Identifying Immunogenetic Features That Distinguish Immune Mediated, Immunosuppression-Sensitive Disease in Aplastic Anemia (AA)

• Published in: Blood 2012-11, Vol.120 (21), p.3481-3481
• Main Authors: Afable, Manuel G., Guo, Theresa, Przychodzen, Bartlomiej P, Rybicki, Lisa, Clemente, Michael J., Jerez, Andres, Husseinzadeh, Holleh D, Evans, Edward P, Lichtin, Alan E., Wodnar-Filipowicz, Aleksandra, Sekeres, Mikkael A., Maciejewski, Jaroslaw P.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.3481.3481

Abstract 3481 A significant proportion of patients with idiopathic AA respond to immunosuppressive therapy (IST), suggestive an ex juvantibus autoimmune pathogenesis. Refractory cases may be due to either insufficient intensity of IST or exhaustion of stem cell reserves. Similarly, there may be a non-immunological component of the disease that cannot be distinguished clinically to date. Multiple trials of various ISTs often delay potentially curative therapy with bone marrow transplantation (BMT); hence, identification of this subtype is of great importance. Immune-mediated AA may have measurable immunogenetic determinants, such as HLA genes, that modify susceptibility to, character of, or intensity of autoimmune reactions. We hypothesize that genetic polymorphisms may exist in immune cytokines, cytokine receptors, and immune regulatory genes that may be markers of immune-mediated disease. We applied a custom cancer chip (Illumina) containing 211,155 probes for mostly non-synonymous single-nucleotide polymorphisms (SNPs) to perform focused bioanalysis on 32 immunogenetic polymorphisms. Our cohort included 152 patients; AA (N=91), AA/PNH (N=38), and PNH (N=23). Results were compared to internal control and previously published results with comparable populations. Median age was 45 years (5–80 years); 92% (N=109) had normal cytogenetics; 67% (N=96) had IST with an overall response rate (ORR) of 65%; 11% (N=17) underwent hematopoietic stem cell transplant; 43% (N=49/114) were positive for HLA DR15. The following genotypes had higher incidence in our AA cohort vs. controls: IL1A C(1202)T (rs1800794) CC 60% vs. 35% (p=C (rs2070874) CC 68% vs. 29% (p=T (rs2243250) CC 95% vs. 74% (p=G (rs1800797) AA 17% vs. 8% (p=.006), IL10 –1082G>A (rs1800896) AA 39% vs. 20% (p=A (rs1800629) GG 95% vs. 71% (p=C (rs1800872) AA 16% vs. 6% (p=.005). Among AA subtypes, we compared the frequency of each genotype: IL10 –592 A>C (rs1800872) was more frequent in AA vs. PNH (p=.003); both homozygous genotypes, CC and TT of TGF b1 codon 10 +869 C/T (rs1800470) were increased in AA vs. AA/PNH (p=.007). Frequency of CC genotype of CR2 C>T (rs2802221) was increased in AA vs. PNH (p=.003). Differences were also present in CR2 (S663P exon 11, rs4308977) and CR2 (rs6667140) in AA vs. AA/PNH (p=.001), AA vs. PNH (p=.031), and in AA vs. AA/PNH (p=.002)