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Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

ABSTRACT: We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

SUBMITTER: Slager SL

PROVIDER: S-EPMC3412347 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

Slager Susan L SL Skibola Christine F CF Di Bernardo Maria Chiara MC Conde Lucia L Broderick Peter P McDonnell Shannon K SK Goldin Lynn R LR Croft Naomi N Holroyd Amy A Harris Shelley S Riby Jacques J Serie Daniel J DJ Kay Neil E NE Call Timothy G TG Bracci Paige M PM Halperin Eran E Lanasa Mark C MC Cunningham Julie M JM Leis Jose F JF Morrison Vicki A VA Spector Logan G LG Vachon Celine M CM Shanafelt Tait D TD Strom Sara S SS Camp Nicola J NJ Weinberg J Brice JB Matutes Estella E Caporaso Neil E NE Wade Rachel R Dyer Martin J S MJ Dearden Claire C Cerhan James R JR Catovsky Daniel D Houlston Richard S RS

Blood 20120613 4

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk g ...[more]

PMID: 22700719

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Project description:Previous studies have shown increased familial risk for chronic lymphocytic leukemia. In the most comprehensive study to date, we evaluated risk of chronic lymphocytic leukemia and lymphoproliferative disorders among first-degree relatives of chronic lymphocytic leukemia cases compared to first-degree relatives of controls.Population-based registry data from Sweden were used to evaluate outcomes in 26,947 first-degree relatives of 9,717 chronic lymphocytic leukemia patients (diagnosed 1958-2004) compared with 107,223 first-degree relatives of 38,159 matched controls. Using a marginal survival model, we calculated relative risks (RR) and 95% confidence intervals as measures of familial aggregation.Compared to relatives of controls, relatives of chronic lymphocytic leukemia patients had an increased risk for chronic lymphocytic leukemia (RR=8.5, 6.1-11.7) and other non-Hodgkin's lymphomas (NHLs) (RR=1.9, 1.5-2.3). Evaluating NHL subtypes, we found a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. No excesses of aggressive B-cell or T-cell lymphomas were found. There was no statistical excess of Hodgkin's lymphoma, multiple myeloma, or the precursor condition, monoclonal gammopathy of undetermined significance, among chronic lymphocytic leukemia relatives.These familial aggregations are striking and provide novel clues to research designed to uncover early pathogenetic mechanisms in chronic lymphocytic leukemia including studies to identify germ line susceptibility genes. However, clinicians should counsel their chronic lymphocytic leukemia patients emphasizing that because the baseline population risks are low, the absolute risk for a first-degree relative to develop chronic lymphocytic leukemia or another indolent lymphoma is low. At this time, an increased medical surveillance of first-degree relatives of chronic lymphocytic leukemia patients has no role outside research studies.

Dataset Information

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

Publications

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

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