Dataset Information

Common genetic variants in candidate genes and risk of familial lymphoid malignancies.

ABSTRACT: Familial aggregation, linkage and case-control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (WM) and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T>A) to be associated with non-Hodgkin lymphoma, as this allele was found to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in TNFSF10 were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL.

SUBMITTER: Liang XS

PROVIDER: S-EPMC2890251 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Common genetic variants in candidate genes and risk of familial lymphoid malignancies.

Liang Xueying Sharon XS Caporaso Neil N McMaster Mary Lou ML Ng David D Landgren Ola O Yeager Meredith M Chanock Stephen S Goldin Lynn R LR

British journal of haematology 20090701 4

Familial aggregation, linkage and case-control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (W ...[more]

PMID: 19573080

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Project description:Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.

Dataset Information

Common genetic variants in candidate genes and risk of familial lymphoid malignancies.

Publications

Common genetic variants in candidate genes and risk of familial lymphoid malignancies.

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