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SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma.

ABSTRACT: Inherited risk determinants for follicular lymphoma (FL) have recently been described in the immune gene-rich human leukocyte antigen region on chromosome 6p. The known importance of host immune response to FL survival led us to evaluate these germline factors in FL outcome. We confirm the association of single nucleotide polymorphisms rs10484561 (P = 3.5 × 10??) and rs6457327 (P = .008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index.

SUBMITTER: Wrench D

PROVIDER: S-EPMC3062316 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma.

Wrench David D Leighton Pamela P Skibola Christine F CF Conde Lucia L Cazier Jean-Baptiste JB Matthews Janet J Iqbal Sameena S Carlotti Emanuela E Bödör Csaba C Montoto Silvia S Calaminici Maria M Gribben John G JG Lister T Andrew TA Fitzgibbon Jude J

Blood 20110113 11

Inherited risk determinants for follicular lymphoma (FL) have recently been described in the immune gene-rich human leukocyte antigen region on chromosome 6p. The known importance of host immune response to FL survival led us to evaluate these germline factors in FL outcome. We confirm the association of single nucleotide polymorphisms rs10484561 (P = 3.5 × 10⁻⁹) and rs6457327 (P = .008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL trans ...[more]

PMID: 21233317

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Genetics of follicular lymphoma transformation.

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Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.

Project description:Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

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Project description:Follicular lymphoma (FL) is a heterogeneous disease whose pathogenesis remains partially unknown. Around 20% of FL patients experience early progression or treatment-refractory disease and 2-3% of patients per year experience histological transformation (HT) into a more aggressive lymphoma (tFL). Here, we evaluate the immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in 187 FL cases to assess its impact on clinical outcome and histological transformation. The IGHV gene repertoire was remarkably biased in FL. The IGHV4-34 (14%), IGHV3-23 (14%), IGHV3-48 (10%), IGHV3-30 (9%) and IGHV3-21 (7%) genes accounted for more than half of the whole cohort. IGHV3-48 was overrepresented in cases of tFL (19%) compared with non-transformed FL at 5 years (5%, P?=?0.05). Patients with the IGHV3-48 gene were significantly more likely to have had HT after 10 years than those who used other genes (71% vs. 25%, P?<?0.05), irrespective of the therapy they received. Moreover, IGHV3-30 was also overrepresented in cases of FL (9%) and tFL (13%) compared with diffuse large B-cell lymphoma in which it was nearly absent. In conclusion, our results indicate a role for antigen selection in the development of FL, while the use of IGHV3-48 could help predict histological transformation.

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Association of HLA-DQB1 alleles with risk of follicular lymphoma.

Project description:In a recent genome-wide association study of follicular lymphoma (FL), we identified novel risk alleles on chromosome 6p21.33 that appeared to be part of an extended haplotype including HLA-DRB1*0101, DQA1*0101, and DQB1*0501. To follow up on these findings, we obtained 2-4 digit HLA-DQB1 allelotypes on a subset of 265 cases of FL and 757 controls using a novel assay that applies multiplexed ligation-dependent probe amplification (MLPA). We confirmed a positive association between FL and the HLA-DQB1*05 allele group (OR = 1.70, 95% CI 1.28-2.27; adjusted p-value = 0.013) and also identified an allele group inversely associated with FL risk, HLA-DQB1*06 (OR = 0.51, 95% CI 0.38-0.69; adjusted p-value = 4.46 × 10(-5)). Although these findings require verification, the role of HLA class II proteins in B-cell survival and proliferation makes this a biologically plausible association.

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Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression.

Project description:Multiple follicular lymphoma (FL) susceptibility single-nucleotide polymorphisms in the human leukocyte antigen (HLA) class I and II regions have been identified, including rs6457327, rs3117222, rs2647012, rs10484561, rs9268853 and rs2621416. Here we validated previous expression quantitative trait loci results with real-time reverse transcription quantitative PCR and investigated protein expression in B-lymphoblastoid cell lines and primary dendritic cells using flow cytometry, cell-based enzyme-linked immunosorbent assay and western blotting. We confirmed that FL-protective rs2647012-linked variants, in high linkage disequilibrium with the extended haplotype DRB1*15:01-DQA1*01:02-DQB1*06:02, correlate with increased HLA-DQB1 expression. This association remained significant at the protein level and was reproducible across different cell types. We also found that differences in HLA-DQB1 expression were not related to changes in activation markers or class II, major histocompatibility complex, transactivator expression, suggesting the role of an alternative regulatory mechanism. However, functional analysis using RegulomeDB did not reveal any relevant regulatory candidates. Future studies should focus on the clinical relevance of increased HLA-DQB1 protein expression facilitating tumor cell removal through increased immune surveillance.

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Transformation Scoring System (TSS): A new assessment index for clinical transformation of follicular lymphoma.

Project description:Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy-proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2-4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy.

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Association of attention-deficit/hyperactivity disorder with a candidate region for reading disabilities on chromosome 6p.

Project description:BACKGROUND:Reading disabilities (RD) and attention-deficit hyperactivity/disorder (ADHD) are two common childhood disorders that co-occur by chance more often than expected. Twin studies and overlapping genetic linkage findings indicate that shared genetic factors partially contribute to this comorbidity. Linkage of ADHD to 6p, an identified RD candidate locus, has previously been reported, suggesting the possibility of a pleiotropic gene at this locus. RD has been previously associated with five genes in the region, particularly DCDC2 and KIAA0319. METHODS:To test whether these genes also contribute to ADHD, we investigated markers previously associated with RD for association with ADHD and ADHD symptoms in a sample of families with ADHD (n = 264). Markers were located in two subregions, VMP/DCDC2 and KIAA0319/TTRAP. RESULTS:Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. CONCLUSIONS:Overall this study supports a previous linkage study of ADHD indicating a risk gene for ADHD on 6p and points to VMP or DCDC2 as the most likely candidates.

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