Genetic polymorphisms in tumor necrosis factor- α (TNF-α) -308 [601398]

Title Page:

Article Title:
Genetic polymorphisms in tumor necrosis factor- α (TNF-α) -308
and lymphotoxin- α (LT-α) +252in Egyptian patients with acute
lymphoplastic leukemia

Authors' names:
*WaelAlkhiary; **NaglaaMokhtar;***Mona Talaab; *SherinM.Abd El-Aziz

*Hematology Unit, Clinical pathology Department,Faculty of Medicine, Mansoura
University
**Medical Biochemistry Department, Faculty of Medicine, Mansoura University
*** Clinical Hematology Department, Facu lty of Medicine, Mansoura University

Corresponding Author:
NaglaaMokhtar Medical Biochemistry department, Faculty of Medicine, Mansoura University El-Goumhoria St., Mansoura, Egypt.
E-mail address: [anonimizat]
Mobile: 01006278584

Genetic polymorphisms in tumor necrosis factor- α (TNF-α) -308
and lymphotoxin- α (LT-α) +252in Egyptian patients with acute
lymphoplastic leukemia
By
*WaelAlkhiary; **NaglaaMokhtar;***M ona Talaab; *SherinM.Abd El-Aziz
*Hematology Unit, Clinical pathology Department,Faculty of Medicine, Mansoura
University
**Medical Biochemistry Department,Facu lty of Medicine, Mansoura University
*** Clinical Hematology Department, Facu lty of Medicine, Mansoura University

ABSTRACT
Acute lymphoblastic leukemia (ALL) is one of the hematologicalcancersthat have been
originated from lymphoid origin. It has been proposed that cytokine deregulation could be
involvedwith developement, progression of many diseases. Genetic polymorphisms in
tumor necrosis factor- α (TNF-α) at position -308 andgenetic polymorphisms in other
important cytokine likelymphotoxin- α (LT-α) at position+252 can distress their expression
and so leads to increase their level in the blood. The occurrence of the polymorphisms
inthese two cytokines are different in AL L cases among differentpopulations. This
studyaimed to analyze the distribution and therole of TNF- α gene polymorphism at position
-308 G>Aas well as LT- α + 252 A>G polymorphism inthe development of ALL in
Egypt.One hundred and twenty sixpatients with ALL (96 pediatric and 30 adult),besideone
hundred and thirty healthy controlswere recruited in the study whose age and sex matched with the patient group. Polymorphism variants of LT- α and TNF- α genes were studied by
PCR-RFLP on genomic DNA isolated from blood leukocytes of all st udied individuals.
This studydemonstrated thatTNF- α polymorphism at position -308 was significantly
associated withpediatric ALL patients with no association with ALL adult patients. TNF
AA genotype and A allele showed significant risk of development of pediatric ALL.
However, there was no connection about LT α (+252) in both pediatric and adult ALL. In
conclusion, theTNF AA genotype and A allele showed significant risk of development of pediatric ALL.

INTRODUCTION
Acute lymphoblastic leukemia (ALL) affect both youngand adults, yet its peaks of
incidence between 2-5 years of age (Ofran& Rowe 2014 ), being the most common
childhood cancers (Lacour&Clavel, 214). The complex etiology of ALL has not been
fully elucidated. While the roles of some environmental factors have been questioned as
potential risk factors (Zuckerman&Rowe 2014, Bhojwani et al.2015), cumulative
evidencesuggests that there is genetic predisposition for development ALL (Mullighan
,2013&Urayama&Manabe ,2014).
Tumor Necrosis Factor (TNF) is a family of cytokines capable of causing cellular
apoptosis. Tumor Necrosis Factor-alpha (TNF- α) is secreted mainly by T-helper
lymphocytes (Th-1, CD4+). Lymphotoxin- α (LT-α; formerly TNF- β) is produced
mainly by mitogen-stimulated T-lymphocytes and leukocytes (Šedý et al.,2014,
Fulda,2014). Both TNF- α and LT-α are capable of stimulation of normal B cellsgrowth
as well as they are potent controllers of both B and T lymphocytes, by signaling via TNF receptors
(Figgett et al.,2014, ).
The human TNF- α gene maps to chromosome 6p23-6q12. The gene encoding LT- α is
approximately 1.2 kb downstream of the TNF- α gene (Spies et al.,1986). However, both
genes are regulated independently (Šedý et al.,2014). Some single nucleotide
polymorphisms (SNPs) have been reported in TNF- α and LT- α gene. The most
significance is TNF- α (G>A) polymorphism at -308 position (rs1800629), and SNP in
LT-α gene (A>G) at 252 position (rs909253), where the mutated allele is associated with
enhanced corresponding cytokine expression (Wilson et al.,1997,).
Owing to the biological roles of TNF superfamily, its genes along with SNPs may be
suitable candidates for the study of lymph proliferative disorders. In the literature, there are a number of reports that investigated these two SNPs; LT- α +252 (A>G) and TNF- α
-308 ( G>A ) in chronic lymphocytic leukemia, however, the results remain to be
controversial (He et al.2014, Cao et al.,2014, Jevtovic-Steimenov et al.,2008).
RegardingALL, only two conflicting studies are present, both were held in Asian
populations (Nasiri et al.,2013, Zhao et al.,2003). Thus, in the present case–control
study,the aime is to investigate whether TNF- α -308 ( G>A ) and LT- α +252 (A>G)
SNPs represent a risk factors for the development of children and adults ALL in Egypt.

MATERIALS AND METHODS

The current study included 126 patients (96 pediatric and 30 adult) with denovo ALL
who's chosen from Mansoura Oncology Center; Mansoura University. In addition to 130 healthy individuals with matched age and sex as a control group.
Samples from bone marrow and peripheral blood were obtained from patients at diagnosis. The diagnosis of ALL was raised on ;clinical evaluation (fever /infection, bleeding tendency, splenomegaly, hepatomegaly,and lymphadenopathy), CBC,
examination of the bone marrow followed by immunophenotype flowcytometry to confirm the diagnosis.A written consent were obtained from participating
subjects.Ethical approval had been obtaine d from Medical Research Ethics Committee
of Mansoura Faculty of Medicine (code no: R/16.08.40)
DNA Extraction and Genotyping :
Blood samples were collected in EDTA-c ontaining tubes. Using Thermo Scientific
DNA extraction.Analysis ofthe polymorphism of TNF- α(-308) & LT- α(+252) geneswas
done by PCRusing the following primers.

Table (1) :The primers sequencesfor TNF- α (-308) and LT- α(+252), restriction enzyme and
fragment lengths.

Gene Primers Sequences PCR products
and
fragment lengths Restriction
enzyme
TNF-α F:
5'-AGGCAATAGGTTTTGAGGGCCAT-'3
107 bp
(20 and 87 bp)

NcoI R:
5'-TCCTCCCTGCTCCGATTCCG -'3
LT-α F:
5'-CTCCTGCACCTGCTGCCTGGATC -'3 371bp
(134 and 237 bp)
R: 5'- GAAGAGACGTTCAGGTGGTGTCAT-'3

Table (2) :PCR conditions forstudied gene polymorphisms
Genes/Conditions Starting Denatu ration Annealing Extension Final
extension
TNF-α(-308) (G →A) 95°C for 4
min. At 95°C for 20
sec. At 58◦C for
20 sec. 72°C for 40
sec. 72°C for 7
min.
35 cycles
LT-α(+252) (A →G) 95°C for 4
min. At 95°C for 45
sec. At 60◦C for
45 sec. 72°C for
45sec. 72°C for 5
min.
32 cycles

.
Then the amplified products were digested by FastDigest NcoI Restriction enzyme
(Fermentas, Cat. No. FD0574).
The 107 bp band of normal TNF- α allele homozygous for guanine (GG allele) was
digested by NcoI to two bands at 87and 20 bp.While the TNF- α homozygousallele for
adenine (AA allele) persisted with out digestion and represented by one band.The presence ofthree bands at 107, 87 and 20 bp represented heterozygous TNF- α allele
(AGallele)(Tables 1) (Fig.1 ).
As regard LT- α +252 after digestion of the PCR product with the enzyme,a single band
371 bp represented(AA allele)homozygous for an adenine; two bands at 134 and 237 bp
representedhomozygous(GG allele) while,hete rozygous (GA allele) represented by three
bands 371, 134 and 237 bp (Tables 1) (Fig.2).

Statistical analysis
The statistical analysis was performed by using SPSSprogram (statistical package for
social science)version20.Qualitative data were presented as frequency and percentage. Chi square and Fisher’s exact tests were us ed to compare groups. Quantitative data were
presented as mean and standard deviation or median and range. The quantitative data
were examined by Kolmogorov Smirnov test for normality. For comparison between
two groups; student t-test and Mann-Whitney test (for non-parametric data) were used
value is significant at level ˂0.05 at confidence interval 95%

RESULTS
Table (3).Baseline characteristics of all studied patients.
Pediatric ALL Adult ALL
N=96 N=30
Age (years); mean±SD 7.5 1.3 36.9 9.7
Males; N (%) 64 66.7 17 56.7
Females; N (%) 23 24 13 43.3
Fever /infection; N (%) 76 79.2 22 73.3
Bleeding tendency; N (%) 40 41.7 13 43.3
Splenomegaly; N (%) 42 43.8 27 90
Hepatomegaly; N (%) 57 59.4 23 76.7
Lymphadenopathy; N (%) 42 43.8 23 76.7
Total leucocytic count (X109/L); median (range) 23.34 1.5-83 48.1 2.7-520
Hemoglobin concentration (g/dL) ; median
(range) 9 3.1-12 8.3 5.2-13.8
Platelet count (X109/L) ; median (range) 41.9 11-277 56.9 10-188
Peripheral blasts (%); median (range) 40 12-70 60 12-80
Bone marrow blasts (%); median (range) 90 45-92 90 70-96
LDH (IU/L) 856.5 181-4007 1250 477-2574
ALT (U/L) 17.95 9-104 36.5 12-101
AST (U/L) 26.45 16-92 35.7 10-172
Albumin (g/dL) 4.3 3.8-5 4.24 2.9-5.6
Bilirubin (mg/dL) 0.7 0.2-1.7 0.74 0.2-1.2
Creatinin (mg/dL) 0.5 0.2-3.2 1.11 0.8-8.2
Uric acid (mg/dL) 3.6 1.8-18.4 6.6 2.9-33.2
Immunophenotypes; N, % B 80 83.3 24 80
T 16 16.7 6 20
Complete remission; N (%) 64 66.7 18 60
Failure of complete remission; N (%) 32 33.3 12 40
Total mortality; N (%) 36 37.5 26 86.7

Table (4).Distribution of TNF, LT alleles a nd genotypes in pediatric ALL patients and
control.

Genotypes
and alleles Control
(n=100) Cases
(n=96) P OR 95%CI
No % No %
TNF G 165 82.5 138 71.9
0.012 * 1.845 1.140 2.986
A 35 17.5 54 28.1
GG 67 67 53 55.2 1
AG 31 31 32 33.30.393 1.181 0.806 1.732
AA 2 2 11 11.50.008 * 3.212 1.363 7.569
GG+AG 33 33 43 44.8 0.091 1.647 0.923 2.940
HW p 0.462 0.086
LT A 150 75 142 74
0.813 1.056 0.671 1.664
G 50 25 50 26
AA 54 54 51 53.1 1
GA 42 42 40 41.7 0.977 1.005 0.700 1.444
GG 4 4 5 5.2 0.688 1.192 0.506 2.805
GA+GG 46 46 45 46.9 0.902 1.036 0.591 1.816
HW p 0.230 0.424
*p˂ 0.05 OR: Odd's ratio CI: confidence interval

TNF AA genotype and A allele showed significant risk of development of pediatric ALL with no significant associations was found between LT genotype, alleles and pediatric
ALL.

Fig.(1): Genotypes of TNF- α (-308) by agarose gel electrophoresis.
Lane M: ladder ( 50-1000bp). Lane 5: TNF- α (-308) AG heterotype showing 107,
87bp bands. Lanes1,2, 3, 4 ,6,7,8,9,10TNF- α (-308) GG genotype showing 87bp
band.

Table (5):Comparison of TNF, LT genoty pes in adult ALL patients and control.

Genotypes
and alleles Control
(n=30) Cases
(n=30) P OR 95%CI
No % No %
TNF G 48 80 46 76.7
0.658 1.217 0.510 2.908
A 12 20 14 23.3
GG 20 66.7 19 63.3 1
AG 8 26.7 8 26.7 0.931 1.033 0.498 2.141
AA 2 6.7 3 10 0.635 1.330 0.409 4.326
GG+AG 10 33.3 11 36.7 0.787 1.158 0.400 3.348
LT A 40 66.7 46 76.7
0.224 0.609 0.272 1.360
G 20 33.3 14 23.3
AA 12 40 18 60 1
GA 16 53.3 10 33.3 0.705 0.776 0.210 2.875
GG 2 6.7 2 6.7 0.108 0.579 0.297 1.128
GA+GG 18 60 12 40 0.124 0.444 0.158 1.249
*p˂ 0.05 OR: Odd's ratio CI: confidence interval

No significant associations were found betw een TNF, LT genotypes, alleles and adult
ALL cases.

Fig.(2): Genotypes LT- α(+252) by agarose gel electrophoresis.
LaneM:ladder (50-1000bp ).Lanes 2, 3, 5, 7, 8, 9,10,11,12,13: LT- α(+252) AA
genotype showing 371bp band.Lanes 1,4: LT- α(+252) GA heterotype showing 371,
237,134bp bands. Lanes 6: LT- α (+252) GG genotype showing 237,134bp bands.
Table (6).Comparison of haplotype frequency in cases and controls.
Pediatric Adult
Haplotypes Control Cases P Control Cases p
GA 0.607 0.552 0.544 0.508 0.563 0.907
GG 0.218 0.167 0.407 0.292 0.248 0.579
AA 0.143 0.188 0.482 0.158 0.203 0.865
AG 0.032 0.094 0.013 0.042 0.030 0.993

AG haplotype showed significant association with ALL development in pediatric
subjects.

DISCUSSION
Data from a number of studies suggest that the polymorphisms of TNF- α and LT- α
may play a role in development of lymphoid malignancies.In this studypolymorphism of TNF-α – at position 308 (G>A), but not the LT- α gene polymorphism at position+252

(A>G), represented a significant risk of de velopment of pediatric ALL patients. The
mutant TNF AA genotype and (A ) allele was increased in pediatric ALL patients,
compared with the controls. In contrast, Nasiri et al.(2013) found that in ALL patients;
the frequencies of the mutated (A) allele and heterozygous AG genotype of TNF- α -308
polymorphism were significantly decreased in ALLgroupcompared to health control .
Alternatively, two studies in Takeuchi et al.(2002)& Kidas et
al.(2009), demonestratedthat TNF- α -308 gene polymorphism was not related to
development ofchildhood ALL. Regarding LT- α +252 gene polymorphism, Nasiri et
al.(2013)& Zhao et al.(2003) reported absence of any significant relationship with
ALL.Several studies have demonestrate d different prevalences of TNF- α -308 (G>A)
polymorphism and its association with NHL. Skibola et al.(2009) screened the risk of
developemnt of NHL in different ethnicity and found that TNF- α (–308 A) allele was
linked to an increased risk of NHL in non-Hispanic white as well as blacks, however, a
decreased risk of NHL in Asians was found. Moreover, TNF- α -308 G>A
polymorphism was not associated with NHL risk in a pooled analysis. However, Zhai et
al.,( 2014) demonestrated that the TNF- α -308 A allele was linked to higher risk of T-
cell lymphomas ,NHL and B-cell lymphomas, in Caucasians. But not in Asians .The
same findings were mostly obtained from another meta-analysis by He et al.,(2014).
Furtherore, the study by Jevtovic-Stoimenov et al.(2008) proofed the in fluence of TNF- α
308 G/A genotype specifically the A alleles on NHLsusceptibility , and the correlation
of LT- α G/G genotype with the development of chronic lymphocytic leukemia (CLL).
Notably, TNF- α 308 genotype (AA) distribution was found higher in NHL in
Egypt (Ibrahim et al.,2012). Instead, Seidemann et al.(2005) did not
reporteanysignificant association regarding TNF-genetic polymorphisms and pediatric or adolescent NHL in Caucasians .
In a meta-analysis by Cao et al.,(2014), they reported that LT- α +252 gene
polymorphism not association with NH L . However, subgroup analysis revealed that
LT-α +252 polymorphism was concidered as a risk factorfor the occurance of NHL in
North Americans
Regarding multiple myeloma (MM) evidences exist for a decreased risk of MM with the presence of mutant allele (A) of TNF- α-308 (Morgan et al.,2005).
The risk of relapse in childhood ALL and thepolymorphisms of LT- α +252 (A>G) and
TNF-α -308 (G>A) genes were not found in the study of Stanullaet al.,(2001).

However, recently, the polymorphism of TNF- α (G>A) at position -308 has a bad
prognostic significance in ALL (Yang et al.,2015).
In this study, the mutated (A) allele of TNF- α -308 (G>A) represent a high risk forthe
development of ALL inpediatric patients. Si milarily, this haplotype was higher in
patients with NHL (Ibrahim et al.,2012 , Jevtovic-Stoimenov et al., 2008 &Seidemann
et al., 2005).
A potential explanation for the effect of TNF- α -308 (A) and and LT- α +252 (G) alleles
is that both are associated with higher transcriptional activation, and enhanced TNF- α
expression (Higuchi et al.,1998 ), and thus, enhanced NF-kB pathway. NF-kB has anti-
apoptotic properties with malignancy poten tial and it stimulates pro inflammatory
cytokines that enhance the longivety and proliferation of the cells (Purdue et al.,2006 &
Wang et al., 2009). Of note, TNF- α – 308 (G>A) gene polymorphism was reported to be
associated with several autoimmune disorders e.g. rheumatoid arthritis (Elahi et
al.,2009). Further,TNF- α -308 AA genotype could in fluence the innate immmunity and
controltumor growth (Kazzi et al.,2004) and may modulate the susceptibility to apoptosis
in leukemic cells (Jevtovic-Stoimenov et al., 2008 ) . The discrepancy of the results
may be due to genetic heterogeneity in different populations. In addition, the
environmental complexity rela ted to differences in patient populations (as age, course
duration, severity, treatment) may le ad to different roles and results .
In conclusion, this study suggeststhat the associations of the TNF- α -308 (G>A)
polymorphism but not LT α+ 252 G haplotype with genetic predisposition forpediatric
ALL. Also, suggest that TNF- α might affect lymphoid malignancies development in
different populations. Additional studies ar e warranted to clarify the mechanisms
involved in ALL pathogenesis and to esta blish the prognostic valu e of these genetic
polymorphisms in the development of lymphoid malignancy .

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اﻟﻣﻠﺧص العربي

في الدم بسرطان المصابين المصريين المرضى TNF α -308 و LT-α +252 اتلتباينا الجيني الليمفاوي ھلجيني
الحاد
الخياري وائل – * مختار نجالء -** تعلب مني – *** عبدالعزيز شيرين *
اﻟدم أﻣراض اﻻﻛﻠﻳﻧﻳﻛﻳﺔﻗﺳﻣوﺣدة ﺎﻟﺑﺎﺛوﻟوﺟﻳﺎ* -ﻗﺳم اﻟطﺑﻳﺔ اﻟﺣﻳوﻳﺔ اﻟﻛﻳﻣﻳﺎء–**أﻣراض وﺣدة
اﻟﺑﺎطﻧﺔاﻟدم ﻗﺳم*** – اﻟطب ﻛﻠﻳﺔ اﻟﻣﻧﺻورة ﺟﺎﻣﻌﺔ

ھو الحاد الليمفاوي الدم أحدسرطان اللمفاوية األنسجة من مصدرھا التي الرئيسية الدموية الخبيثة األورام
منLT-α , TNF αاألمراضك من العديد نشوء الى السيتوكاينات في الخلل يسبب قد من ل ويعد األورام و
البالزما في مستوياتھما ارتفاع الي لھما الجيني التباين يؤدي التي الھامة السيتوكينات مسببا ئف وظا في خلل
كلLT-α +252 وTNF-α-308 اليمنھما الدراسة ھذه تھدف لجينو الجيني التباين دور دراسة ي
المصابين المصريين المرضى الحادفي الليمفاوي الدم بسرطان .
اشتملت قد و على الدراسة 126 مريض) 96 و األطفال من 30البالغين من( بمرض المصابين سرطان الدم
والحادالليمفاوي 130 ضابطة كمجموعه أصحاء أشخاص . قد تمو العظام نخاع فحص الكامل الدم عد و و للتأكد
التشخيص من .
تم قد و دم عينات أخذ) 1 مل( المشارك جميع ينمن ومضاعفته النووى الحامض الستخالص ذلك و البحث في
TNF-α -308 (G>A) and LT- α +252 (A>G الجينية التباينات وتحديد يلجين )
TNF-α -308 الدراسة ھذه نتائج أظھرت وقد لجين الجيني التباين بين احصائية داللة ذو عالقة وجود
االصابة الحادو الليمفاوي الدم سرطان بمرض األطفال في المرض بھذا المصابين البالغين في ليس و. حيث خطرا
كذلك و األطفال لدى الحاد الليمفاوي الدم بسرطان االصابة في كبيرا (AA) التباين يمثل
الدم بسرطان االصابة وLTα (+252) . لجين الجيني التباين بين احصائية عالقة توجد ال بينما( A ) األليل
الحاالل ديمفاوي .
له وطيدة عالقة بحدوث الليمفاوي الدم سرطان TNF-α -308 لجين الجينى التباين ان الدراسه ھذه اثبتت
األطفال لدي الحاد