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Abstract

BACKGROUND:

Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells.

OBJECTIVE:

to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians.

METHODS:

Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls.

RESULTS:

The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR $=$ 1.76; 95%CI $=$ 1.01–3.22 and OR $=$ 1.89; 95%CI $=$ 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR $=$ 3.57; 95%CI $=$ 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR $=$ 3.39, 95% CI: 1.61–7.16).

CONCLUSION:

TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population.

Keywords

B-NHL TRAIL-R1 C626G A683C -A1322G Egypt

1. Introduction

Non-Hodgkin Lymphoma (NHL) is the most common hematologic malignancy worldwide. It comprises a biologically diverse group with variable clinical course ranging from indolent to highly aggressive [1, 2]. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two major subtypes. DLBCL accounts for nearly 30% of newly diagnosed cases about 80% of aggressive lymphomas [3, 4]. In Egypt, lymphoid neoplasms represent 10–12% of all malignancies. The National Population-Based Cancer Registry Program reported that NHLs were the fourth most common cancer in males and the fifth in females in 2014. Genetic variations that promote B-cell growth and survival either through dysregulation of proliferation and differentiation or disruption of apoptosis have been contributed with the increased risk of lymphoid neoplasms in numerous studies [5].

Apoptosis is a fundamental biochemical cell-death pathway essential for normal tissue homeostasis, cellular differentiation and development [6]. There are two well-characterized pathways. The “extrinsic” pathway is mediated by death receptors (DR), a subgroup of the tumor necrosis factor (TNF) receptor superfamily and the “intrinsic” (Cytochrome C-mediated) apoptotic pathway [7].

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, TNFRSF10) is a potent stimulator of apoptosis. It is an important immune effecter molecule in the surveillance and elimination of developing tumors [8].

TRAIL induces apoptosis by binding to its receptors (TRAIL-R1 & R2) which are widely expressed on normal and neoplastic cells [8, 9]. Binding of TRAIL to TRAIL-R1 (TNFRST10A, Death receptor 4; DR4) or TRAIL-R2 (TNFRSF10B, Death receptor 5; DR5) on the cell membrane triggers apoptotic proteases to regulate apoptosis [10]. Inactivation of the TRAIL-TRAIL-R pathway and/or escape from TRAIL-mediated immunosurveillance might play a role in tumor onset and progression [8].

TRAIL-R1, a member of TNF superfamily, is encoded by TNFRSF10 gene on chromosome 8p21-22. Allelic losses of the chromosome 8p21-22 have been reported as a frequent event in several cancers [11, 12]. Genetic alterations of TRAIL-R1 gene and allelic loss affecting its locus (8p21-22) have been associated with many cancers such as lung cancer, head and neck [13], bladder [14], breast [15], prostate [16], ovarian [17], colorectal [18], hepatocellular carcinoma [19] and lymphomas [20, 21, 22, 23, 24].

Despite many investigations, the associations between TRAIL-R1 polymorphisms and the risk of human cancers is incompletely understood because of inter/intra ethnic variability. In this study, we aimed to investigate the possible association between TRAIL-R1-626G, -A683C, and -A1322G SNPs and the susceptibility to B-NHL in a cohort of Egyptians.

2. Material and methods

2.1 Study participants

This case-control study involved 100 newly diagnosed adult Egyptian B-NHL patients recruited from The National Cancer Institute (NCI), Cairo University. The control group consisted of 150 unrelated, ages and gender matched healthy, Egyptian volunteers recruited from the Donation Unit of the central blood bank of Kasr Al Ainy Teaching Hospital, Cairo University. The study was approved by the Research Ethics Committee of Faculty of Medicine and NCI, Cairo University. Informed written consents were obtained from all participants prior to enrollment in the study. All procedures performed were in accordance with recommendation of the Declaration of Helsinki the 1964 and its later amendments or comparable ethical standards. B-NHL patients were diagnosed by lymph node excision biopsy. Histological and immunohistochemical studies were performed for proper stratification according to the WHO classification (2016). Patients were subjected to full history taking, clinical examination, radiological and laboratory assessment for proper staging. The extent of the disease was categorized according to Ann Arbor classification and the performance status (PS) of the patients was assessed by Eastern Cooperative Oncology Group (ECOG) criteria and Ann Arbor Classification system. Demographic and clinical data of the patients at presentation are presented in Table 1.

Table 1
Demographic and clinical data of B-NHL patients at presentation

Items	B-NHL patients ( $n=$ 100)
	No.	(%)
Gender
Female	42/100	42%
Male	58/100	58%
Lymphadenopathy	74/100	74%
Lymph nodes involved
Cervical	49/100	49%
Axillary	33/100	33%
Inguinal	30/100	30%
Abdominal	28/100	28%
Para-aortic	20/100	20%
Submandibular	18/100	18%
Mesenteric	7/100	7%
Extra-nodal involvement
$<$ 2 site	67/100	67%
$\geqslant$ 2 sites	33/100	33%
Bone marrow involvement	10/100	10%
Splenomegaly	38/100	38%
Hepatomegaly	34/100	34%
B-symptoms (Fever, night sweats, weight loss)	30/100	30%
Lactate dehydrogenase (LDH) level
Normal	44/100	44%
Elevated	56/100	56%
Clinical stage
I & II	25/100	25%
III & IV	75/100	75%
Performance status (PS)
Score $<$ 2	41/100	41%
Score $\geqslant$ 2	59/100	59%
International prognostic index (IPI) risk groups for DLBCL patients
Low/Intermediate low (1,2)	32/100	40%
Intermediate high/ High (3,4)	48/100	60%
Histological classification
Diffuse large B-cell lymphoma (DLBCL)	80/100	80%
Small lymphocytic lymphoma (SLL)	11/100	11%
Follicular lymphoma (FL)	5/100	5%
MALT lymphoma	2/100	2%
Marginal zone (MZL)	2/100	2%

2.2 Genotyping of TRAIL-R1 SNPs

Genomic DNA was isolated from peripheral blood samples of all participant using Gene JET Whole Blood Genomic DNA Purification Mini Kit (Ferments Life Sciences, Canada), and stored in elution buffer at $-$ 20 ${}^{\circ}$ C until being used. Genotyping of TRAIL-R1-C626G and -A683C SNP was performed by real time PCR, TaqMan SNP genotyping assay (Applied Biosystems, Foster City, USA), while PCR-based Amplified Refractory Mutation System (ARMS-PCR) was used for genotyping of TRAIL-R1 -A1322G SNP [19]. For quality control, genotyping of 20% of the samples with respect to case-control status was repeated and interpreted blindly by two different observers and was proved to be 100% concordant.

Table 2
Genotypes and allelic frequencies of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL patients and controls

Genotype	Control group ( $n=$ 150)	B-NHL Patients ( $n=$ 100)	OR	95% CI	$P$ value
TRAIL-R1-C626G (rs20575)
CC	49 (32.7%)	18 (18%)	1 (Reference)
CG	69 (46%)	49 (49%)	1.85	0.95–3.7	0.08
GG	32 (21.3%)	33 (33%)	1.82	1.03–3.22	0.014
CC $+$ CG*	118 (78.7%)	67 (67%)	0.55	0.31–0.97	0.039
CG $+$ GG**	101 (67.3)	82 (82%)	2.21	1.19–4.08	0.01
Allele C	0.56	0.42	1.76	1.01–3.08	0.048
Allele G	0.44	0.58
TRAIL-R1-A683C (rs20576)
AA	96 (64%)	65 (65%)	1 (Reference)
AC	48 (32%)	30 (30%)	0.92	0.5–1.69	0.79
CC	6 (4%)	5 (5%)	1.23	0.32–4.79	0.76
AA $+$ AC*	144 (96%)	95 (95%)	0.79	0.24–2.67	0.71
AC $+$ CC**	54 (36%)	35 (35%)	0.95	0.53–1.71	0.88
Allele A	0.80	0.80	1	0.5–2	1
Allele C	0.20	0.20
TRAIL-R1-A1322G (rs2230229)
AA	106 (71%)	54 (54%)	1 (Reference)
AG	38 (25%)	36 (36%)	1.65	1.001–3.52	0.05
GG	6 (4%)	10 (10%)	2.65	0.96–2.87	0.07
AA $+$ AG*	144 (95.7%)	90 (90%)	0.38	0.13–1.07	0.058
AG $+$ GG**	44 (29%)	46 (46%)	2.1	1.2–3.48	0.007
Allele A	0.83	0.72	1.89	1.01–3.75	0.049
Allele G	0.17	0.28

${}^{*}$ Recessive model; ${}^{**}$ Dominant model OR $=$ Odds ratio 95% CI $=$ 95% Confidence interval.

2.3 Statistical analysis

SPSS statistical package version 17 was used for data analysis. Mean, standard deviation, and the range were used for representing parametric numeric data, while median and interquartile ranges were used for non-parametric data. Frequency and percentage were used to represent qualitative data. For comparing categorical data, Chi-square ( $\chi^{2}$ ) test was performed. Exact test was used instead when the expected frequency was less than 5. Mann-Whitney test was used for non-parametric numerical data. Unconditional logistic regression analysis was performed to calculate 95% confidence intervals (CI) and odds ratios (OR) for risk estimation. Chi square ( $\chi^{2}$ ) test was used to assess deviation from Hardy-Weinberg equilibrium in controls. $P$ -value $<$ 0.05 was considered significant. Based on the frequency of the studied SNPs in NHL patients and healthy controls of subjects with Caucasians descents [15, 23, 24], the expected frequencies in Egyptian NHL patients and controls were applied to calculate the sample size of the current study. It was shown that 198 participants (99 in each arm) were found to yield a power of 80% at a p value of 0.05. Detection of -C626G polymorphism was the primary outcome of the current study, while the detection of other SNPs was the secondary outcome.

3. Results

The frequency of TRAIL-R1 gene polymorphisms in the studied groups is presented in Table 2. Genotypes distribution of TRAIL-R1-C626G (rs20575), -A683C (rs20576), and -A1322G (rs2230229) in the control group was in alliance with the Hardy-Weinberg equilibrium ( $P>$ 0.05).

Regarding TRAIL-R1-C626G SNP, the homozygous genotype; GG was significantly higher in B-NHL patients compared to control group conferring twofold increased risk of B-NHL (OR $=$ 1.82; 95% CI $=$ 1.03–3.22). The dominant model (CG $+$ GG vs CC) conferred twofold increased risk (OR $=$ 2.2, 95%CI $=$ 1.19–4.08). The polymorphic (G) allele conferred almost two folds increased risk of B-NHL (OR $=$ 1.76; 95% CI $=$ 1.01–3.08). The risk increased for DLBCL to be three folds (OR $=$ 3.39; 5% CI $=$ 1.61–7.16) Table 3. The distribution of the polymorphic genotypes in SLL and FL was close to that of the control group. As for TRAIL-R1-A683C, the distribution of the allele/genotypes in B-NHL cases was comparable to that of the control group and the difference between the two groups was statistically insignificant.

Table 3
Distribution of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL subtypes

TRAIL-R1 SNPs	Controls (n/%)	SLL ( $n=$ 11) (n/%)	OR (95% CI)	$P$ value	FL ( $n=$ 5) (n/%)	OR (95% CI)	$P$ value	DLBCL ( $n=$ 80) (n/%)	OR (95% CI)	$P$ value
-626G
CC	49/32.7%	3/27.3%	1.29	0.71	2/40%	0.73	0.73	10/12.5%	3.34	0.001
CG & GG	101/67.3%	8/72.7%	(0.33–5.09)		3/60%	(0.12–4.49)		70/ 87.5%	1.61–7.16)
-683C
AA	96/64%	6/54.5%	1.48	0.53	3/60%	0.37	0.29	54/67.5%	0.86	0.59
AC & CC	54/36%	5/55.5%	(0.43–5.08)		2/40%	(0.1–2.31)		26/32.5%	(0.48–1.52)
-A1322G
AA	106/71%	6/54.5%	2.01	0.27	3/60%	1.61	0.61	40/50%	2.41	0.002
AG & GG	44/29%	5/55.5%	(0.58–6.92)		2/40%	(0.26–9.95)		40/50%	(1.37–4.23)

SLL $=$ Small lymphocytic lymphoma, FL $=$ Follicular lymphoma, DLBCL $=$ Diffuse large B – cell lymphoma, OR $=$ Odds ratio, 95% CI $=$ Confidence interval.

The heterozygous genotype (AG) of TRAIL-R1-A1322G SNP was associated with almost twofold increased risk of B-NHL (OR $=$ 1.65; 95% CI $=$ 1.001–3.52) and the risk was higher for the dominant model (AG $+$ GG vs AA) (OR $=$ 2.1; 95% CI: 1.2–3.48). The polymorphic (G) allele conferred twofold increased risk of B-NHL (OR $=$ 1.89, 95%CI: 1.01–16–3.75). The risk increased for DLBCL (OR $=$ 3.39, 95% CI $=$ 1.61–7.16).

Combined genotype analysis revealed that coinheritance of the variant genotypes of TRAIL-R1-C626G and -A1322G SNPs conferred almost threefold increased risk of B-NHL (OR $=$ 3.57, 95%CI: 1.29–9.84), while coinheritance of -A683C and -A1322G SNPs or the three studied SNPs was not associated with susceptibility to B-NHL Table 4.

Table 4

Combined genotypes analysis of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL patients and controls

Combined genotypes of TRAIL-R1 SNPs	Controls $n$ (%)	B-NHL patients $n$ (%)	OR	95% CI	$P$ value
-A683C & -C626G
AA+CC	23 (15.3%)	6 (6%)	1 (Reference)
CG+GG/AC+CC	29 (19.3%)	16 (16%)	2.11	0.42–6.27	0.18
-C626G & -A1322G
AA+CC	20 (13.3%)	7 (7%)	1 (Reference)
CG+GG/AG+GG	24 (16%)	30 (30%)	3.57	1.29–9.84	0.014
-A683C & -A1322G
AA+AA	66 (44%)	40 (40%)	1 (Reference)
AC+CC/AG+GG	6 (4%)	4 (4%)	2.47	0.65–9.3	0.18
-C626G, -A683C & -A1322G
CC+AA+AA	6 (4%)	4 (4%)	Reference
CG+GG/AC+CC/AG+GG	10 (6.6%)	11 (11%)	1.65	0.36–7.6	0.52

OR $=$ Odds ratio, CI $=$ 95% Confidence interval.

4. Discussion

Multiple genetic factors are involved in the pathogenesis of NHL and dysregulation of apoptosis could be one of them [5]. Deregulation of apoptosis plays a crucial role in carcinogenesis as it provides a growth advantage to cancer cells [6]. The trio -C626G, -A683C and -A1322G SNPs of TRAIL-R1 were linked to different types of cancers [13, 14, 15, 16, 17, 18, 19, 20]. TRAIL-R1-C626G (Thr209Arg, rs20575) is a missense mutation at nucleotide 626 with change of a cytosine to a guanine and subsequently, a substitution of an arginine for threonine. This alteration results in amino acid changes in or near the ligand-binding domain of TRAIL-R1 [13]. The A to C nucleotide exchange on nucleotide 683 of TRAIL-R1 gene leads to replacement of the negatively charged, large amino acid glutamate by the uncharged, small amino acid alanine, within a highly sensitive region of TRAIL/TRAIL-R1 complex formation. The expected consequence is an obstructed induction of caspase-8 dependent apoptosis, resulting in a longer survival rate of tumor cells [21]. In TRAIL-R1-A1322G (Lys441Arg, rs2230229) polymorphism, transition of Adenine to Guanine at nucleotide 1322 results in the conversion of the lysine at codon 441 to arginine [24]. These findings raised the possibility that genetic variations affecting TRAIL-R1 affinity for TRAIL could decline its apoptotic function and contribute to carcinogenesis [25, 26].

The current case-control study has been designed to clarify the role of TRAIL-R1 gene polymorphisms as potential susceptibility loci for B-NHL in a cohort of Egyptians. This type of studies may serve to identify at risk populations and to verify important disease mechanisms. Genotypic analysis showed that the frequency of the polymorphic genotypes of TRAIL-R1-C626G polymorphism in B-NHL patients was 49% and 33% for the (CG) and (GG) polymorphic genotypes respectively. These frequencies were close to that reported in B-NHL patients of Caucasian descents being 48% and 44% for the CG genotype and 29 and 32.2% for the GG genotype [23, 27]. Statistical analysis showed that the homozygous genotype; GG and the G allele conferred twofold increased risk of B-NHL. However, Fernandez et al. [24] and Heredia-Galvez [23] reported that this SNP was not associated with B-NHL risk as the frequency of the polymorphic genotypes in NHL patients were close to that of controls. This could be attributed to the difference in sample size or the proportions of B-NHL subtypes included in these studied. Further stratification of the patients according to their histological subtypes showed that the risk conferred by TRAIL-R1-C626G SNP increased in DLBCL to be three folds (OR $=$ 3.39, 95% CI: 1.61–7.16).

Genotyping of TRAIL-R1 -A683C SNP revealed that 30% of B-NHL cases harbor the heterozygous genotype (AC), while 5% harbor the homozygous genotype (CC). These frequencies were in line with that reported in Spanish NHL patients being 38% and 35% for the AG genotype and 6.6% and 10% for the CC genotype respectively [23, 27]. There was no statistical difference in the distribution of -A683C genotypes between NHL cases and controls. Accordingly, this SNP was not associated with B-NHL risk in our cohort. This is in agreement with the studies of Heredia-Galvez et al. [18] and Gutiérrez-Cívicos et al. [27]. Wolf et al. [21] analyzed the complete coding region of TRAIL-R1 and -R2 in a series of 32 MCL and 101 CLL samples and detected a single nucleotide polymorphism in TNFRSF10A (A683C) with tumor specific allele distribution. They reported that - A683C polymorphism did not co-segregate with other TRAIL-R1 polymorphisms previously described and recommended screening for -A683C SNP might be important in diagnosis and/or treatment of these malignancies. Furthermore, they found that the C allele was more frequent in CLL and MCL. In our study, although the frequency of the polymorphic genotypes in lymphoma patients was higher than that of controls, the difference between the two groups did not reach a statistically significant level. So, TRAIL-R1-A683C polymorphism could not be considered as a genetic risk factor for indolent B-NHL subtypes as SLL or FL.

Genotyping of TRAIL-R1 -A1322G SNP showed that 36% of B-NHL cases harbor the heterozygous genotype (AC), while 10% harbor the homozygous genotype (CC). These frequencies are close to that reported by Heredia-Galvez et al. [18] and Fernandez et al. [19], while lower frequencies were reported in the study of Gutiérrez-Cívicos et al. [27]. Statistical analysis showed that the heterozygous genotype (AG) conferred almost two folds increased risk of B-NHL. On the contrary, -A1322G polymorphism was not associated with susceptibility to B-NHL in the studies of Heredia-Galvez et al. [23] and Fernandez et al. [24]. The study of Fernandez et al. [19] showed that -A1322G SNP was associated with susceptibility to mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) but not DLBCL. The differences between the studies could be referred to the different sample size as well as the different histological subtypes of B-NHL patients included in these studies.

Combined genotype analysis showed that coinheritance of the polymorphic genotypes of TRAIL-R1-C626G and -A1322G polymorphisms increased the risk of B-NHL conferred by each of which solely (OR $=$ 3.57, 95%CI: 1.29–9.84), while coinheritance of the variant genotypes of -A683C and -A1322G or those of the three SNPs was not associated with B-NHL risk. ;Most anticancer agents can sensitize tumor cells but not normal cells to TRAIL by increasing the levels of TRAIL-R1 and R2. Understanding the regulation of TRAIL/TRAIL-Rs apoptotic pathway aid in the development of TRAIL-based therapies as recombinant forma of TRAIL, TRAIL receptor agonists and other therapeutic agents [28]. Targeting the TRAIL/TRAIL-R apoptotic pathway with recombinant TRAIL or antibodies against TRAIL-R1 and R2 conjoined with chemotherapeutic agents is a logical approach for the treatment of the hematological malignancies [22]. The combination of an agonist monoclonal antibody targeting TRAILR1 with an anti-CD20 monoclonal antibody was found to be more effective in controlling lymphoma growth than anti-CD20 solely [29, 30]. The major problem in the clinical trials of TRAIL-based therapies is either intrinsic or acquired resistance to TRAIL. This resistance could be attributed to TRAIL-R gene polymorphisms which confer low TRAIL binding capacity. Thus screening for TRAIL-R gene polymorphisms should be considered when TRAIL-based therapy is recommended.

5. Conclusions

Data analysis showed that TRAIL-R1-C626G and -A1322G gene polymorphisms could be considered as molecular risk factors for B-NHL in Egyptian population whether solely or when co-inherited. Our study has provided preliminary insight into genetic variations of TRAIL-R1 gene in a cohort of Egyptian B-NHL patients as well as controls. These findings highlight the importance of studying the prevalence of putative disease-causing variants in an ethnic-specific cohort in order to confirm their pathogenicity in their respective population. Functional studies on knockout animal or cellular models will help to verify disease mechanisms and identify relevant pathways of lymphomagenesis. Furthermore, larger collaborative studies followed by replication and multicenter pooled analyses are needed for deeper insight into the contribution of TRAIL-R1 genetic polymorphisms in NHL. Screening for TRAIL-R1 gene polymorphisms would be of value in the era of personalized therapy as targeting TRAIL/TRAIL-Receptors system in NHL is a novel promising non-chemotherapy therapeutic modality.

Funding

Self funding.

Ethical approval

The study was approved by the Research Ethics Committee of Faculty of Medicine and NCI, Cairo University, Egypt. All procedures performed were in accordance with recommendation of the Declaration of Helsinki the 1964 and its later amendments or comparable ethical standards.

Informed consent

Informed written consents were obtained from all participants prior to enrollment in the study. All procedures performed were in accordance with recommendation of the Declaration of Helsinki the 1964 and its later amendments or comparable ethical standards.

Footnotes

Conflict of interest

All authors declare that there is no conflict of interest.

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Genetic variations in tumor necrosis factor related apoptosis-inducing ligand receptor-1 (TRAIL-R1) gene and the susceptibility to b-cell non-hodgkin lymphoma (B-NHL) in Egypt 1

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Material and methods

2.1 Study participants

Table 1 Demographic and clinical data of B-NHL patients at presentation

Table 2 Genotypes and allelic frequencies of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL patients and controls

3. Results

Table 3 Distribution of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL subtypes

5. Conclusions

Funding

Ethical approval

Informed consent

Footnotes

Conflict of interest

References

Table 1
Demographic and clinical data of B-NHL patients at presentation

Table 2
Genotypes and allelic frequencies of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL patients and controls

Table 3
Distribution of TRAIL-R1-C626G (rs20575), -A683C (rs20576) and -A1322G (rs2230229) SNPs in B-NHL subtypes