Identification of Genes Associated with Risk to Aplastic Anemia (AA) Using Array-Based Genotyping.

In this study we tested whether 3104 SNPs in 200 candidate genes were associated with risk to aplastic anemia (AA). Genes were considered potential candidates for their known or suspected roles in DNA repair system, pharmacogenomics and transcriptional regulation in hematopoiesis or putative pathways related to development of AA. Selection of SNPs was performed using dbSNP and HapMap project databases, with emphasis on non-synonymous SNPs or haplotype tagging SNPs. To discover potential SNPs responsible for AA susceptibility, a case-control study using Affymetrix targeted genotyping 3K array was designed. We applied 3K array to analyze the samples from 132 AA patients and 382 healthy controls. Genotyping were processed using GeneChip scanner 3000 TG(Affymetrix) and analyzed with GCOS software(Affymetrix). In total more than 160,000 SNPs were genotyped for this study. Samples with suboptimal call rates were excluded. Statistical testing were carried out using χ², Cochran-Armitage trend, Fisher’s exact, odds ratio, haplotype estimation, LD block definition. Here we report that 19 SNPs in 14 genes are associated with elevated or reduced risk to AA. Three associated genes map to chromosome 11 and 16 respectively. Some of associated genes were transcription factors such as RARB and ZNF233. Among those associated SNPs, one was located in coding region while the rest of SNPs were located in introns of associated genes. In conclusion, we identified SNPs responsible for AA susceptibility by candidate gene-based SNP array approach. These promising data when supported by further molecular validation would greatly enhance the current understanding of AA predisposition and diseases progression. Implication of polymorphic variants in AA etiopathogenesis will be presented and discussed.