A two-stage evaluation of genetic variation in immune and inflammation genes with risk of non-Hodgkin lymphoma identifies new susceptibility locus in 6p21.3 region.
BACKGROUND
Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology.


METHODS
To identify susceptibility immune genes, we conducted a 2-stage analysis of single-nucleotide polymorphisms (SNP) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the OR and 95% confidence intervals (CI).


RESULTS
In the pooled analysis, only the TAP2 coding SNP rs241447 (minor allele frequency = 0.26; Thr655Ala) at 6p21.3 (OR = 1.34, 95% CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (P = 3.1 × 10(-5)). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR = 1.82, 95%CI 1.46-2.26; p = 6.9 × 10(-8)), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR = 1.38, 95% CI 1.08-1.77; P = 0.011), but not chronic lymphocytic leukemia (OR = 1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors.


CONCLUSIONS
Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3.


CONCLUSIONS
Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. cerhan.james@mayo.edu
James R
JR
Cerhan
Zachary S
ZS
Fredericksen
Anne J
AJ
Novak
Stephen M
SM
Ansell
Neil E
NE
Kay
Mark
M
Liebow
Ahmet
A
Dogan
Julie M
JM
Cunningham
Alice H
AH
Wang
Thomas E
TE
Witzig
Thomas M
TM
Habermann
Yan W
YW
Asmann
Susan L
SL
Slager
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; C071692:TAP2 protein, human