Post-GWAS Functional Characterization of Susceptibility Variants for Chronic Lymphocytic Leukemia

Abstract

Recent genome-wide association studies (GWAS) have identified several gene variants associated with sporadic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Many of these CLL/SLL susceptibility loci are located in non-coding or intergenic regions, posing a significant challenge to determine their potential functional relevance. Here, we review the literature of all CLL/SLL GWAS and validation studies, and apply eQTL analysis to identify putatively functional SNPs that affect gene expression that may be causal in the pathogenesis of CLL/SLL. We tested 12 independent risk loci for their potential to alter gene expression through cis-acting mechanisms, using publicly available gene expression profiles with matching genotype information. Sixteen SNPs were identified that are linked to differential expression of SP140, a putative tumor suppressor gene previously associated with CLL/SLL. Three additional SNPs were associated with differential expression of DACT3 and GNG8, which are involved in the WNT/β-catenin- and G protein-coupled receptor signaling pathways, respectively, that have been previously implicated in CLL/SLL pathogenesis. Using in silico functional prediction tools, we found that 14 of the 19 significant eQTL SNPs lie in multiple putative regulatory elements, several of which have prior implications in CLL/SLL or other hematological malignancies. Although experimental validation is needed, our study shows that the use of existing GWAS data in combination with eQTL analysis and in silico methods represents a useful starting point to screen for putatively causal SNPs that may be involved in the etiology of CLL/SLL.

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140

“…Multiple SNPs are in perfect linkage disequilibrium (LD) ( r 2 ≥ 0.90; D ′ ≥ 0.98) with the top CD-associated intronic SNPs rs7423615 and rs6716753 (Fig. 4A) (16, 17), including those associated with CLL (rs13397985) (18) and MS (rs10201872) (19), and hence may act coordinately (hereafter collectively referred to as SNP +/+ ). All of these SP140 SNPs are intronic, except for a single SNP in exon 7 (rs28445040) that was recently suggested to be the causal SNP (45).…”

“…Here, we report on SP140, a previously uncharacterized immune-restricted epigenetic reader that has previously reported SNPs that associate with CD (16, 17), CLL (18), and MS (19). We show that individuals bearing CD-associated SP140 SNPs, most of which are intronic and in perfect LD with SP140 SNPs associated with CLL and MS, have alterations in SP140 mRNA splicing that ultimately result in loss of SP140 protein, consistent with the findings from a recent publication (45).…”

“…The bromodomain-containing protein SP140 is preferentially expressed in cells of the immune system (15), suggesting an immune-specific role for this epigenetic reader. Moreover, single-nucleotide polymorphisms (SNPs) within SP140 have been significantly associated with immune disorders, such as Crohn’s disease (CD) (16, 17), B cell chronic lymphocytic leukemia (CLL) (18), and multiple sclerosis (MS) (19), and autoantibodies against SP140 have been detected in patients with primary biliary cirrhosis (20). Despite these findings, the function of SP140 and the consequence of disease-associated SP140 SNPs have remained unknown.…”

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

“…Single nucleotide polymorphisms (SNPs) in several genetic loci like 8q24, 22q13 and 17q12 were reported to be linked to PCa susceptibility, early onset of the disease and tumor agressiveness (Al Olama, et al, 2014; Berndt, et al, 2015; Chang, et al, 2009; Cheng, et al, 2009; Eeles, et al, 2009; Eeles, et al, 2013; Gudmundsson, et al, 2009; Helfand, et al, 2015; Levin, et al, 2008; Salinas, et al, 2008; Schumacher, et al, 2011; Takata, et al, 2010; Thomas, et al, 2008; Witte, 2007). Although little is known about the functional aspect of risk SNPs, some studies showed cancer SNPs predominately present in multiple putative regulatory elements (2011; Sille, et al, 2012). SNPs in the promoter of the KLK3 gene, encoding the commonly used PCa marker protein prostate specific antigen (PSA), were reported to increase serum PSA and PSA promoter activity (Cramer, et al, 2003), while a C→T substitution of SNP rs10993994:C>T in the 5′ region of the prostate cancer suppressor gene MSMB was shown to affect gene expression level (Chang, et al, 2009).…”

Structure of human Sp140 PHD finger: an atypical fold interacting with Pin1

“…Sp140 localization to PML-NBs, which are subnuclear structures involved in the regulation of gene transcription, cellular growth, apoptosis and maintenance of chromatin architecture [9], along with the presence of several chromatin related modules in its primary structure, suggest a role in chromatin-mediated regulation of gene expression. Indeed coactivator activity was inferred for Sp140 by virtue of its Gal4 DNA-binding domain fusion activity in transfected COS cells [10,11]; it has therefore been hypothesized that Sp140 might regulate the expression of genes involved in CLL development [5]. In line with its putative role in transcriptional regulation, Sp140 has strong sequence homology with autoimmune regulator (AIRE), a transcriptional activator governing the ectopic expression of peripheral tissue-specific antigens in the thymus [12].…”