- Research article
- Open Access
- Open Peer Review
Lymphotoxin-alpha polymorphisms and presence of cancer in 1,536 consecutive autopsy cases
© Takei et al; licensee BioMed Central Ltd. 2008
- Received: 20 December 2007
- Accepted: 13 August 2008
- Published: 13 August 2008
Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine with anti-tumor activity. The objective of this study was to determine whether LTA polymorphisms influence the presence of cancer.
LTA polymorphisms C804A (rs1041981, T60N) and T495C (rs2229094, C13R) were determined in 1,536 consecutive autopsy cases and were registered in the Japanese single-nucleotide polymorphisms (SNPs) for geriatric research (JG-SNP) Internet database. Tumors were systematically reviewed, pathologically confirmed, and assessed in relation to LTA genotype.
The study population consisted of 827 males and 709 females, with a mean age of 80 years. Altogether, we studied 606 subjects without cancer and 930 subjects with cancer of the stomach (n = 183), lung (n = 164), colon or rectum (n = 143), or other sites. The presence of cancer was higher in males than in females. The C804A and T495C polymorphisms were associated with cancer in males (CA + AA: CC, adjusted OR = 0.72, 95% CI = 0.53 – 0.99; TC + CC: TT, adjusted OR = 1.45, 95% CI = 1.04 – 2.02; respectively) but not in females. In males, the C804A polymorphism was associated with lung cancer (CA + AA: CC, adjusted OR = 0.60, 95% CI = 0.37 – 0.97), whereas the T495C polymorphism was associated with gastric cancer (TC + CC: TT, adjusted OR = 1.68, 95% CI = 1.06 – 2.65).
We found some evidence of an association between LTA polymorphisms and cancer risk in elderly Japanese men. Further studies in larger populations should examine this hypothesis.
- T495C Polymorphism
- Lower Presence
- C804A Genotype
- Alcohol Drinking Status
- Melting Temperature Analysis
Elderly people often experience chronic and low-grade inflammation, whereupon the levels of certain inflammatory serum markers (e.g., C-reactive protein) and pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6) are elevated. However, increases in circulating inflammatory markers are often not noticeable in healthy elderly persons and are much below the levels experienced during acute infections [1, 2]. Moreover, it is well known that the prevalence of cancer increases sharply with age, and that the majority of cancer cases occur in patients over the age of 65 . Persistent inflammation is thought to trigger certain cancers, particularly those of the stomach, colon, and lung . Although it has been established that the risks of cancer and inflammation increase with age , the influence of inflammatory cytokine polymorphisms on the genetic predisposition to cancer remains unclear.
Lymphotoxin-alpha (LTA), a member of the tumor necrosis factor (TNF) family of cytokines, was initially isolated on the basis of an anti-tumor activity. Later, this cytokine was shown to have inflammatory and immunologic activities . The LTA gene is located within the class III region of the major histocompatibility complex (MHC) in chromosome 6p21.3 . LTA plays a key role in communication between lymphocytes and stromal cells, thereby eliciting cytotoxic effects on cancer cells [7, 8]. LTA induces the expression of vascular cell-adhesion molecule 1 (VCAM1) on vascular endothelial cells and recruits natural killer (NK) cells to parenchymal organs and tumor lesions . NK cells have nonspecific host-defense mechanisms that aid in tumor rejection and protection from metastases. Previous studies have shown that tumor growth and metastasis are enhanced in LTA-deficient mice, which produce NK cells that have reduced anti-tumor potential [10, 11]. Thus, LTA signaling plays an important role in anti-tumor surveillance via the maturation and recruitment of NK cells.
Previous studies have examined the relationship between LTA polymorphisms and various cancers, and found that the NcoI restriction fragment length polymorphism (A252G) in the first intron is in tight linkage disequilibrium with C804A, resulting in the substitution of threonine with asparagine at codon 60 in exon 3 [12, 13]. The LTA 252G allele increases LTA at the levels of mRNA and protein . Previous studies have found that the relationship between the risk of cancer and the rate of survival among those with the LTA polymorphism varies according to the cancer type [14–17]. However, the effect of LTA polymorphisms on the presence of cancer in general is not known.
Toward this end, we searched for two non-synonymous polymorphisms, C804A (rs1041981, T60N) and T495C (rs2229094, C13R), in consecutive autopsy cases and determined whether they influenced cancer presence.
The study population consisted of 1,536 consecutive autopsy cases performed at the Tokyo Metropolitan Geriatric Hospital between 1995 and 2004. LTA polymorphisms were registered in the Internet database of Japanese single-nucleotide polymorphisms (SNPs) for geriatric research (JG-SNP) . Subjects were enrolled regardless of the cause of death and autopsies were performed on 40% of patients who died at the hospital. The study population included subjects who died from malignant disease (33%), coronary heart disease (20%), and pneumonia (13%). These proportions were similar to the causes of death reported in a survey conducted by the Ministry of Health, Labor and Welfare of Japan http://www.mhlw.go.jp/toukei/saikin/hw/jinkou/tokusyu/gaikoku07/09d.html which found that 30% of the Japanese population died from malignant disease, 16% from coronary heart disease, and 10% from pneumonia. The presence, absence, and histopathology of cancers were determined from autopsy findings. Histories of smoking and alcohol drinking status were retrospectively determined from medical records, and subjects were classified as smokers (including ex-smokers) versus non-smokers, and alcohol drinkers versus non-drinkers. Information on smoking and alcohol drinking status was missing from 109 and 118 patient histories, respectively. Written informed consent was obtained from the family of each patient at the time of autopsy. The study protocol was approved by the ethical Committees of the Tokyo Metropolitan Geriatric Hospital and the Tokyo Medical and Dental University.
Genomic DNA was extracted from the renal cortex using a standard procedure. LTA polymorphisms were genotyped via melting curve analysis . PCR primers and probes were as follows. For LTA C804A (rs1041981, T60N): 5'-GTT GGC CTC ACA CCT TCA-3' (forward primer), 5'-TGG ATG CTT GGG TTC CTG-3' (reverse primer), CAG CAC CCT CAA ACC TGC-Fluorescein (anchor probe), and LC Red 640-GCT CAC CTC ATT GGT AAA CAT CCA CCT GAC CTC C-Phosphate (detection probe). For LTA T495C (rs2229094, C13R): 5'-CTC TTT CTC TGC AGG TTC TC-3' (forward primer), 5'-GCT CTA GGG CTC AAG GTT T-3' (reverse primer), CTC CCA AGG GTG GGT G-Fluorescein (anchor probe), and LCRed640-CAC CAC CCT ACA CCT CCT CCT TCT GG-Phosphate (detection probe). The PCR amplification reaction was performed in 5 μl volume using the LightCycler PCR kit (Roche Diagnostics, Penzberg, Germany). Each well contained 1 × PCR buffer, 4 mM of MgCl2, 0.2 mM of dNTPs, 0.05 μM of forward primer, 0.5 μM of reverse primer, 0.2 μM of each anchor and detection probe, 0.1 U of Faststart Taq polymerase, and 10 ng of genomic DNA. The cycling protocol was performed as follows: initial denaturation at 94°C for 10 min; followed by 40 cycles of 94°C for 15 sec, 55°C for 15 sec, and 72°C for 15 sec; and a final extension step at 72°C for 10 min. After completion of PCR, the plates were heated from 40°C to 90°C with a gradient of 0.1°C per second immediately before melting temperature analysis on the LightCycler 480 Instrument (Roche Diagnostics). The genotype was determined based on melting profiles automatically classified by LightCycler Genotyping software (Roche Diagnostics). C804A and T495C polymorphisms were genotyped with success rates of 96% and 95%, respectively. Genotyping accuracy was confirmed by sequencing randomly selected samples. The melting temperature analysis correlated entirely with the direct sequencing results.
Statistical analysis was performed using SAS software, version 9.1.3 (SAS Institute Inc., Cary, NC). The distribution of subjects with and without cancer, and associations with other variables, were compared using Fisher's exact test. Hardy-Weinberg equilibrium (HWE) was assessed using a permutation test. Odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model that compared genotype frequencies in subjects with and without cancer, with respect to LTA polymorphisms. The OR was adjusted by age, sex, smoking, and alcohol drinking status. This study had a statistical power of 0.8 to detect an OR of 1.5 in carriers of at least one polymorphic allele, compared with carriers of homozygous wild-type alleles. LTA haplotype frequencies were estimated using Haploview software http://www.broad.mit.edu/mpg/haploview/. Chi-square values were calculated to determine the distribution of LTA haplotypes among subjects with and without cancer. A probability level of 5% was considered statistically significant for all analyses.
Characteristics of the study subjects
Selected demographic variables, including the sites and histological types of cancers, and risk factors are shown in Table 1 (Additional file 1). The mean age of subjects was 80.2 ± 8.9 years. The study population consisted of 827 (54%) males and 709 (46%) females. Altogether, we studied 606 subjects without cancer and 930 subjects with cancer. When the total number of subjects was divided by the number of subjects over or under the median age of 80 years, the distributions of subjects with or without cancer did not significantly differ. The frequency of cancer was significantly higher in males than in females. No differences in smoking and alcohol drinking status between cancer-bearing and cancer-free subjects were observed. The most frequent sites of cancer were the stomach (n = 183), lung (n = 164), and colon or rectum (n = 143).
Genotype and allele frequencies of LTApolymorphisms
C804A and T495C were genotyped in all subjects. The genotype frequencies of C804A were 37% for CC, 48% for CA, and 15% for AA. The minor allele frequency was 39%, and the allele distribution was consistent with HWE (p = 0.65). The genotype frequencies of T495C were 66% for TT, 31% for TC, and 3% for CC. The minor allele frequency was 19% and the allele distribution was consistent with HWE (p = 0.48).
Association of LTApolymorphisms with cancer overall
The associations between C804A and T495C polymorphisms and the presence of cancer are shown in Table 2 (Additional file 1). Among cancer-free subjects, the frequencies of the C804A genotypes CC, CA, and AA were 33%, 49%, and 18%, respectively, in males, and 33%, 54%, and 13%, respectively, in females (Table 3) (Additional file 1). In comparison with the CC genotype, the CA genotype was associated with a significantly lower presence of cancer in all subjects (adjusted OR = 0.78, 95% CI = 0.61 – 0.99). In males, the CA + AA genotype was associated with a significantly lower presence of cancer compared with the CC genotype (adjusted OR = 0.72, 95% CI = 0.53 – 0.99). The association between the C804A polymorphism and cancer in females was not significant (CA + AA: CC, adjusted OR = 0.92, 95% CI = 0.66 – 1.29). Additionally, cancer frequency was not associated with C804A (data not shown).
In cancer-free subjects, the frequency of the T495C genotypes TT, TC, and CC were 70%, 28%, and 2%, respectively, in males, and 66%, 31%, and 3%, respectively, in females (Table 3 in Additional file 1). Compared with the TT genotype, the CC genotype was associated with a significantly higher presence of cancer (adjusted OR = 2.24, 95% CI = 1.09 – 4.61). In males, the TC + CC genotype was associated with a significantly higher presence of cancer, compared with the TT genotype (adjusted OR = 1.45, 95% CI = 1.04 – 2.02). The association between the T495C polymorphism and cancer in females was not significant (TC + CC: TT, adjusted OR = 1.08, 95% CI = 0.77 – 1.50).
Additionally, we explored the relationship between the presence of C804A and T495C haplotypes and tumor formation. C804A and T495C appeared to be present in moderate linkage disequilibrium (r2 = 0.15, D' = 1.0) and three major haplotypes were identified (495T-804C, 495T-804A, and 495C-804C). None of these haplotypes were associated with the presence of cancer (data not shown).
Association of LTApolymorphisms with specific types of cancers
Significant associations between LTA polymorphisms and the presence of cancer in males prompted us to explore the relationships between these polymorphisms and the sites of cancer. After analyzing subjects with stomach, lung, colorectal, prostate, breast, liver, biliary tract, kidney or urinary tract, and hematopoietic malignancies, we observed a positive association between LTA polymorphisms and lung and stomach cancers (Table 4 in Additional file 1). Among male subjects with lung cancer, the C804A CA + AA genotype was associated with a significantly lower presence of cancer than was the CC genotype (adjusted OR = 0.60, 95% CI = 0.37–0.97). The association between C804A polymorphism and lung cancer in females was not significant (CA + AA: CC, adjusted OR = 0.65, 95% CI = 0.35 – 1.23).
The T495C polymorphism was not associated with the presence of lung cancer, but the TC + CC genotype was associated with a significantly higher presence of gastric cancer in males, compared with the TT genotype (adjusted OR = 1.68, 95% CI = 1.06–2.65). The association between T495C polymorphism and gastric cancer was not significant in females (TC + CC: TT, adjusted OR = 1.16, 95% CI = 0.61 – 2.21).
Our findings demonstrate that the LTA polymorphism C804A is associated with a lower presence of cancer, particularly lung cancer, in elderly Japanese men, consistent with previous studies showing that LTA has anti-tumor activity.
Several laboratories have recently published a functional analysis of the LTA C804A (T60N). Compared with the C allele, the A allele is more bioactive with regards to the induction of VCAM1 in cultured human coronary-artery smooth muscle cells . Furthermore, C804A is present in very high linkage disequilibrium with another polymorphism, LTA A252G. These two polymorphisms have been shown to be completely concordant in Japanese subjects [16, 17]. Compared with the A allele, the G allele of the A252G genotype confers higher transcriptional activity in Jurkat cells  and phytohemagglutinin-stimulated peripheral blood mononuclear cells . Thus, the C and A alleles are considered low and high bioactive alleles in LTA, respectively. Accordingly, the data suggest that the lower presence of cancer in our study population may reflect enhanced LTA activity because of the presence of high-bioactive alleles.
The C804A and A252G polymorphisms have been studied with regards to cancer survival rates and risks of developing various type of cancer, including lung , stomach [15, 20, 21], colorectal , breast , cervix , endometrium  and bladder  cancers, as well as leukemia , lymphoma [26, 27], and myeloma . The high-bioactive genotype was associated with the risk of developing cancers of the lung , colon or rectum , non-Hodgkin lymphoma [26, 27], and myeloma . Low-bioactive genotypes were associated with the risk of developing cervical  and endometrial cancers , but not gastric [15, 20, 21], breast , bladder cancers , or leukemia . These differences may be partially explained by the multi-functionality of LTA. LTA can promote cell growth and adhesion, and can potentially favor the growth of certain tumors.
It remains unclear why C804A is associated with cancer in males but not in females. However, gender is known to play an important role in the development of various cancers. Recent studies also suggest that cytokine secretion and innate immunity differ between the genders [29, 30].
The C13R (T495C) polymorphism has not been as thoroughly studied as the T60N (C804A) polymorphism. Previous study reported there was not an association between the T495C polymorphism and lung cancer . The T495C polymorphism is a haplotype component associated with altered LTA expression and increased levels of vascular- and autoimmune-mediated inflammation . These findings suggest that the T495C polymorphism is also associated with cancer. We observed an association between the C allele of the T495C polymorphism and the presence of cancer, particularly gastric cancer. However, as the minor allele frequency for this polymorphism was low, these results must be confirmed in a larger study population.
The LTA gene is located within the class III region of the MHC, in the 6p21.3 chromosome . This region contains many other genes, including that encoding the pro-inflammatory cytokine, TNF. It is well-known that this region shows high degrees of linkage disequilibrium. Thus, associations identified in this study may reflect the effects of other gene variants in this region.
As this was a hospital-based autopsy study, we had limited access to information on lifestyle variables that could potentially influence the development of cancer. Furthermore, although autopsies were performed on many of the deaths (40%) that occurred in the hospital, and the causes of death among our autopsy cases were similar to those reported in a national survey, we cannot rule out the possibility of selection bias. Such bias can arise from chance of admission, consent to autopsy, cause of death, and autopsy practice. Survival bias is also a possibility, as particular genotypes may be associated with other diseases or influence the lifespan of certain subjects, thereby introducing bias into the study population. However, the C804A genotype frequency was similar to that reported in other Japanese population studies [16, 17], and any effects of such possible bias did not cause our results to deviate from HWE.
We found some evidence of an association between LTA polymorphisms and cancer risk in elderly Japanese men. Further studies in larger populations should examine this hypothesis.
This work was partly supported by grant-in-aid from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology, Japan.
We thank Kenta Takahashi, of the Tokyo Medical and Dental University, for assisting genotype analysis.
- Bruunsgaard H, Pedersen M, Pedersen BK: Aging and proinflammatory cytokines. Current opinion in hematology. 2001, 8 (3): 131-136. 10.1097/00062752-200105000-00001.View ArticlePubMedGoogle Scholar
- Caruso C, Lio D, Cavallone L, Franceschi C: Aging, longevity, inflammation, and cancer. Annals of the New York Academy of Sciences. 2004, 1028: 1-13. 10.1196/annals.1322.001.View ArticlePubMedGoogle Scholar
- Serrano M, Blasco MA: Cancer and ageing: convergent and divergent mechanisms. Nature reviews. 2007, 8 (9): 715-722. 10.1038/nrm2242.View ArticlePubMedGoogle Scholar
- Coussens LM, Werb Z: Inflammation and cancer. Nature. 2002, 420 (6917): 860-867. 10.1038/nature01322.View ArticlePubMedPubMed CentralGoogle Scholar
- Aggarwal BB: Signalling pathways of the TNF superfamily: a double-edged sword. Nature reviews. 2003, 3 (9): 745-756. 10.1038/nri1184.PubMedGoogle Scholar
- Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T: Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proceedings of the National Academy of Sciences of the United States of America. 1987, 84 (23): 8535-8539. 10.1073/pnas.84.23.8535.View ArticlePubMedPubMed CentralGoogle Scholar
- Vassalli P: The pathophysiology of tumor necrosis factors. Annual review of immunology. 1992, 10: 411-452. 10.1146/annurev.iy.10.040192.002211.View ArticlePubMedGoogle Scholar
- Ware CF, Crowe PD, Grayson MH, Androlewicz MJ, Browning JL: Expression of surface lymphotoxin and tumor necrosis factor on activated T, B, and natural killer cells. J Immunol. 1992, 149 (12): 3881-3888.PubMedGoogle Scholar
- Fogler WE, Volker K, McCormick KL, Watanabe M, Ortaldo JR, Wiltrout RH: NK cell infiltration into lung, liver, and subcutaneous B16 melanoma is mediated by VCAM-1/VLA-4 interaction. J Immunol. 1996, 156 (12): 4707-4714.PubMedGoogle Scholar
- Ito D, Back TC, Shakhov AN, Wiltrout RH, Nedospasov SA: Mice with a targeted mutation in lymphotoxin-alpha exhibit enhanced tumor growth and metastasis: impaired NK cell development and recruitment. J Immunol. 1999, 163 (5): 2809-2815.PubMedGoogle Scholar
- Smyth MJ, Johnstone RW, Cretney E, Haynes NM, Sedgwick JD, Korner H, Poulton LD, Baxter AG: Multiple deficiencies underlie NK cell inactivity in lymphotoxin-alpha gene-targeted mice. J Immunol. 1999, 163 (3): 1350-1353.PubMedGoogle Scholar
- Messer G, Spengler U, Jung MC, Honold G, Blomer K, Pape GR, Riethmuller G, Weiss EH: Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. The Journal of experimental medicine. 1991, 173 (1): 209-219. 10.1084/jem.173.1.209.View ArticlePubMedGoogle Scholar
- Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Sato H, Hori M, Nakamura Y, Tanaka T: Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nature genetics. 2002, 32 (4): 650-654. 10.1038/ng1047.View ArticlePubMedGoogle Scholar
- Shimura T, Hagihara M, Takebe K, Munkhbat B, Odaka T, Kato H, Nagamachi Y, Tsuji K: The study of tumor necrosis factor beta gene polymorphism in lung cancer patients. Cancer. 1994, 73 (4): 1184-1188. 10.1002/1097-0142(19940215)73:4<1184::AID-CNCR2820730410>3.0.CO;2-Y.View ArticlePubMedGoogle Scholar
- Shimura T, Hagihara M, Takebe K, Munkhbat B, Ogoshi K, Mitomi T, Nagamachi Y, Tsuji K: 10.5-kb homozygote of tumor necrosis factor-beta gene is associated with a better prognosis in gastric cancer patients. Cancer. 1995, 75 (6 Suppl): 1450-1453. 10.1002/1097-0142(19950315)75:6+<1450::AID-CNCR2820751510>3.0.CO;2-V.View ArticlePubMedGoogle Scholar
- Niwa Y, Hirose K, Matsuo K, Tajima K, Ikoma Y, Nakanishi T, Nawa A, Kuzuya K, Tamakoshi A, Hamajima N: Lymphotoxin-alpha polymorphism and the risk of cervical cancer in Japanese subjects. Cancer letters. 2005, 218 (1): 63-68. 10.1016/j.canlet.2004.09.021.View ArticlePubMedGoogle Scholar
- Niwa Y, Ito H, Matsuo K, Hirose K, Ito N, Mizuno M, Hamajima N, Tajima K, Nakanishi T: Lymphotoxin-alpha polymorphisms and the risk of endometrial cancer in Japanese subjects. Gynecologic oncology. 2007, 104 (3): 586-590. 10.1016/j.ygyno.2006.09.007.View ArticlePubMedGoogle Scholar
- Sawabe M, Arai T, Kasahara I, Esaki Y, Nakahara K, Hosoi T, Orimo H, Takubo K, Murayama S, Tanaka N: Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP). Mechanisms of ageing and development. 2004, 125 (8): 547-552. 10.1016/j.mad.2004.06.005.View ArticlePubMedGoogle Scholar
- Oda K, Tanaka N, Arai T, Araki J, Song Y, Zhang L, Kuchiba A, Hosoi T, Shirasawa T, Muramatsu M, Sawabe M: Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Human molecular genetics. 2007, 16 (6): 592-599. 10.1093/hmg/ddl483.View ArticlePubMedGoogle Scholar
- Guo W, Wang N, Li Y, Zhang JH: Polymorphisms in tumor necrosis factor genes and susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in a population of high incidence region of North China. Chinese medical journal. 2005, 118 (22): 1870-1878.PubMedGoogle Scholar
- Lee SG, Kim B, Yook JH, Oh ST, Lee I, Song K: TNF/LTA polymorphisms and risk for gastric cancer/duodenal ulcer in the Korean population. Cytokine. 2004, 28 (2): 75-82. 10.1016/j.cyto.2004.06.009.View ArticlePubMedGoogle Scholar
- de Jong MM, Nolte IM, te Meerman GJ, van der Graaf WT, de Vries EG, Sijmons RH, Hofstra RM, Kleibeuker JH: Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 2002, 11 (11): 1332-1352.PubMedGoogle Scholar
- Gaudet MM, Egan KM, Lissowska J, Newcomb PA, Brinton LA, Titus-Ernstoff L, Yeager M, Chanock S, Welch R, Peplonska B, Trentham-Dietz A, Garcia-Closas M: Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk. Human genetics. 2007, 121 (3-4): 483-490. 10.1007/s00439-006-0315-x.View ArticlePubMedGoogle Scholar
- Nonomura N, Tokizane T, Nakayama M, Inoue H, Nishimura K, Muramatsu M, Okuyama A: Possible correlation between polymorphism in the tumor necrosis factor-beta gene and the clinicopathological features of bladder cancer in Japanese patients. Int J Urol. 2006, 13 (7): 971-976. 10.1111/j.1442-2042.2006.01450.x.View ArticlePubMedGoogle Scholar
- Demeter J, Porzsolt F, Ramisch S, Schmidt D, Schmid M, Messer G: Polymorphism of the tumour necrosis factor-alpha and lymphotoxin-alpha genes in chronic lymphocytic leukaemia. British journal of haematology. 1997, 97 (1): 107-112. 10.1046/j.1365-2141.1997.9912636.x.View ArticlePubMedGoogle Scholar
- Purdue MP, Lan Q, Kricker A, Grulich AE, Vajdic CM, Turner J, Whitby D, Chanock S, Rothman N, Armstrong BK: Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. Carcinogenesis. 2007, 28 (3): 704-712. 10.1093/carcin/bgl200.View ArticlePubMedGoogle Scholar
- Wang SS, Cerhan JR, Hartge P, Davis S, Cozen W, Severson RK, Chatterjee N, Yeager M, Chanock SJ, Rothman N: Common genetic variants in proinflammatory and other immunoregulatory genes and risk for non-Hodgkin lymphoma. Cancer research. 2006, 66 (19): 9771-9780. 10.1158/0008-5472.CAN-06-0324.View ArticlePubMedGoogle Scholar
- Davies FE, Rollinson SJ, Rawstron AC, Roman E, Richards S, Drayson M, Child JA, Morgan GJ: High-producer haplotypes of tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment. J Clin Oncol. 2000, 18 (15): 2843-2851.PubMedGoogle Scholar
- Moxley G, Posthuma D, Carlson P, Estrada E, Han J, Benson LL, Neale MC: Sexual dimorphism in innate immunity. Arthritis and rheumatism. 2002, 46 (1): 250-258. 10.1002/1529-0131(200201)46:1<250::AID-ART10064>3.0.CO;2-T.View ArticlePubMedGoogle Scholar
- Aulock SV, Deininger S, Draing C, Gueinzius K, Dehus O, Hermann C: Gender difference in cytokine secretion on immune stimulation with LPS and LTA. J Interferon Cytokine Res. 2006, 26 (12): 887-892. 10.1089/jir.2006.26.887.View ArticlePubMedGoogle Scholar
- Engels EA, Wu X, Gu J, Dong Q, Liu J, Spitz MR: Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer. Cancer research. 2007, 67 (13): 6520-6527. 10.1158/0008-5472.CAN-07-0370.View ArticlePubMedGoogle Scholar
- Belfer I, Buzas B, Hipp H, Dean M, Evans C, Lorincz I, Max MB, Goldman D: Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans. Genes and immunity. 2004, 5 (6): 505-512. 10.1038/sj.gene.6364118.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://0-www.biomedcentral.com.brum.beds.ac.uk/1471-2407/8/235/prepub
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