, J J Pointon, Millicent A. Stone, David M. Evans, Roger D. Sturrock, Tugce Karaderi, Louise Appleton, Udo Oppermann, C. Farrar, Matthew A. Brown |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Linkage disequilibrium Genotype Protein Conformation Single-nucleotide polymorphism Biology Aminopeptidases Polymorphism Single Nucleotide Linkage Disequilibrium Cohort Studies Minor Histocompatibility Antigens 03 medical and health sciences 0302 clinical medicine Gene Frequency Genetics Humans Genetic Predisposition to Disease Spondylitis Ankylosing Genetic variability International HapMap Project Allele Molecular Biology Allele frequency Genetics (clinical) 030304 developmental biology Genetic association 0303 health sciences Association Studies Articles General Medicine Sequence Analysis DNA 3. Good health Protein Structure Tertiary Logistic Models Case-Control Studies Imputation (genetics) 030215 immunology |
| Zdroj: | Human Molecular Genetics |
| DOI: | 10.1093/hmg/ddp371 |
| Popis: | A strong association between ERAP1 and ankylosing spondylitis (AS) was recently identified by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium (WTCCC-TASC) study. ERAP1 is highly polymorphic with strong linkage disequilibrium evident across the gene. We therefore conducted a series of experiments to try to identify the primary genetic association(s) with ERAP1. We replicated the original associations in an independent set of 730 patients and 1021 controls, resequenced ERAP1 to define the full extent of coding polymorphisms and tested all variants in additional association studies. The genetic association with ERAP1 was independently confirmed; the strongest association was with rs30187 in the replication set (P = 3.4 x 10(-3)). When the data were combined with the original WTCCC-TASC study the strongest association was with rs27044 (P = 1.1 x 10(-9)). We identified 33 sequence polymorphisms in ERAP1, including three novel and eight known non-synonymous polymorphisms. We report several new associations between AS and polymorphisms distributed across ERAP1 from the extended case-control study, the most significant of which was with rs27434 (P = 4.7 x 10(-7)). Regression analysis failed to identify a primary association clearly; we therefore used data from HapMap to impute genotypes for an additional 205 non-coding SNPs located within and adjacent to ERAP1. A number of highly significant associations (P < 5 x 10(-9)) were identified in regulatory sequences which are good candidates for causing susceptibility to AS, possibly by regulating ERAP1 expression. |
| Databáze: | OpenAIRE |
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