Multi‐locus HLA class I and II allele and haplotype associations with follicular lymphoma

Abstract

Follicular lymphoma (FL) is an indolent, sometimes fatal disease characterized by recurrence at progressively shorter intervals and is frequently refractive to therapy. Genome-wide association studies have identified SNPs in the human leukocyte antigen (HLA) region on chromosome 6p21.32–33 that are statistically significantly associated with FL risk. Low to medium resolution typing of single or multiple HLA genes has provided an incomplete picture of the total genetic risk imparted by this highly variable region. To gain further insight into the role of HLA alleles in lymphomagenesis and to investigate the independence of validated SNPs and HLA alleles with FL risk, high-resolution HLA typing was conducted using next-generation sequencing in 222 non-Hispanic white FL cases and 220 matched controls from a larger San Francisco Bay Area population-based case-control study of lymphoma. A novel protective association was found between the DPB1*03:01 allele and FL risk (OR=0.39, 95% CI 0.21–0.68). Extended haplotypes DRB1*01:01-DQA1*01:01-DQB1*05:01 (OR=2.01, 95% CI 1.22–3.38) and DRB1*15-DQA1*01-DQB1*06 (OR=0.55, 95% CI 0.36–0.82) also influenced FL risk. Moreover, DRB1*15-DQA1*01-DQB1*06 was highly correlated with an established FL risk locus, rs2647012. These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region.

Role of Polymorphic Loci in HLA-Region rs2647012 and rs805288 in the Development of Non-Hodgkin’s Malignant Lymphomas in Western Siberia

“…Here and in Table 3: level of statistical significance (after Bonferroni correction for multiple comparisons). studies involving other population groups, this locus showed an association with a lower risk of follicular lymphoma [4,9,12] and increased risk of marginal cell lymphoma [12], but not with the risk of diffuse large cell lymphoma [12]. The infl uence of rs2647012 on the increase in the risk of these lymphomas in Western Siberia can be caused by a not identifi ed factor.…”

“…This means that if the effect of nucleotide substitution is less pronounced, the association could remain undetected. In the work [12], locus rs2647012 reduced the risk for follicular lymphoma in 1.42 times, and in the studies [4,9] -1.8 times. The size of the group should be >70 subjects in order to reach 80% statistical power to detect such effect.…”

“…In particular, association of rs2647012 (G/A) locus in 6p21.32 with reduced risk of follicular lymphoma (p=4×10 -12 ) has been demonstrated in genome-wide analysis [12] and then confi rmed [4]. It has been also demonstrated [9] that rs2647012 is in close linkage disequilibrium (D'=1) with HLA-DRB1*15-DQA1*01-DQB1*06(*) haplotype that is also associated with reduced risk of follicular lymphoma. Allele A of rs2647012 locus enhanced HLA-DQB1 gene expression in lymphoblast cell lines that may underlie its protective effect [6].…”

“…Recent large association studies including four genome-wide association studies showed that 6p21.3 region contained polymorphic loci associated with the risk of non-Hodgkin's lymphomas [3][4][5]7,[9][10][11][12]. In particular, association of rs2647012 (G/A) locus in 6p21.32 with reduced risk of follicular lymphoma (p=4×10 -12 ) has been demonstrated in genome-wide analysis [12] and then confi rmed [4].…”

Next-Generation HLA Sequencing Using the 454 GS FLX System

“…In an international alpha-trial testing of 20 blinded samples, the 454 Life Sciences GS FLX System sequencing method demonstrated 98 % concordance with known genotypes between eight participating labs [2]. In our other studies, using at least one control per PTP region per run, 100 % of control sample genotypes (previously characterized by Sanger Sequencing with ambiguity reduction) were concordant [4, 5]. The average rate of detection of novel alleles was ~0.04 % (8/19,069 loci) in Caucasoid study populations [4, 5].…”