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From SNPedia

Geno Mag Summary
(A;A) 1.7 0.5x reduced risk of multiple myeloma, general reduced risk of cancer
(A;G) 1.5 0.8x reduced risk of multiple myeloma, general reduced risk of cancer
(G;G) 1 Increased risk of multiple myeloma, B-cell neoplasms, and cancer in general
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
1000 genomesrs1052576
23andMe allrs1052576
SNP Nexus

GWAS Ctlgrs1052576
Max Magnitude1.7
? (A;A) (A;G) (G;G) 28
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 [PMID 24531918] [23251262?dopt=Abstract PMID 23251262OA-icon.png] [18381704?dopt=Abstract PMID 18381704OA-icon.png] [PMID 17285546] [PMID 17071630].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 [PMID 24531918]. 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<0.05 threshold as well as an FDR cutoff of 0.1 to correct for the multiple testing conditions. For rs1052576 p=0.042. Odds ratio could not be determined from the data provided in the manuscript.

In another recent study, Yan et al performed a meta-analysis of the rs1052576 SNP in CASP-9 [23251262?dopt=Abstract PMID 23251262OA-icon.png]. Seven case-control studies with a total of 1668 cancer cases and 2294 healthy controls were analyzed. Six types of cancer were studied: gastric cancer, lymphoma, lung cancer, colon cancer, myeloma and liver cancer. Four studies were performed in China, two in the USA and one in Russia. The “A” allele carriers of rs1052576 had overall reduced risk for cancer: the "A" allele conferred an OR=0.72( 0.58-0.89) p=0.003. However, these data were only statistically significant in Asian populations: rs1052576-A resulted in an OR=0.60 with a 95% confidence interval 0.44-0.81 and a p<0.001, in Asians irrespective of the national origin of the study. Caucasian carriers of rs1052576-A did trend towards a lower OR, however, these data did not reach statistical significance and may warrant further studies: OR=0.85(0.70-1.04), p=0.11.

In 2009, Andrew et al identified SNPs to predict bladder cancer susceptibility and survival [19252927?dopt=Abstract PMID 19252927OA-icon.png]. They performed a case-controlled study with 832 bladder cancer cases and 1,191 controls using a population of New Hampshire residents; 95% of this cohort was of Caucasian origin. SNPs that modulated bladder cancer survival were selected using an FDR threshold of <0.5. They found that the rs1052576-G allele reduced survival time for carriers with bladder cancer and increased risk of death due to bladder cancer OR=1.4 (0.8-2.4) and p=0.003.

Hosgood, et al performed a population based case control study of 128 cases of women with multiple myeloma and 516 controls all from Connecticut [18381704?dopt=Abstract PMID 18381704OA-icon.png]. rs1052576-AG conferred a decreased risk of multiple myeloma OR=0.8 (0.5-1.3) p=0.41, rs1052576-AA OR=0.5 (0.3-0.9)p=0.02, p=0.02 for the trend. These data need to be considered with care, as the rs1052576-AA odds ratio was the only value that reached near statistical significance on its own. Apoptosis is particularly important in the development of B-lymphocytes. A role for CASP9 in these B-cell lymphomas is likely to be of mechanistic importance.

In 2006, Lan et al investigated the effect of SNPs in CASP3 [Ex8-280C>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.

[PMID 17071630] 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)

[PMID 18381704OA-icon.png] 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)

[PMID 17285546] [A study on the expression of CASP9 gene and its polymorphism distribution in non-small cell lung cancer].

[PMID 19252927OA-icon.png] Bladder cancer SNP panel predicts susceptibility and survival.

[PMID 19531679OA-icon.png] Polymorphisms and haplotypes in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer: a population-based, case-control study in a Chinese population.

GET Evidence
aa_change Gln221Arg
aa_change_short Q221R
impact not reviewed
qualified_impact Insufficiently evaluated not reviewed
overall_frequency 0.587005

[PMID 23251262OA-icon.png] Role of the CASP-9 Ex5+32 G>A polymorphism in susceptibility to cancer: A meta-analysis

[PMID 24879622] Association of caspase9 promoter polymorphisms with the susceptibility of AML in south Indian subjects