rs1052576

also known as Q221R rs1052576 is located on chromosome 1p36.21 in the coding region of CASP9. The CAG to CGG transition results in the allele Q221R. This SNP is associated with ADHD, general cancer risk, multiple myeloma, non-small cell lung cancer and non-Hodgkin lymphoma .Generally the A allele confers protection from a variety of cancers. An intact apoptotic pathway is essential for many cellular processes including development, immune response and prevention of cellular transformation. Caspases are cysteinyl aspartate proteases involved in signal transduction cascades that result in programmed cell death. CASP9 is an initiator caspase and part of the intrinsic pathway, which is an evolutionarily conserved apoptotic pathway. It is responsible for cleaving and activating the executioner caspases CASP3, CASP6, CASP7, leading to nuclear membrane breakdown, DNA fragmentation and apoptosis. In their 2014 study, Lee et al performed an ADHD GWAS meta-analysis to identify casual SNPS in ADHD by focusing on SNPs in coding regions as well as a secondary analysis for pathway enrichement . They identified 11 candidate SNPS, three in the CASP9 gene, rs1052576, rs1052571, rs1820204. This GWAS was performed on a dataset that contained 428,074 SNPS from a publicly available database. This data set is derived from the IMAGE project which comprises of 924 trios of European decent, either an affected child and both parents or an affected child and one sibling and one parent. Patients in this study had to meet stringent criteria as well as live with one biological parent and one full sibling to control for environmental factors. The authors identified SNPS using two approaches. The first approach filtered SNPs by linkage disequilibrium analysis followed by a second approach to that enriched for SNPs using pathway based analysis algorithm called i-GSEA. The authors used a p A (rs6948) and Ex8+567T>C (rs1049216)], CASP8 Ex14-271A>T (rs13113), casp9 Ex5+32G>A (rs1052576) and CASP10 Ex3-171A>G (rs3900115) in the risk of Non-Hodgkin Lymphoma. Genotyping was performed by real-time PCR. rs1052576-AA genotype had an OR=0.7 (0.5-1.0) p=0.044 for all Non-Hodgkin’s lymphomas. In addition, there were protective effects for the rs1052576-A allele in B-cell lymphomas specifically: rs1052576-AA OR=0.7 (0.5-1.0) p=0.040. The protective effect of the rs1052576-A allele was not statistically significant in T cell lymphomas. This may reflect a small sample size or an inherent difference in the biology of the two cell types. Finally, B-cell lymphomas were further divided into three subtypes: Diffuse large B cell lymphoma, Follicular lymphoma, and marginal zone lymphoma and B cell chronic lymphocytic leukemia. The rs1052576-AG conferred an OR=0.6 (0.4-1.0) p=0.039 for follicular lymphoma. It is likely that the rs1052576-AA genotype is protected, however the numbers were small of this genotype and did not reach statistical significance. CASP9 is an important member of the apoptotic pathway and has clear mechanistic importance in the regulation of apoptosis. rs1052576 -G confers an increased risk of cancer in numerous studies. There does seem to be a dose dependent effect, however, this remains to be confirmed with more studies. A allele associated with lower odds of Non-Hodgkin Lymphoma (OR(AA+AG) = 0.6, 95% CI, 0.4-1.0) among 996 women located in Connecticut (461 cases, 535 controls) A allele associated with lower odds of Multiple myeloma (OR(AG) = 0.8, 95% CI = 0.5-1.3; OR(AA) = 0.5, 95% CI = 0.3-0.9; p-trend = 0.02) among 664 women located in Connecticut (128 cases, 516 controls)

T;T

A number of small studies with fairly low p-values, but with low heterogeneity across studies, show a protective effect for the A allele which is greater in homozygotes.

C;T

A number of studies with lowish p-values but low heterogeneity across studies show a reduced risk of multiple myeloma, greater in homozygotes, for the A allele. There is also a generalized reduction in cancer risk. B-cell neoplasms may be particularly affected.

C;C

A number of small studies with lowish p-values but low heterogeneity across studies suggest the A allele is protective against cancer. B-cell neoplasms may be particularly affected. Most studies showed a protective role for the A allele, which, by inference, means a higher (but not quantified) risk for the G allele.