Person:

Birmann, Brenda

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; (P=2.33x10^{-21})), rs2523607 at 6p21.33 (HLA-B; (2.40x10^{-10})), rs79480871 at 2p23.3 (NCOA1; (P=4.23x10^{-8})), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; (P=9.98x10^{-13}) and (P=3.63x10^{-11}), respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

Background: Specific foods and nutrients, including alcohol, may contribute to gut barrier dysfunction. However, to our knowledge, the influence of whole diets is currently unknown. Objective: We aimed to cross-sectionally investigate associations of dietary patterns with plasma soluble CD14 (sCD14), which is released by macrophages on stimulation with endotoxin and has been used as a marker of gut hyperpermeability. Methods: We used food-frequency questionnaire data collected from 689 women in the Nurses’ Health Study and 509 men in the Health Professionals Follow-Up Study. Our principal component analysis identified 2 dietary patterns: “Western” (higher intakes of red meat, processed meat, desserts, and refined grains) and “prudent” (higher intakes of fruits, vegetables, fish, and whole grains). In multivariable-adjusted logistic regression analyses, we estimated ORs and 95% CIs for high (equal to or greater than the median compared with less than the median) sCD14 concentrations in quintiles of each dietary pattern. Using logistic regression, we also investigated the joint association of the Western dietary pattern and alcohol intake or C-reactive protein (CRP) with sCD14 concentrations. Results: Western dietary pattern scores were positively associated with sCD14 concentrations (OR: 1.86; 95% CI: 1.24, 2.79; P-trend = 0.0005; comparing extreme quintiles). Analyses of joint associations suggested that the strongest associations with higher sCD14 concentrations were for persons with both high Western pattern scores and high alcohol intake compared with participants with low scores for both (OR: 2.96; 95% CI: 1.61, 5.45) or for participants with both high Western pattern scores and high CRP values compared with those with low scores for both (OR: 4.11; 95% CI: 2.57, 6.58). The prudent pattern was not associated with sCD14 concentrations. Conclusions: Higher consumption of the Western dietary pattern is associated with a marker of macrophage activation and gut hyperpermeability, especially when coupled with high alcohol intake and heightened systemic inflammation. Our findings need confirmation in studies with additional markers of gut barrier dysfunction.