GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32
and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell
Lymphoma
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.
Vyšlo v časopise:
GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32
and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell
Lymphoma. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1001378
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001378
Souhrn
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.
Zdroje
1. Jaffe
ES
Harris
NL
Stein
H
Vardiman
J
2001
World Health Organization classification of tumours pathology and
genetics, tumours of hematopoietic and lymphoid tissues.
Lyon
IARC Press
2. Morton
LM
Wang
SS
Cozen
W
Linet
MS
Chatterjee
N
2008
Etiologic heterogeneity among non-Hodgkin lymphoma
subtypes.
Blood
112
5150
5160
3. Altieri
A
Bermejo
JL
Hemminki
K
2005
Familial risk for non-Hodgkin lymphoma and other
lymphoproliferative malignancies by histopathologic subtype: the Swedish
Family-Cancer Database.
Blood
106
668
672
4. Chang
ET
Smedby
KE
Hjalgrim
H
Glimelius
B
Adami
HO
2006
Reliability of self-reported family history of cancer in a large
case-control study of lymphoma.
J Natl Cancer Inst
98
61
68
5. Skibola
CF
Bracci
PM
Halperin
E
Conde
L
Craig
DW
2009
Genetic variants at 6p21.33 are associated with susceptibility to
follicular lymphoma.
Nat Genet
41
873
875
6. Conde
L
Halperin
E
Brown
KM
Smedby
KE
Rothman
N
2010
Genome-wide association study of follicular lymphoma identifies a
risk locus at 6p21.32.
Nat Genet
42
661
664
7. de Bakker
PI
Ferreira
MA
Jia
X
Neale
BM
Raychaudhuri
S
2008
Practical aspects of imputation-driven meta-analysis of
genome-wide association studies.
Hum Mol Genet
17
R122
128
8. Cerhan
JR
Ansell
SM
Fredericksen
ZS
Kay
NE
Liebow
M
2007
Genetic variation in 1253 immune and inflammation genes and risk
of non-Hodgkin lymphoma.
Blood
110
4455
4463
9. Wang
SS
Cerhan
JR
Hartge
P
Davis
S
Cozen
W
2006
Common genetic variants in proinflammatory and other
immunoregulatory genes and risk for non-Hodgkin lymphoma.
Cancer Res
66
9771
9780
10. Zhang
Y
Holford
TR
Leaderer
B
Boyle
P
Zahm
SH
2004
Hair-coloring product use and risk of non-Hodgkin's
lymphoma: a population-based case-control study in
Connecticut.
Am J Epidemiol
159
148
154
11. Hughes
AM
Armstrong
BK
Vajdic
CM
Turner
J
Grulich
A
2004
Pigmentary characteristics, sun sensitivity and non-Hodgkin
lymphoma.
Int J Cancer
110
429
434
12. Spinelli
JJ
Ng
CH
Weber
JP
Connors
JM
Gascoyne
RD
2007
Organochlorines and risk of non-Hodgkin lymphoma.
Int J Cancer
121
2767
2775
13. Song
YS
Hein
J
2005
Constructing minimal ancestral recombination
graphs.
J Comput Biol
12
147
169
14. Bandelt
HJ
Forster
P
Rohl
A
1999
Median-joining networks for inferring intraspecific
phylogenies.
Mol Biol Evol
16
37
48
15. de Bakker
PI
McVean
G
Sabeti
PC
Miretti
MM
Green
T
2006
A high-resolution HLA and SNP haplotype map for disease
association studies in the extended human MHC.
Nat Genet
38
1166
1172
16. Leslie
S
Donnelly
P
McVean
G
2008
A statistical method for predicting classical HLA alleles from
SNP data.
Am J Hum Genet
82
48
56
17. Wang
SS
Abdou
AM
Morton
LM
Thomas
R
Cerhan
JR
2010
Human leukocyte antigen class I and II alleles in non-Hodgkin
lymphoma etiology.
Blood
115
4820
4823
18. Abdou
AM
Gao
X
Cozen
W
Cerhan
JR
Rothman
N
2010
Human leukocyte antigen (HLA) A1-B8-DR3 (8.1) haplotype, tumor
necrosis factor (TNF) G-308A, and risk of non-Hodgkin
lymphoma.
Leukemia
24
1055
1058
19. Bateman
AC
Howell
WM
1999
Human leukocyte antigens and cancer: is it in our
genes?
J Pathol
188
231
236
20. Dixon
AL
Liang
L
Moffatt
MF
Chen
W
Heath
S
2007
A genome-wide association study of global gene
expression.
Nat Genet
39
1202
1207
21. Plenge
RM
Seielstad
M
Padyukov
L
Lee
AT
Remmers
EF
2007
TRAF1-C5 as a risk locus for rheumatoid arthritis–a
genomewide study.
N Engl J Med
357
1199
1209
22. Baecklund
E
Backlin
C
Iliadou
A
Granath
F
Ekbom
A
2006
Characteristics of diffuse large B cell lymphomas in rheumatoid
arthritis.
Arthritis Rheum
54
3774
3781
23. Rothman
N
Skibola
CF
Wang
SS
Morgan
G
Lan
Q
2006
Genetic variation in TNF and IL10 and risk of non-Hodgkin
lymphoma: a report from the InterLymph Consortium.
Lancet Oncol
7
27
38
24. Skibola
CF
Bracci
PM
Nieters
A
Brooks-Wilson
A
de Sanjose
S
2010
Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA)
polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph
Consortium.
Am J Epidemiol
171
267
276
25. Alizadeh
AA
Eisen
MB
Davis
RE
Ma
C
Lossos
IS
2000
Distinct types of diffuse large B-cell lymphoma identified by
gene expression profiling.
Nature
403
503
511
26. Smedby
KE
Hjalgrim
H
Melbye
M
Torrang
A
Rostgaard
K
2005
Ultraviolet radiation exposure and risk of malignant
lymphomas.
J Natl Cancer Inst
97
199
209
27. Plenge
RM
Padyukov
L
Remmers
EF
Purcell
S
Lee
AT
2005
Replication of putative candidate-gene associations with
rheumatoid arthritis in >4,000 samples from North America and Sweden:
association of susceptibility with PTPN22, CTLA4, and PADI4.
Am J Hum Genet
77
1044
1060
28. Magnusson
C
Baron
J
Persson
I
Wolk
A
Bergstrom
R
1998
Body size in different periods of life and breast cancer risk in
post-menopausal women.
Int J Cancer
76
29
34
29. Price
AL
Weale
ME
Patterson
N
Myers
SR
Need
AC
2008
Long-range LD can confound genome scans in admixed
populations.
Am J Hum Genet
83
132
135; author reply 135-139
30. Stephens
M
Smith
NJ
Donnelly
P
2001
A new statistical method for haplotype reconstruction from
population data.
Am J Hum Genet
68
978
989
31. Lyngsø
R
Song
Y
Hein
J
2005
Minimum recombination histories by branch and bound, proceedings
of workshop on algorithms in bioinformatics.
Lect Notes Comput Sci
3692
239
250
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 4
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Survival Motor Neuron Protein Regulates Stem Cell Division, Proliferation, and Differentiation in
- PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease
- Variable Pathogenicity Determines Individual Lifespan in
- An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing