Hjalgrim, Henrik

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions These data suggest several plausible genetic links between DLBCL and SLE.

Abstract Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. A somatic activating mutation, MYD88 L265P, occurs in 85+% of WM and in 25%-50% of patients with the precursor condition, IgM monoclonal gammopathy of undetermined significance (MGUS); however, germline MYD88 mutations have not been observed in WM patients, and the genetic basis for WM predisposition remains undefined. To identify novel WM susceptibility loci we conducted a two-stage genome-wide association study (GWAS) in over 450 WM cases and 4300 controls of European ancestry. Discovery (stage 1) included 217 WM cases (40% familial) and 3798 controls genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms following standard quality control procedures. The genotyped data were imputed using the Haplotype Reference Consortium panel as a reference and analyzed using logistic regression. In stage 1, we identified three loci on chromosomes 6, 14 and 3 significantly associated (P<5.0x10-8) with risk of WM. Eleven promising SNPs in these and other suggestive loci (P<5.0x10-7) were selected for replication (stage 2) in 269 WM or LPL cases (4% familial) and 571 controls, and genotyping was conducted using standard methods on Taqman and Sequenom platforms or Sanger sequencing (1 SNP). Preliminary results confirm replication of the chromosome 6 locus. Stratification on familial status will illuminate the contribution of familial disease. These results will provide insight into the underlying genetic basis of WM susceptibility. Citation Format: Mary L. McMaster, Sonja I. Berndt, Shengchao A. Li, Susan Slager, Joseph Vijai, Charles C. Chung, Bin Zhu, Laurie Burdette, Brenda Birmann, Elizabeth E. Brown, James R. Cerhan, Karin Ekstrom-Smedby, Henrik Hjalgrim, Geffen Kleinstern, Brian K. Link, James McKay, Alain Monnereau, Lindsay M. Morton, Alexandra Nieters, Nathaniel Rothman, Christine F. Skibola, Alex Smith, Lauren R. Teras, Claire M. Vajdic, Roel Vermeulen, Belynda Hicks, Lynn R. Goldin, Neil E. Caporaso. A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1318. doi:10.1158/1538-7445.AM2017-1318

Abstract Background. Follicular lymphoma (FL) is an indolent B-cell malignancy with a variable clinical course that may transform to more aggressive forms of lymphoma. Previous modestly powered GWAS have reported multiple FL susceptibility loci in the HLA class I and II regions at 6p21.32-33, but novel non-HLA susceptibility loci and the genetic architecture of FL associations in the HLA region remain to be elucidated. Methods. We conducted the largest GWAS of FL to date consisting of 2,142 cases and 6,221 controls of European ancestry from 22 studies scanned on the Illumina OmniExpress. After imputation of common SNPs using IMPUTE2 and 1,000 Genomes Project v3 data, we conducted a meta-analysis of these data with two previous FL GWAS (n=586 cases, 1,537 controls) and replicated top hits in an additional 629 cases and 4,283 controls. Expression quantitative trait loci (eQTL) analyses were performed to evaluate the effects of associated variants on gene expression. Classical HLA allele imputations and stepwise regression analyses are underway to further characterize the HLA associations. Results. In the joint meta-analysis, the strongest association with FL risk was observed in the HLA region, where a large number of SNPs showed genome-wide significance (P<5x10-8 to P= 1.84x10-84), particularly in HLA class II at 6p21.32 where several HLA eQTLs were identified (P < 0.05). Outside HLA, we identified four novel loci associated with FL at 11q23.3 (CXCR5, rs4938573; P=3.14x10-15), 11q24.3 (ETS1, rs4937362; P=3.33x10-9), 3q13.33 (CD86, rs2681416; P=9.79x10-11) and 3q28 (LPP, rs6444305, P=2.55x10-8). These novel susceptibility loci were located in four biologically relevant genes involved in immune regulation: CXCR5 and its ligand, CXCL13, are involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. ETS1 is expressed in lymphoid cells and regulates immune cell function including differentiation, survival, and proliferation. CD86 and CD80 are classic members of the B7 costimulatory pathway that is important in maintaining immune function, suppression of autoimmunity and antitumor surveillance. LPP encodes a LIM domain-containing protein of the zyxin family and participates in cell adhesion, cell migration, proliferation and transcription dynamics. Conclusions. This large GWAS provides further support for the important role of common genetic variation in non-HLA genes and further evidence of the key role that HLA immune-regulatory genes play in the pathogenesis of FL. Citation Format: Christine F. Skibola, Sonja I. Berndt, James R. Cerhan, Zhaoming Wang, Joseph Vijai, Lucia Conde, Paul de Bakker, Sophia S. Wang, Claire M. Vajdic, Brenda M. Birmann, Susan L. Slager, James McKay, Paige M. Bracci, Alexandra Nieters, Qing Lan, Angela R. Brooks-Wilson, Martha S. Linet, Demetrius Albanes, John J. Spinelli, Roel C.H. Vermeulen, Mark P. Purdue, Meredith Yaeger, Lauren R. Teras, Silvia de Sanjose, Alain Monnereau, Simon Crouch, Jia Nee Foo, Henrik Hjalgrim, Gianluca Severi, Brian K. Link, Kimberly A. Bertrand, Yawei Zhang, Karin E. Smedby, Stephen J. Chanock, Nathaniel Rothman, NHL GWAS Consortium. Meta-analysis of genome-wide association studies identifies novel susceptibility loci for follicular lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5072. doi:10.1158/1538-7445.AM2014-5072

Abstract Despite limited discovery stages (<1,125 cases), genome-wide association studies (GWAS) have successfully identified 13 loci associated with risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL); however, these loci only explain a portion of the heritability. To identify additional genetic loci associated with CLL susceptibility, we conducted the largest meta-analysis of GWAS, to date, including 3,100 CLL cases and 7,667 controls of European ancestry from 25 independent studies genotyped on four different SNP microarrays. Association testing was conducted assuming a log-additive genetic model, adjusting for age, sex, and significant principal components. Meta-analyses were performed using the fixed effects inverse variance method based on the beta estimates and standard errors from each study. Promising loci were taken forward for replication in three additional studies totaling 788 cases and 4,872 controls. In the meta-analysis of both the discovery and replication studies, we conclusively identified ten independent SNPs in nine novel loci that reached genome-wide significance (P<5 x 10−8): 10q23.31 (FAS; P=1.22x10−14), 18q21.33 (BCL2; P=2.66x10−12 and P=7.76x10−11), 11p15.5 (C11orf21; P=2.15x10−10), 4q25 (LEF1; P=4.24x10−10), 2q33.1 (CASP8; P=2.50x10−9), 9p21.3 (CDKN2B-AS1; P=1.27x10−8), 18q21.32 (PMAIP1; P=2.51x10−8), 15q15.1 (BMF; P=2.71x10−10), and 2p22.2 (QPCT; P=1.68x10−8) as well as an independent signal at an established locus (2q13, ACOXL, P=2.08x10−18). We also found evidence for two additional promising loci that reached marginal genome-wide significance (P<2.0x10−7) at 8q22.3 (ODF1; P=5.40x10−8) and 5p15.33 (TERT; P=1.92x10−7). Although further studies are required, the proximity of five of the novel loci to genes involved in apoptosis suggests a possible unifying underlying biological mechanism. Together with the previously established loci, these genetic loci explain ~17% of the familial risk of CLL. Citation Format: Sonja I. Berndt, Christine F. Skibola, Vijai Joseph, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Wendy Cozen, Alain Monnereau, Rachel S. Kelly, Silvia de Sanjose, Martha S. Linet, Elio Riboli, Paolo Vineis, Henrik Hjalgrim, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Susan L. Slager. Meta-analysis of genome-wide association studies identifies multiple loci associated with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-23. doi:10.1158/1538-7445.AM2013-LB-23

Abstract Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.