The rs5743836 polymorphism in TLR9 confers a
population-based increased risk of non-Hodgkin
A Carvalho1,2,3, C Cunha1,2,3, AJ Almeida1,2, NS Oso ´rio1,2, M Saraiva1,2, M Teixeira-Coelho1,2,
S Pedreiro4, E Torrado1,2, N Domingues5, AG Gomes-Alves1,2, A Marques6, JF Lacerda7, MG da Silva8,
M Gomes9, AC Pinto9, F Torres10, P Rendeiro10, P Tavares10, M Di Ianni11, R Medeiros5, P Heutink12,
PM Bracci13, L Conde14, P Ludovico1,2, J Pedrosa1,2, P Maciel1,2, L Pitzurra3, F Aversa11, H Marques6,
A Paiva4, CF Skibola14, L Romani3, AG Castro1,2,15and F Rodrigues1,2,15
1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal;2ICVS/3B’s—PT
Government Associate Laboratory, Braga/Guimara ˜es, Portugal;3Microbiology Section, Department of Experimental Medicine and
Biochemical Sciences, University of Perugia, Perugia, Italy;4Centro de Histocompatibilidade do Centro, Coimbra, Portugal;5Portuguese
Institute of Oncology, Porto, Portugal;6Hospital de Sa ˜o Marcos, Braga, Portugal;7Hospital de Santa Maria, University of Lisbon,
Lisbon, Portugal;8Department of Haematology, Portuguese Institute of Oncology, Lisbon, Portugal;9Portuguese Institute of Oncology,
Coimbra, Portugal;10CGC—Centro de Gene ´tica Clı ´nica, Porto, Portugal;11Division of Hematology and Clinical Immunology,
Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy;12Section Medical Genomics, Department
of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands;13Department of Epidemiology and Biostatistics,
University of California San Francisco, San Francisco, CA, USA and14School of Public Health, Division of Environmental Health
Sciences, University of California, Berkeley, CA, USA
Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune
conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been
regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on
TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the
association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major
subtypes in three independent case–control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls,
494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly
overtransmitted in both Portuguese (odds ratio (OR), 1.85; P¼7.3E?9) and Italian (OR, 1.84; P¼6.0E?5) and not in the US
cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring
rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.
Genes and Immunity (2012) 13, 197–201; doi:10.1038/gene.2011.59; published online 25 August 2011
Keywords: toll-like receptors; non-Hodgkin lymphoma; single nucleotide polymorphism; TLR9
Non-Hodgkin lymphoma (NHL) includes a heteroge-
neous group of malignant lymphoproliferative diseases
whose incidence has substantially increased over the
past decades in Western countries.1Individuals with
specific immune deficiencies associated with immune-
suppressive therapy after transplantation, HIV infection
and congenital conditions are among those with higher
incidence rates of lymphoid malignancies. Additionally,
clinical and experimental data consistently associated
several autoimmune and chronic inflammatory disorders
with increased risk of NHL.2,3
Toll-like receptors (TLRs) are widely studied members
of the pattern recognition receptor family with a
major role in activation and homeostasis of the immune
system upon pathogen recognition.4Among the TLRs
that bind nucleic acids, TLR9 recognizes unmethylated
CpG DNA motifs (present at a much higher frequency
in the genomes of prokaryotes than of eukaryotes) as
a ‘danger signal’ that activates the innate immune
system. In humans, this receptor is expressed in
plasmacytoid dendritic cells and B lymphocytes, known
to have a diverse TLR repertoire, where TLR9 predomi-
nates.5A role for TLR9 on viral, fungal, mycobacterial
and Helicobacter pylori infections has been described.6–10
Received 26 April 2011; revised 7 July 2011; accepted 19 July 2011;
published online 25 August 2011
Correspondence: Dr F Rodrigues, Life and Health Sciences Research
Institute (ICVS), School of Health Sciences, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal.
15These authors share author leadership.
Genes and Immunity (2012) 13, 197–201
& 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12
TLR9 (and TLR7) has been also involved in the
recognition of self-nucleic acids, which is believed to
have an important role in the pathogenesis of auto-
immune diseases, particularly in systemic lupus erythe-
In addition to self-recognition, inappropriate TLR9
activation leading to disease may also involve mechan-
isms of transcriptional deregulation of the TLR9 gene.
Consistently, cells from different lymphoma types (mantle
cell, B-cell small lymphocytic, follicular and diffuse large
B-cell) have been reported to overexpress TLR9 and to
show an increased proliferation upon CpG stimulation,
although with a heterogeneous pattern when comparing
either different lymphomas or different patients.5,13More
specifically, the highly prevalent rs5743836 polymorphism
in the TLR9 gene (1237T4C), has been demonstrated to
predispose to Hodgkin lymphoma, as well as to several
autoimmune and chronic inflammatory diseases, includ-
ing asthma and Crohn’s disease.14–18
Given the substantial weight of evidence for immune
dysfunction as the underlying basis of lymphomagenesis,
a genetic variant unbalancing the regulation and expres-
sion of TLR9-associated mechanisms may have a major
impact upon host anti-tumoral responses and therefore,
an important role in NHL pathogenesis. Epidemiological
and genetic studies have shown that inflammatory and
infectious conditions, particularly bacterial and viral
infections, are associated with increased NHL risk,3,19–22
suggesting that chronic immune stimulation has a role in
Given the role of TLR9 in bacterial and viral recogni-
tion, and the link of the TLR9 rs5743836 polymor-
phism with Hodgkin lymphoma, we hypothesized that
rs5743836 could also influence NHL risk. We therefore
analyzed whether this polymorphism was associated
with susceptibility to B-cell-derived NHL in a large-scale,
Results and discussion
All cases were histologically confirmed and coded
according to the World Health Organization (WHO)
control individuals (n¼1160) for rs5743836 were in
Hardy–Weinberg equilibrium (P40.05). A comparison
of genotype distribution between the NHL patients
(n¼797, including cases of follicular lymphoma (FL)
n¼240, 30.1%; diffuse large B-cell lymphoma (DLBCL)
n¼200, 25.1%, marginal zone lymphoma n¼125, 15.7%,
chronic lymphoid leukemia/small lymphocytic lym-
phoma, (CLL/SLL) n¼85, 10.7%, mantle cell lymphoma
n¼82, 10.3%; B-lymphoblastic lymphoma, n¼55, 6.9%,
and Burkitt lymphoma, n¼10; 1.2%) and controls
revealed a positive association between the presence of
rs5743836 and risk of NHL (Table 1), using the dominant
(P¼7.3E?9, odds ratio (OR)¼1.85, 95% confidence
interval (CI), (1.50–2.27)) or the additive (P¼1.1E?7,
OR¼1.66) genetic models. Accordingly, significant asso-
ciations were also observed for the major NHL subtypes,
such as FL (P¼2.9E?4; OR¼1.77; 95% CI, 1.30–2.42),
DLBCL (P¼7.2E?6; OR¼2.07; 95% CI, 1.50–2.85) and
CLL/SLL (P¼7.06E?6; OR¼2.76; 95% CI, 1.74–4.35),
thus pointing to a broad impact of rs5743836 in B-cell
NHL, independently of its subtypes.
To validate our findings, two independent Caucasian
populations were used: an Italian cohort (467 NHL cases,
including cases of CLL/SLL, n¼242, 49.0%; FL, n¼150,
30.4%; DLBCL, n¼55, 11.1%; mantle cell lymphoma,
n¼22, 4.5%; marginal zone lymphoma, n¼18, 3.6% and
mucosa-associated lymphoid tissue lymphoma, n¼7,
1.4%, and 468 controls) and a US population of European
ancestry (821 NHL cases, including cases of CLL/SLL,
n¼201, 24.5%; FL, n¼194, 23.6%; DLBCL, n¼255,
31.1%; mantle cell lymphoma, n¼31, 3.8%; marginal
zone lymphoma, n¼80, 9.7%, other B-NHL cases, n¼60,
rs5743836 frequencies for controls were in Hardy–
Weinberg equilibrium (P40.05). Whereas the association
with overall NHL (with either the dominant (P¼6.0E?5;
OR¼1.84; 95% CI, 1.36–2.48) or the additive (P¼1.1E?4;
OR¼1.60) genetic models) or its major subtypes FL
(P¼1.9E?2; OR¼1.66; 95% CI, 1.08–2.53), DLBCL
(P¼1.7E?2; OR¼2.07; 95% CI, 1.13–3.81) and CLL/
SLL (P¼3.3E?4; OR¼1.91; 95% CI, 1.34–2.73) was
confirmed in the Italian cohort, no association between
NHL susceptibility and the presence of rs5743836 was
found in the US cohort (Table 1).
There are several possible reasons for the discrepant
results obtained for the association of rs5743836 with
NHL. It is noteworthy that several other studies have
found minor allele control frequencies of rs5743836,
similar to those assessed in our European popula-
tions.8,28,29This suggests that, despite the fact that the
populations enrolled in our study shared the same
population bottleneck expanding out of Europe, the
decreased minor allele frequency detected in the Portu-
guese and Italian cohorts likely reflects a greater genetic
drift in Europe.30On the other hand, familial aggregation
and twin studies for lymphoproliferative disorders have
ruled out the role of highly penetrant genes in affecting
risk of the majority of NHL cases.31It is therefore likely
that the additive effects of genetic variants and inter-
actions with environmental and infectious agents may
have a significant role in the differential relevance of
the rs5743836 polymorphism in the risk for NHL. This
hypothesis is in agreement with epidemiological and
genetic studies, showing that inflammatory and infec-
tious conditions are associated with increased NHL risk,
suggesting that chronic immune stimulation has a role in
The rs5743836 polymorphism in TLR9 has been
consistently associated with increased transcriptional
activity.9,32,33Indeed, we have also found that unstimu-
lated mononuclear cells isolated from both healthy
controls and NHL patients bearing the rs5743836 poly-
morphism display increased TLR9 mRNA expression
(Figure 1), thereby supporting the notion that rs5743836
triggers an enhanced TLR9 function. Therefore, it is
possible to predict that the complex immunological
response of various cell types to CpG, involving both
direct and indirect effects of TLR9, is likely deregulated
in individuals carrying the rs5743836 polymorphism. In
fact, it has been shown that increased B-cell proliferation
upon CpG stimulation is a common feature of different
NHL subtypes, even though the proliferation pattern
varies among NHL subtypes and individual patients.13
Signal transduction initiated by TLR9 activation results
in nuclear translocation of nuclear factor-kB34that
may enhance lymphocyte neoplastic transformation by
rs5743836 polymorphism in TLR9
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Analysis of rs5743836 genotype frequencies in B-cell non-Hodgkin lymphoma patients and controls
N (% frequency)a,b
P-value*OR (95% CI)
Controls 1160934 (80.5) 217 (18.7)9 (0.8)
Controls 468379 (81.0)81 (17.3) 8 (1.7)
55 37 (67.3)
Controls (n¼972)972674 (69.3)275 (28.3) 23 (2.4)
Abbreviations: CI, confidence intervals; DLCBL, diffuse large B-cell lymphoma; FL, follicular cell lymphoma; MALT, mucosa-associated
lymphoid tissue lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; OR, odds ratio;
SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia.
aPortuguese and Italian patients had a mean age of 60.4±15.8 (51.7% males, 48.3% females) and 62.8±12.4 (58.9% males, 41.1% females),
respectively. Controls were unrelated healthy blood donors frequency-matched to cases by gender and age. Patients and controls with history
of transplantation, hematological malignancy or HIV infection were excluded from the study. USA patients derived from a study conducted
in the San Francisco Bay Area (California, USA) that included incident cases diagnosed from 2001 through 2006. Details of the process, criteria
for subject selection and full description of patients have been described elsewhere.38Note that the number of patients in the table is smaller
than that stated in the text as a result of individuals with undetermined genotype. All study participants provided written informed consent.
bFor the Portuguese and Italian studies, genotyping was performed using bi-directional PCR amplification of specific alleles (Bi-PASA) as
described.39Accurate genotyping was validated by direct sequencing randomly selected DNA samples. Concordant results were obtained for
100% of the samples in blind analysis. In addition, as routine quality control, each Bi-PASA genotyping set comprised randomly selected
replicates of previously typed samples and two negative controls (water). For the US study, DNA was isolated from peripheral blood
mononuclear cells using the QIAamp DNA Blood Maxi Kit protocol (Qiagen, Valencia, CA, USA) and quantified using PicoGreen dsDNA
Quantitation kits (Invitrogen, Carlsbad, CA, USA) according to the manufacturers’ specifications. Genotyping was performed using TaqMan
SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) on the ABI Prism 7700 Sequence Detection System. Replicate, blinded
quality control samples were included to assess reproducibility of the above genotyping procedures. Ambiguous genotypes were
regenotyped as necessary. All plates contained positive (all three genotypes) and negative (water) controls. Reactions were done with the
following protocol: 951C for 10min, then 40 cycles of 951C for 15s, and 601C for 1min. Probes and primer sets used were as follows: forward
primer, 50-GCCTTGGGATGTGCTGTTC-30; reverse primer, 50-CAGAGACATAATGGAGGCAAAGGA-30; T probe, 50-CCTGAAAACTCCC-30;
and C probe, 50-CTGGAAACTCCC-30.
cAssociation tests were conducted using a dominant and an additive model (Cochran–Armitage trend test) tests. For the Portuguese and
Italian studies, Fisher’s exact test and Pearson’s w2-test were used to compare genotype frequencies between patients and controls.
Unconditional logistic regression was used to compute odds ratios (ORs) and corresponding 95% confidence intervals (CI) adjusted for age
and sex. For the US study, association tests were conducted using the PLINK 1.04 software. ORs and 95% CI were calculated by median-
unbiased estimation using the mid-p method from the epitools R package (http://sites.google.com/site/medepi/epitools). P-values were
calculated regarding dominant * or the additive ** genetic model.
dNo significant associations were found when considering other features of clinical value including international prognostic indexes (IPI and
FLIPI), clinical stage of the disease or overall survival (data not shown).
rs5743836 polymorphism in TLR9
A Carvalho et al
Genes and Immunity
promoting proliferation and survival of mutated cells.35
In this regard, it may be worthwhile to investigate
whether the rs5743836 polymorphism displays a prefer-
ential association with lymphoma subtypes with con-
stitutive activationof nuclear
The neoplastic process leading to the development of
NHL may be usurping impairments in TLR signaling
pathways to advance cancer progression, which suggests
that targeting these pathways may open novel thera-
peutic avenues. CpG molecules are now regarded as
highly promising for cancer therapy, mostly due to
their direct effect on TLR9 activation on immune cell
subpopulations that have an important role in anti-
tumor immunity, including B cells.36However, thera-
peutic applications of these CpG should be individually
tailored, as individual genetic variations may affect the
outcome of the TLR9 signaling pathway.
In summary, our results suggest a potential role for
the host genetic background in B-cell NHL susceptibi-
lity. Altogether, and despite the fact that B-cell lympho-
mas are known for their ability to trigger disparate
responses to TLR9 agonists,13the genetic associations
found herein were not, for the most part, subtype-
specific. This suggests that altered TLR9 signaling
pathways may underlie shared mechanisms of suscept-
ibility to B-cell NHL, particularly to the subtypes
where the findings were stronger, such as CLL/SLL.
As a matter of fact, apoptosis of human CLL B-cells has
been found to be intimately related with TLR9 activa-
tion,37thereby suggesting that genetic variation of this
receptor may also impact the outcome of TLR9 agonist
therapy. However, deeper insights into the pathogenetic
mechanisms underlying TLR9-mediated mechanisms in
NHL are needed. Ultimately, functional studies dissect-
ing the role of the rs5743836 may allow the identification
of potential therapeutic targets.
Conflict of interest
The authors declare no conflict of interest.
AC, NSO, MTC and AJAwere financially supported by a
fellowship from Fundac ¸a ˜o para a Cie ˆncia e Tecnologia,
Portugal. MS is a Cie ˆncia 2007 fellow. This study was
supported by Fundac ¸a ˜o para a Cie ˆncia e Tecnologia,
Calouste Gulbenkian, Servic ¸o de Sau ´de e Desenvolvi-
mento Humano, Portugal (Grant Number:Proc/60666-
MM/734). CFS, PB and LC were supported by National
CA104682, and PB also by NIH grants CA45614 and
CA89745. We are grateful to Paulo Vieira, Cecı ´lia Lea ˜o,
Manuel T Silva, Nuno Sousa, Jorge Correia-Pinto, Joana
Palha, Margarida Correia-Neves, Margarida Lima and
Matthew Berry for all their input throughout these
studies and critical reading of the manuscript. We are
grateful to the patients who joint this study, as well as to
all members of the Life and Health Sciences Research
Institute and School of Health Sciences, University of
Minho, who contributed in any way to the development
of this work.
and byFundac ¸a ˜o
grants CA122663 and
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rs5743836 polymorphism in TLR9
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