GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma

Abstract

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

“…The variant rs2647012, a marker for DRB3/DRB5 lineages [53] and a protective marker for lymphoma [34], showed a statistically significant risk association among Hispanics, but not in non-Hispanics (P interaction = 0.003 for ethnicity). Our study appears to be the first looking at a…”

“…We re-examined five previously discovered single nucleotide polymorphisms (SNPs) of known associations to leukemia (rs7089424, rs10821936, rs10994982, rs4132601, and rs2239633), along with three HLA region susceptibility markers for lymphomas, since lymphoma and ALL both stem from lymphoid cells. These included rs2395185, a marker of HLA DRB4 lineage [23] which has previously shown associations with major leukemias including childhood ALL [24,25] and other diseases including Hodgkin lymphoma [26], lung cancer [27], rheumatoid arthritis [28], asthma [29], and ulcerative colitis [30][31][32]; rs10484561, which has been shown to be a strong risk marker in follicular lymphoma (FL) [33]; and rs2647012, which is a protective marker for FL [34]. These SNPs were examined in a multiethnic sample (non-Hispanic Whites, Hispanic Whites, and Blacks) from Houston, Texas to assess their association with ALL.…”

A review of the role of lymphoma markers and occupational and environmental exposures

“…Additional evidence of the integral role of the immune system in lymphomagenesis can be seen from epidemiologic studies that examined polymorphisms in genes coding for cytokines that modulate the inflammatory process or are linked to B cell activation (Wang et al 2007;Ambinder et al 2010;Skibola et al 2010). In addition, recent genomewide association studies (GWAS) of the follicular subtype of NHL identified association with two variants within the human leukocyte antigen (HLA) region (Skibola et al 2009;Smedby et al 2011).…”

“…However, a potential role of obesity in lymphomagenesis cannot be excluded because, on one hand, several studies showed that obesity is a lowgrade chronic inflammatory state and, on the other hand, a chronic inflammatory condition has been linked to NHL risk in previous epidemiological studies (Smedby et al 2011). It therefore seems that a broader investigation of markers of the immune system, such as, for instance, markers of chronic B cell activation (sCD30), might be warranted to further investigate the possible immune mediated association between obesity and NHL.…”

Genetic Markers, Birth Characteristics, and Childhood Leukemia Risk

“…These included rs2395185, a marker of HLA DRB4 lineage [38] which has previously shown risk associations with major leukemias including childhood ALL and other diseases [39][40][41][42][43][44][45][46][47][48][49]; rs10484561, which has been shown to be a strong risk marker in follicular lymphoma (FL) [50]; and rs2647012, which is a protective marker for FL [51]. These SNPs were examined in a multi-ethnic sample (non-Hispanic Whites, Hispanic Whites, and Blacks)…”