Abstract
Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.
Highlights
Human leukocyte antigens (HLA) are among the most polymorphic genes in humans and result in variations of the peptide-binding cleft, influencing the antigens bound and presented to T cells [1]
We reported HLADRB1*01:01 as a novel susceptibility allele in non-Hodgkin lymphoma (NHL) risk [4], for the follicular lymphoma subtype, which was consistent with results from a genome-wide association study [4]
We previously evaluated the joint effects between tumor necrosis factor (TNF) G-308A and NHL risk factors [8], we have since demonstrated that the ancestral haplotype 8.1 (AH 8.1: HLA-A*01-B*08-DR*03-TNFG-308A) whereby HLA alleles are in linkage disequilibrium with TNF, is associated with diffuse large B-cell lymphoma (DLBCL) [9]
Summary
Human leukocyte antigens (HLA) are among the most polymorphic genes in humans and result in variations of the peptide-binding cleft, influencing the antigens bound and presented to T cells [1]. We previously evaluated the joint effects between TNF G-308A and NHL risk factors [8], we have since demonstrated that the ancestral haplotype 8.1 (AH 8.1: HLA-A*01-B*08-DR*03-TNFG-308A) whereby HLA alleles are in linkage disequilibrium with TNF, is associated with DLBCL [9]. Confirmed risk factors for NHL include autoimmune conditions [11], certain infectious agents [12], and family history of lymphoma [13]. The present analysis was conducted on study participants who provided blood and for whom HLA typing was completed (685 cases, 646 controls). Because no association was observed between genotype and race or between race and risk factors evaluated, we present results for all participants to maximize our sample size and power for evaluation of interactions. We evaluated risk for NHL and two major histologic subtypes: DLBCL (ICD-O-2: 9680-84, 9688) and follicular lymphoma (9690-91, 9695-98)
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