Genetic variation in tumor factor and lymphotoxin-alpha (TNA-LTA) and breast cancer risk

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Human Genetics (Impact Factor: 4.82). 06/2007; 121(3-4):483-90. DOI: 10.1007/s00439-006-0315-x
Source: PubMed


Tumor necrosis factor (TNF) is critical to regulation of inflammation. Genetic variation in the promoter region of TNF has been associated with expression differences, and a range of auto-immune, infectious, and oncologic diseases. We analyzed eight common single nucleotide polymorphisms (SNPs) (rs746868, rs909253, rs1799964, rs1800630, rs1800750, rs1800629, rs361525, and rs1800610) to capture most of the genetic variation in TNF in addition to SNPs in lymphotoxin-alpha (LTA), a pro-inflammatory cytokine in linkage disequilibrium with the TNF promoter region. SNPs were genotyped in a USA population-based case-control study (3,318 cases, 2,841 controls). Promising results were followed-up in an independent population-based case-control study in Poland (2,228 cases, 2,378 controls). In both studies, women carrying the variant allele of rs361525 were at elevated breast cancer risk compared to the GG genotype (per allele OR = 1.18, 95% CI 1.04-1.35; P for trend = 0.008). Other SNPs were not significantly associated with breast cancer risk. Haplotype analyses did not reveal any additional associations between TNF and breast cancer risk. Data from 5,269 cases and 4,982 controls suggested that the rs361525 A allele, located in the TNF promoter region, was associated with a modest increase in breast cancer risk. Additional studies are required to replicate these findings and to determine whether rs361525 is a causative SNP or is a marker of a causative SNP.

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    • "Madeleine MM (2011) 848/866 AC North American rs2229094 PB Age, ethnicity Wang SS (2006) 1029/842 HM North American rs2239704 PB Age, gender Lan Q (2006) 417/499 HM North American rs2239704 PB Age, ethnicity, residence Liu X (2006) 822/861 AC North American rs2239704 PB Age, ethnicity, date of blood collection Purdue MP (2007) 210/602 OC b North American rs2239704 PB Age, gender, ethnicity, date of collection Purdue MP (2007) 296/602 OC b North American rs2239704 PB Age, gender, ethnicity, date of collection Purdue MP (2007) 352/463 HM European rs2239704 HB Age, gender, residence Cerhan JR (2008) 441/474 HM North American rs2239704 HB Age, gender, residence Jacobs EJ (2008) 453/1184 AC North American rs2239704, rs746868 HB Age, ethnicity, date of blood collection Ennas MG (2008) 38/112 HM European rs2239704 PB Age, gender Lee SG (2004) 328/253 AC Asian rs1041981 PB Gender, study region Niwa Y (2005) 44/320 AC Asian rs1041981 HB Gender, study region Niwa Y (2005) 87/320 SC b Asian rs1041981 HB Gender, study region Niwa Y (2007) 110/220 AC Asian rs1041981 HB Age, gender Aissani B (2009) 135/140 HM North American rs1041981 HB CD4+ counts, the duration of HIV infection Castro FA (2009) 951/1707 SC b European rs1041981 PB Age, ethnicity, study region Sainz J (2012) 1760/1727 AC European rs1041981 PB Age, gender, study region Gunter MJ (2006) 219/205 AC North American rs746868 HB Age, gender, ethnicity, study region Gaudet MM (2007) 1622/1288 AC North American rs746868 PB Age, residence Garcia-Gonzalez (2007) 404/404 AC European rs746868 HB Age, gender, ethnicity, residence Crusius JB (2008) 428/1124 AC European rs746868 PB Age, gender, residence, date of collection García-González (2009) 57/24 AC European rs746868 HB Ethnicity, study region a: PB, "
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    ABSTRACT: Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I(2) = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I(2) = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I(2) = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I(2) = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01-1.20, P = 0.023, I(2) = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I(2) = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.
    PLoS ONE 12/2013; 8(12):e82519. DOI:10.1371/journal.pone.0082519 · 3.23 Impact Factor
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    • "We also considered 4 other SNPs (rs361525, rs1800629, rs1799964, rs1800630) located in the promoter region of TNFA, but no significant associations were found in EA women, similar to findings from other studies [18,20,47]. TNFA-rs361525 was associated with a modest increase in breast cancer risk among EAs in a study of ~5300 cases and 4900 controls [21], but this was not replicated within the Breast Cancer Association Consortium of 30,000 breast cancer cases and 30,000 controls [20]. A recent Meta-Analysis reported a small decreased risk of breast cancer (OR=0.91, "
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    ABSTRACT: African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women's Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.
    PLoS ONE 08/2013; 8(8):e72619. DOI:10.1371/journal.pone.0072619 · 3.23 Impact Factor
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    • "SNPs in a promoter or regulatory region alter the transcriptional activity of cytokine genes. SNPs in certain alleles of cytokines or chemokines have been associated with susceptibility to a wide range of infectious or oncological diseases, including pulmonary and systemic pathologies [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]. The role that polymorphisms in cytokine genes play in the severity of the symptoms and the high mortality rate of the disease is unclear, but these polymorphisms may influence the nature and intensity of the inflammatory immune response [22] "
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    ABSTRACT: In Mexico, the initial severe cases of the 2009 influenza pandemic virus A (H1N1) [A(H1N1)pdm09] were detected in early March. The immune mechanisms associated with the severe pneumonia caused by infection with this new virus have not been completely elucidated. Polymorphisms in interleukin genes have previously been associated with susceptibility to infectious diseases due to their influence on cytokine production. The present case-control study was performed to compare several immunologic and genetic parameters of patients and controls during the initial phase of the pandemic. Sixty-five patients who were hospitalized due to infection with the influenza A(H1N1)pdm09 virus and 46 healthy controls were studied. A hemagglutination inhibition assay (HIA) was performed to measure anti-influenza antibody titers in these subjects. Protein levels of the cytokines interleukin (IL)-4, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), interferon gamma (IFNγ), transforming growth factor beta (TGFβ)1 and TGFβ2 were quantified in plasma. Single nucleotide polymorphisms in IL6, IL10 and TNFα were also assessed. Influenza patients had lower antibody titers and produced significantly higher levels of IL-6, IL-10 and TNFα than healthy controls. The frequencies of the TNFα -308G, IL-10 -592C and IL-10 -1082A alleles and the IL10 -1082(A/A) genotype were associated with susceptibility to severe disease, while the haplotypes TNFα AG and IL-10 GTA and GCA were associated with protection from severe disease [P=0.016, OR (CI)=0.11 (0.01-0.96); P=0.0187, OR (CI)=0.34 (0.13-0.85); P=0.013, OR (CI)=0.39 (0.18-0.83)]. This study demonstrates that the influenza A(H1N1)pdm09 patients and healthy controls have different profiles of immune parameters and that there is an association between IL-10 and TNFα polymorphisms and the outcome of this disease.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 06/2013; 58(1). DOI:10.1016/j.jcv.2013.05.013 · 3.02 Impact Factor
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