In the candidate gene approach, information about the distribution of single nucleotide polymorphisms (SNPs) is a crucial requirement for choosing efficient markers necessary for a case-control association study. To obtain such information, we discovered SNPs in 13 genes related to atherosclerosis by resequencing exon-flanking regions of 32 healthy Thai individuals. In total, 194 polymorphisms were identified, 184 of them SNPs, four insertions, and the rest deletions. Fifty-nine of the SNPs were characterized as novel polymorphisms, and these accounted for 30% of the identified SNPs. Comparing allele frequency distributions of the Thai population with other Asian populations shows similar patterns. In contrast, a low correlation pattern (r = 0.521) was found when comparing with either Caucasian or African populations. However, some rare alleles (rs11574541 and rs10874913) are found in the Thai population but not in other Asian populations. Most of the novel SNPs found were located outside the haplotype blocks generated by known SNPs in the Thai population. Only 5.77% of the novel SNPs lies in these defined haplotype blocks. The selection of haplotype-tagging SNPs shows that 8 of 13 genes benefited from the ethnicspecific genotype information. That is, when at least one novel SNP was present, the tagging SNPs chosen were altered. Functional prediction of 16 nonsynonymous SNPs (nsSNPs) by three different algorithm tools demonstrated that five nsSNPs possibly alter their corresponding protein functions. These results provide necessary information for conducting further genetic association studies involving the Thai population and demonstrate that resequencing of candidate genes provides more complete information for full genetic studies.
BackgroundSpondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Besides the major histocompatibility complex (MHC), more than 25 loci have already been associated to the disease using an unrelated case-control design but they explain only a minor fraction of total heritability.ObjectivesWe conducted a family-based genome-wide association study (GWAS) to identify new non-MHC genetic factors associated with SpA.MethodsNine hundred and six subjects from 156 French multiplex families, including 438 affected with SpA, were genotyped using Affymetrix 250K microarray. After quality control, 230,801 single-nucleotide polymorphism (SNPs) were kept for further analyses. Association was tested with Unphased. The best-associated non-MHC SNPs were then genotyped sequentially in two independent familial trio cohorts, one from France and the other from North America (including 215 and 294 subjects, respectively) in order to replicate associations.ResultsForty-three non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1x10-4). In the extension studies, association was replicated at a nominal p-value <0.05 for 16 SNPs in the second cohort and for 3 of these 16 SNPs in the third cohort. Pooled analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=6.2 x 10-7). Such association was independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified a highly associated polymorphism in MAPK14 that codes for the p38-a MAP kinase, a key kinase in immune cell signalling. Further analyses are needed to understand the functional significance of this genetic association.Disclosure of InterestNone declared
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