Background: Persons living with HIV/AIDS (PLWHA) are at elevated risk for non-Hodgkin lymphoma relative to HIV-negative individuals. AIDS-related non-Hodgkin lymphoma (AIDS-NHL) etiology is characterized by B-cell activation and chronic inflammation in the context of HIV; prior work has highlighted the importance of inflammatory biomarkers in predicting subsequent AIDS-NHL diagnosis. General-population risk factors for NHL include prior family history, suggesting a heritable genetic component to NHL risk that may encompass inflammation-related genes. Previous genome-wide association studies (GWAS) have investigated NHL in the general population, but no AIDS-NHL GWAS has yet been published. We therefore investigate single-nucleotide polymorphisms for association with AIDS-NHL risk using a candidate-gene study in 700 HIV-positive men (178 AIDS-NHL cases), and a GWAS in 1,949 HIV-positive men (172 AIDS-NHL cases), from the Multicenter AIDS Cohort Study (MACS). Pathway analyses of GWAS results complement these two studies.

Methods: Candidate-gene study (30 SNPs; 24 genes): matched case-control design; conditional logistic regression, semi-Bayes correction and multiple imputation for missing covariate data in SAS. GWAS (n=4.86 million SNPs): imputation in MINIMAC3 for missing genotype data; logistic regression on genotype probabilities using SNPTEST v2.5.2 and adjustment for principal components from R package SNPRelate; regional plots using R package LocusExplorer. Pathway analyses: analysis of GWAS p-values using 13,094 gene sets in PASCAL and 6,212 gene sets in VEGAS2.

Results: Candidate-gene study: significant inverse association (dominant OR=0.68; 95%CI 0.47-0.99; log-additive OR=0.71, 95%CI 0.51-0.99) between NHL risk and SNP rs6815391 (3’ UTR, REX1/ZPF42, 4q35.2). GWAS: genome-wide-significant signal (4q33; top SNP rs2195807; p=1.48E-08; white-only p=1.93E-07) in the vicinity of uncharacterized noncoding variant LOC100506122. Pathway analyses: repeated occurrence of gene sets capturing inflammatory processes and muscle fiber/ cytoskeletal integrity at or near the top of most scenarios.

Conclusion: Each method yielded associations with different aspects of AIDS-NHL biology. The candidate-gene study suggests involvement of the REX1/ZPF42 SNP rs6815391 in HIV replication and production of anti-inflammatory cytokines; the GWAS points toward an as-yet-uncharacterized locus (LOC100506122); pathway analyses implicate myosin genes and pathways that may be involved in early stages of B-cell activation. Further candidate-gene, in vivo or in vitro studies may clarify the biological plausibility of observed associations.

Background: AIDS-associated non-Hodgkin lymphoma (AIDS-NHL) remains a significant public health challenge among HIV-infected individuals. Chronic inflammation and immune activation have been documented in the literature to play a crucial role in the etiology of AIDS-NHL. We summarized results from prior work in a meta-analysis of the associations between prospectively measured circulating levels of immune biomarkers and the risk of NHL among both HIV-infected and HIV-uninfected populations. Our second study characterized the temporal variation in 24 pre-AIDS-NHL diagnosis circulating markers of inflammation and immune activation. Finally, we assessed the predictive ability of a set of 13 biomarker levels and AIDS-NHL diagnosis.

Methods: Meta-analysis: Our meta-analysis identified 17 relevant studies from inception of major biomedical databases (PubMed, EMBASE, and Web of Science) until January 1, 2017. We summarized published results using random-effects models for NHL and several histological subtypes of NHL. Longitudinal study: we summarized the slopes and means (intercepts) of biomarker trajectories using linear mixed models. Prediction Models: we calculated incremental discrimination ability (AUC) of models including biomarkers, individually and concurrently, relative to models including only participant characteristics and known risk factors of NHL.

Results: Meta-analysis: Summarizing 17 nested case–control studies, we found elevated levels of several biomarkers associated with increased odds of NHL overall: TNF-α, OR=1.18 [95% CI: 1.04, 1.34]; CXCL13, OR=1.47 [95% CI: 1.03, 2.08]; sCD23, OR=1.57 [95% CI: 1.21, 2.05]; sCD27, OR=2.18 [95% CI: 1.20, 3.98]; sCD30, OR=1.65 [95% CI: 1.22, 2.22]; AIDS-NHL showing stronger associations with IL-6, TNF-α, sCD27, and sCD30. Longitudinal study: prior to HAART, geometric mean biomarkers are elevated for cases relative to controls for IL-2, TNF-α, IL-6, sCD27, sIL-2Rα, IP-10, CXCL13, CRP, and pre-HAART slopes were observed to be higher for cases relative to controls for sIL-6R, sTNFR2, IL-10. Following HAART initiation, geometric mean levels are elevated to a higher degree than pre-HAART for cases relative to controls for BAFF, TNF-α, sIL-2Rα, sTNFR2, IP-10, MCP-1, CRP. Prediction Modeling: Models including individual biomarkers yielded modest improvements in AUC statistics above a base-case model that comprised NHL risk factors and other participant characteristics. A model including IL-6, IL-10, TNF-α, IP10, and CXCL13, concurrently performed better than all other models including individual biomarkers: 0-1: AUC=0.943 95% CI: 0.910, 0.975; 1-3: AUC=0.895 95% CI: 0.856, 0.934; >3: AUC=0.836 95% CI: 0.787, 0.885. Increments in AUC above the risk factors only model were also improved relative to individual biomarker models: 0-1: difference in AUC=0.056 95% CI: 0.021, 0.091; 1-3: difference in AUC=0.032 95% CI: 0.007, 0.057; >3: difference in AUC=0.074 95% CI: 0.030, 0.118.

Conclusion: Each study provided further novel evidence of the association between circulating biomarkers and AIDS-NHL risk, as well as the utility of biomarkers in risk prediction. Our meta-analysis provides an overarching summary of evidence that elevated circulating levels of several markers are associated with an increased risk of NHL. Longitudinal analyses illustrate novel differences between cases and controls in aspects of the trajectories of 24 markers. Our prediction models elucidate the ability of a set of 13 marker levels to discriminate between AIDS-NHL cases versus controls. The totality of new evidence we provide supports the notion that chronic inflammation and immune activation is associated with increased AIDS-NHL risk, and that these biomarkers may have utility in the development of clinical risk prediction models.

Background: MicroRNAs (miRNA) regulate gene expression through binding to the 3' untranslated region of target messenger RNA (mRNA) and have been implicated in lymphomagenesis. Only a few studies have been conducted to evaluate the effects of miRNA-related genes. In this study, we will test hypotheses to determine whether single nucleotide polymorphisms (SNPs) located within miRNA binding sites, miRNA coding regions, or miRNA processing genes, (collectively referred to as miRNA-related SNPs), are associated with susceptibility of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL) among men from the Multicenter AIDS Cohort Study (MACS).

Methods: We genotyped 25 miRNA-related SNPs in 180 AIDS-NHL cases and 529 matched HIV-infected controls. Adjusted odds ratios (OR_adj) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, controlling for age, CD4⁺ T-cell count, HIV viral load, prior AIDS diagnosis, history of anti-retroviral therapy, race, and history of HCV infection, to estimate the associations between miRNA-associated SNPs and overall, systemic and central nervous system (CNS) AIDS-NHL. The semi-Bayes (SB) approach was used to correct for multiple comparisons. Through the incorporation of a normal prior of null-association (prior odds ratio, OR_prior = 1.00; 95% prior limits: 0.25, 4.00), we proposed to pull observed associations toward the null, emphasizing our uncertainty. To give a comprehensive overview of our data and results, we presented both suggested (alpha=0.10) and statistically significant results (alpha=0.05), while noting those that remained evident after SB correction. We did place highlighted emphasis on significant results which remained evident after the SB approach as we were more confident in the report of these results (GEMIN3 rs197412, miR-196a rs11614913, and HIF1A rs2057482). Further, results were focused to those from analyses imputed for HIV viral load at set point and CD4⁺ T-cell count at reference date. Last, we estimated the association between SNPs within miRNA processing genes and mean log_e miRNA serum levels among a subgroup of 77 MACS participants, comprised of 61 AIDS-NHL cases and 16 HIV-infected controls. Mean ratios (MR_adj) and 95% CIs were calculated using linear regression, controlling for AIDS-NHL case-control status, CD4⁺ T-cell count at date of serum sample, and race.

Results: GEMIN3 rs197412, a non-synonymous SNP within a gene involved in miRNA processing and maturation, was associated with AIDS-NHL overall (OR_adj= 1.35 per variant allele; 95% CI: 1.03-1.78). In subgroup analyses, an inverse association was observed between miR-196a rs11614913 and CNS HIV/AIDS NHL (CT/TT vs. CC OR_adj= 0.43; 95% CI: 0.22-0.87). The variant allele of HIF1A rs2057482 was associated with increased risk of systemic AIDS-NHL (OR_adj= 1.83 per variant allele; 95% CI: 1.16-2.90), whereas the same allele was associated with decreased risk of CNS AIDS-NHL (OR_adj= 0.38 per variant allele; 95% CI: 0.17-0.87). These miRNA-related SNP associations with AIDS-NHL remained evident after SB correction. In the evaluation of genotype-phenotype associations, there was a suggested association between carriership of the variant allele (C) of GEMIN3 rs197412 with higher miRNA-222 serum levels compared to those with the referent genotype (MR_adj= 1.21 per variant allele; 95% CI: 0.98-1.49), suggesting a potential functional effect of GEMIN3 rs197412 in relation to miRNA-222 expression.

Conclusion: These results suggest that miRNA-related SNPs are associated with AIDS-NHL susceptibility. Specifically, our study demonstrated that GEMIN3 rs197412 was associated with AIDS-NHL susceptibility, and that genetic variation within this miRNA processing gene may influence subsequent miRNA expression. Further, miR-196a rs11614913 and HIF1A rs2057482 AIDS-NHL were also associated with AIDS-NHL, highlighting the diverse array of biologic mechanisms underlying AIDS-lymphomagenesis.

Purpose of review

Recent findings