Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma

Abstract

Human immunodeficiency virus (HIV) infection is associated with a substantially increased risk of non-Hodgkin lymphoma (NHL). High plasma viral load, low CD4+ T cell counts and absence of antiretroviral treatment (ART) are known predictive factors for NHL. Even in the era of suppressive ART, HIV-infected individuals remain at increased risk of developing NHL compared to the general population. To search for human genetic determinants of HIV-associated NHL, we performed case-control genome-wide association studies (GWAS) in three cohorts of HIV+ patients of European ancestry and meta-analyzed the results. In total, 278 cases and 1924 matched controls were included. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11). The G>A polymorphism creates a new transcription factor binding site for BATF and JUND. Analyses of topologically associating domains and promoter capture Hi-C data revealed significant interactions between the rs7919208 region and the promoter of CXCL12, also known as stromal-derived factor 1 (SDF-1). These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits

“…Kinship was evaluated using PLINK version 2.3 ( Chang et al 2015 ); we used the –king-cutoff option to exclude one from each pair of individuals with a kinship coefficient >0.09375. Initial host genotyping quality control and imputation were done as in Thorball et al (2021) . Subsequent genotyping quality control was performed using PLINK version 2.3 ( Chang et al 2015 ).…”

A phylogeny-aware GWAS framework to correct for heritable pathogen effects on infectious disease traits

“…Kinship was evaluated using PLINK version 2.3 (Chang et al ., 2015); we used the –king-cutoff option to exclude one from each pair of individuals with a kinship coefficient > 0.09375. Initial host genotyping quality control and imputation were done as in Thorball et al . (2021).…”

B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

“…In contrast, genome-wide association studies (GWAS) have identified statistically significant associations with NHL subtypes for multiple common genetic susceptibility loci, but their associations have largely exhibited modest magnitudes of risk (e.g., less than 2-fold; refs. [6][7][8][9][10][11], as is typical for genetic associations studies.…”