Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: a synthesis of genetic association studies

Background: Acute lymphoblastic leukemia (ALL) is a complex disease with genetic background. The genetic association studies (GAS) that investigated the association between ALL and the MTHFR C677T and A1298C gene variants have produced contradictory or inconclusive results. Materials and methods: In order to decrease the uncertainty of estimated genetic risk effects, a meticulous meta-analysis of published GAS related the variants in the MTFHR gene with susceptibility to ALL was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR_G). Cumulative and recursive cumulative meta-analyses were also performed.ResultsThe analysis showed marginal significant association for the C677T variant, overall [OR = 0.91 (0.82–1.00) and OR_G = 0.89 (0.79–1.01)], and in Whites [OR = 0.88 (0.77–0.99) and OR_G = 0.85 (0.73–0.99)]. The A1298C variant produced non-significant results. For both variants, the cumulative meta-analysis did not show a trend of association as evidence accumulates and the recursive cumulative meta-analysis indicated lack of sufficient evidence for denying or claiming an association. Conclusion: The current evidence is not sufficient to draw definite conclusions regarding the association of MTHFR variants and development of ALL.     

Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population

Background: Leukaemia is a heterogeneous disease in which haematopoietic progenitor cells acquire genetic lesions that lead to a block in differentiation, increased self-renewal, and unregulated proliferation. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), involved in folate metabolism, plays a crucial role in cells because folate availability is important for DNA integrity. The aim of this case–control study was to evaluate the association of the C677T MTHFR gene polymorphism with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL). Materials and methods: A total of 275 leukaemia cases – including AML (n = 112), ALL (n = 81), CML (n = 43), CLL (n = 39) – and 251 age/sex-matched healthy control individuals participated in this study. MTHFR C677T polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results: The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total leukaemia cases were 68.73%, 19.64%, and 11.64% in cases, and 71.71%, 24.30%, and 3.98% in healthy controls, respectively. The average frequency of the MTHFR 677T allele was 21.45% among the cases compared to 16.13% among the controls. Conclusions: In the present case–control study we have observed a higher frequency of the MTHFR 677TT genotype in cases of leukaemia (AML, ALL, CML and CLL) as compared with controls; this might be due to ethnic and geographic variation. As per our findings, although the frequency of the MTHFR 677T allele is moderately high in AML, ALL and CLL, no statistically significant association was found; on the other hand statistically significant association was found in the context of CML cases.     

Birth weight and other perinatal characteristics and childhood leukemia in California

Aims. We conducted a large registry-based study in California to investigate the association of perinatal factors and childhood leukemia with analysis of two major subtypes, acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). Methods. We linked California cancer and birth registries to obtain information on 5788 cases and 5788 controls matched on age and sex (1:1). We examined the association of birth weight, gestational age, birth and pregnancy order, parental ages, and specific conditions during pregnancy and risk of total leukemia, ALL and AML using conditional logistic regression, with adjustment for potential confounders. Results. The odds ratio (OR) per 1000 g increase in birth weight was 1.11 for both total leukemia and ALL. The OR were highest for babies weighing ≥4500 g with reference <2500 g: 1.59 (95% CI: 1.05–2.40) and 1.70 (95% CI: 1.08–2.68) for total leukemia and ALL, respectively. For AML, increase in risk was also observed but the estimate was imprecise due to small numbers. Compared to average-for-gestational age (AGA), large-for-gestational age (LGA) babies were at slightly increased risk of total childhood leukemia (OR = 1.10) and both ALL and AML (OR = 1.07 and OR = 1.13, respectively) but estimates were imprecise. Being small-for-gestational age (SGA) was associated with reduced risk of childhood leukemia (OR = 0.81, 95% CI: 0.67–0.97) and ALL (OR = 0.77, 95% CI: 0.63–0.94), but not AML. Being first-born was associated with decreased risk of AML only (OR = 0.70; 95% CI: 0.53–0.93). Compared to children with paternal age <25 years, children with paternal age between 35 and 45 years were at increased risk of total childhood leukemia (OR = 1.12; 95% CI: 1.04–1.40) and ALL (OR = 1.23; 95% CI: 1.04–1.47). None of conditions during pregnancy examined or maternal age were associated with increased risk of childhood leukemia or its subtypes. Conclusions. Our results suggest that high birth weight and LGA were associated with increased risk and SGA with decreased risk of total childhood leukemia and ALL, being first-born was associated with decreased risk of AML, and advanced paternal age was associated with increased risk of ALL. These findings suggest that associations of childhood leukemia and perinatal factors depend highly on subtype of leukemia.     

Maternal and infant MTHFR gene polymorphisms and non-syndromic oral cleft susceptibility: An updated meta-analysis

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial malformation. Irregular folate metabolism plays a significant role in the etiopathology of NSCLP. In this study, we aim to examine the association of the maternal and cleft child methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677 T and A1298C) with nonsyndromic cleft lip with or without cleft palate (NSCLP) by carefully evaluating established studies. The meta-analysis includes 39 studies that focused on MTHFR C677T and A1298C polymorphisms in cleft children or cleft children’s mothers. All statistical data underwent random or fixed effects model with an odds ratio and 95% confidence intervals as effect measures and was preformed using a web tool MetaGenyo. Statistical analyses showed that the MTHFR C677T is significantly associated with the increased risk of NSCLP in children but not in the mothers. In contrast to this, there is no evidence for association between MTHFR A1298C and NSCLP risk in both children and the mothers. Furthermore, there is no evidence for publication bias for both MTHFR C677T and A1298C polymorphisms in cleft children as well as the mothers of cleft children. In conclusion, we determined that there is a strong association between the MTHFR C677 T polymorphism and NSCLP.     

An updated meta-analysis on the association of TGF-β1 gene promoter -509C/T polymorphism with colorectal cancer risk

AimPublished data on the association between transforming growth factor-β1 (TGF-β1) gene promoter-509C/T polymorphism and colorectal cancer (CRC) risk are inconsistent and inconclusive. To derive a more precise estimation of this association, a meta-analysis was carried out.MethodsMeta-analysis was performed to evaluate reported studies of the relationship between TGF-β1 gene promoter-509C/T polymorphism and colorectal cancer risk using fixed-effects model and random-effects model.ResultsWe observed an increased colorectal cancer risk among subjects carrying TGF-β1 gene promoter-509CC + CT genotype (odds ratio (OR) = 1.18%, 95% confidence interval (95% CI): 1.06–1.32) using 4440/6785 cases/controls in total population. We observed an increased risk of the TGF-β1 gene promoter -509CC, CT and CC + CT polymorphisms for colorectal cancer in population-based study (OR = 1.36, 95% CI: 1.19–1.56, OR = 1.18, 95% CI: 1.03–1.34 and OR = 1.26, 95% CI: 1.12–1.43, respectively) in stratified analysis. We observed an increased colorectal risk among CC and CC + CT carriers in European and American population (OR = 1.22, 95% CI: 1.04–1.43 and OR = 1.18, 95% CI: 1.02–1.38, respectively). We also observed an increased risk of colon cancer among subjects carrying CC + CT genotype (OR = 1.31, 95% CI: 1.05–1.63).ConclusionsThe present meta-analysis results suggest that TGF-β1 gene promoter -509C allele variant is a possible risk factor for developing colorectal cancer. Recommendations for further studies include pooling of individual data to verify results from the study and to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental and lifestyle factors.     

Genetic polymorphisms in AURKA,BRCA1, CCNE1 and CDK2 are associated with ovarian cancer susceptibility among Chinese Han women

IntroductionCentrosome aberrations and cell-cycle deregulation have important implications for ovarian cancer development. The AURKA, BRCA1, CCNE1 and CDK2 genes play pivotal roles in centrosome duplication and cell-cycle regulation.MethodsUsing a haplotype-based analysis, this study aimed to investigate whether genetic polymorphisms in these four genes may contribute to ovarian cancer susceptibility. A total of 22 single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 287 cases of ovarian serous cystadenocarcinomas and 618 age-matched cancer-free controls from the Chinese Han population, and then haplotype blocks were reconstructed according to our genotyping data and linkage disequilibrium (LD) status of these SNPs.ResultsFor AURKA, we found that haplotype GA [rs6064391 (T→G) + rs911162 (G→A)] was strongly associated with decreased ovarian cancer risk (adjusted OR = 0.31, 95% CI = 0.15–0.63, P = 0.0012). For BRCA1, we found that haplotype CGTAG was associated with decreased ovarian cancer risk (adjusted OR = 0.64, 95% CI = 0.41–0.98, P = 0.0417). Moreover, women harboring homozygous GA/CGTAG haplotypes showed the lowest risk (OR = 0.12, 95% CI = 0.02–0.94, P = 0.0438). In CCNE1, the SNPs rs3218035 and rs3218042 were significantly associated with increased ovarian cancer risk (rs3218035: adjusted OR = 5.20, 95% CI = 1.85–14.52, P = 0.0017; rs3218042: adjusted OR = 4.98, 95% CI = 1.75–14.19, P = 0.0027). For CDK2, no significant association was found.ConclusionsThis study indicates that genetic polymorphisms of AURKA, BRCA1 and CCNE1 may affect ovarian cancer susceptibility in Chinese Han women.     

Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India

BackgroundInterleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer.Materials and methodsSingle nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (−174G>C; −572G>C, −596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software.ResultSignificantly higher number of smokers (p = 0.047), tobacco chewers (p = <0.001) and those with non-vegetarian food habits (p = 0.016) were seen in the case group. The distribution of genotypes at −174G>C locus differed significantly between cases and controls and the variant genotypes GC + CC were significantly rarer in the cases (p = 0.00073; OR = 0.52 95% CI 0.35–0.75). Variant genotypes (GC + CC) were more common in grade I than grade III tumors (p = 0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p = 0.0103), suggesting a protective effect. Genotype distribution at the other two loci (−572G>C and −596A>G) did not show association with bladder cancer.ConclusionsIL6 (−174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (−572G>C and −596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer.     

Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk

Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case–control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi-square test and multiple logistic regression were used for statistical analyses. The variables age ≥49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P < 0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age ≥49 years, tobacco and alcohol habits (P < 0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P < 0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age ≥49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease.     

Ascaris lumbricoides and Trichuris trichiura infections associated with wastewater and human excreta use in agriculture in Vietnam

BackgroundWe assessed the risk of helminth infections in association with the use of wastewater and excreta in agriculture in Hanam province, northern Vietnam. In two cross-sectional surveys, we obtained samples from 1,425 individuals from 453 randomly selected households. Kato-Katz thick smear and formalin-ether concentration techniques were used for helminth diagnosis in two stool samples per person. Socio-demographic and water, sanitation and hygiene related characteristics, including exposure to human and animal excreta and household wastewater management, were assessed with a questionnaire.ResultsOverall 47% of study participants were infected with any helminth (Ascaris lumbricoides 24%, Trichuris trichiura 40% and hookworm 2%). Infections with intestinal protozoa were rare (i.e. Entamoeba histolytica 6%, Entamoeba coli 2%, Giardia lamblia 2%, Cryptosporidium parvum 5% and Cyclospora cayetanensis 1%). People having close contact with polluted Nhue River water had a higher risk of helminth infections (odds ratio [OR] = 1.5, 95% confidence interval [CI] 1.1–2.2) and A. lumbricoides (OR = 2.1, 95% CI 1.4–3.2), compared with those without contact. The use of human excreta for application in the field had an increased risk for a T. trichiura infection (OR = 1.5, 95% CI 1.0–2.3). In contrast, tap water use in households was a protective factor against any helminth infection (i.e. T. trichiura OR = 0.6, 95% CI 0.4–0.9). Prevalences increased with age and males had generally lower prevalences (OR = 0.8, 95% CI 0.6–1.0), participants performing agricultural (OR = 1.5, 95% CI 1.1–2.1) and having a low educational level (OR = 1.7, 95% CI 1.2–2.4) were significantly associated with helminth infections. None of the factors related to household's sanitary condition, type of latrine, household's SES, use of animal excreta, and personal hygiene practices were statistically significant associated with helminth infection.ConclusionsOur study suggests that in agricultural settings, direct contact with water from Nhue River and the use of human excreta as fertiliser in the fields are important risk factors for helminth infection. Daily use of clean water is likely to reduce the risk of worm infection. Deworming policies and national programs should give more attention to these agricultural at risk populations.     

Association of Interleukin 6 gene polymorphisms with genetic susceptibilities to spastic tetraplegia in males: A case-control study

BackgroundCerebral palsy (CP) is a group of non-progressive motor impairment and permanent disorders causing limitation of activity and abnormal posture. It may be caused by infection (such as chorioamnionitis), asphyxia or multiple genetic factors. The Interleukin 6 gene (IL6) was suggested to be involved in the susceptibilities to CP risk as a kind of proinflammatory cytokine.ObjectiveTo explore the genetic association between the polymorphisms of the IL6 gene and CP in the Chinese population.MethodsA total of 542 CP patients and 483 healthy control children were recruited in this study to detect five single nucleotide polymorphisms (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL6 locus. Genotyping of SNPs was performed by the MassArray platform-based genotyping approach. The SHEsis program was applied to analyze the genotyping data.ResultsOf the five selected SNPs, no significant allelic and genotypic association was found between CP patients and controls. However, subgroup analysis found significant differences in allele frequencies between spastic tetraplegia in males compared with controls at rs1800796 (OR = 1.39, P = 0.033, P = 0.099 after SNPSpD correction) and rs2069837 (OR = 1.58, P = 0.012, P = 0.035 after SNPSpD correction). The frequencies of the C allele of rs1800796 and the A allele of rs2069837 were greater in males with spastic tetraplegia than in the controls. The two SNPs haplotype rs1800796 (G) – rs2069837 (G) were also associated with a decreased risk of spastic tetraplegia in males (OR = 0.619, P = 0.009, P = 0.027 after Bonferroni correction).ConclusionGenetic variation of the IL6 gene may influence susceptibility to spastic tetraplegia in males and its role in cerebral palsy deserves further evaluation in a large-scale and well-designed study.     

Association between polymorphisms of matrix metalloproteinase 11 (MMP-11) and Kawasaki disease in the Korean population

AimsThis study was conducted to investigate the associations between single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) and Kawasaki disease (KD) in the Korean population.Main methodsA total 0f 101 KD patients and 306 healthy controls were examined. MMP7 (rs10502001, G/A, Arg77His), MMP11 (rs738792, T/C, Ala38Val), MMP12 (rs652438, A/G, Ile357Val) and MMP26 (rs2499953, A/G, Lys43Glu) genes were genotyped from the genomic DNA using direct sequencing. The results were then analyzed using logistic regression models, adjusting for gender as covariates.Key findingsThe four SNPs were in Hardy–Weinberg equilibrium. Only the MMP11 polymorphism (rs738792) was associated with KD. The SNP (rs738792) showed a statistically significant association with KD in the codominant (OR = 1.61, 95% CI = 1.11–2.34, P = 0.011) and dominant (OR = 1.92, 95% CI = 1.21–3.06, P = 0.006) models. However, there was no association between polymorphisms of other MMP genes and KD.SignificanceOverall, the results of this study indicate that MMP11 polymorphism may be associated with KD in the Korean population.     

Polymorphisms of tumor-related genes IL-10, PSCA,MTRR and NOC3L are associated with the risk of gastric cancer in the Chinese Han population

BackgroundGastric cancer is the fourth most common cancer in the world. Environmental and genetic factors both play critical roles in the etiology of gastric cancer. Hundreds of SNPs have been identified to have association with the risk of gastric cancer in many races. In this study, 25 SNPs in genes for IL-10, IL-1B, MTRR, TNF-а, PSCA, PLCE1 and NOC3L were analyzed to further evaluate their associations with gastric cancer susceptibility in the Chinese Han population.MethodsTwo hundred and seventy nine gastric cancer patients and 296 healthy controls were recruited in this study. SNP genotyping was conducted using Sequenom MassARRAY RS1000. Data management and statistical analyses were conducted by Sequenom Typer 4.0 Software and Pearson's χ² test.ResultsOne protective allele and three risk alleles for gastric cancer patients were found in this study. The allele “G” of rs1801394 in MTRR showed an association with a decreased risk of gastric cancer: odds ratio (OR) = 0.74, 95% confidence interval (95% CI) = 0.57–0.97, P = 0.030 in the additive model; OR = 0.495, 95% CI = 0.26–0.95, P = 0.034 in the recessive model. The other three SNPs, the allele “C” of rs1800871 in IL10 (OR = 1.33, 95% CI = 1.04–1.90; P = 0.026 in the additive model; OR = 1.46, 95% CI = 1.04–2.06; P = 0.030 in the recessive model), the allele “A” of rs2976391 in PSCA (OR = 1.30, 95% CI = 1.01–1.66; P = 0.041 in the additive model and OR = 1.48, 95% CI = 1.04–2.11, P = 0.028 in the recessive model), and the allele “G” of rs17109928 in NOC3L gene (OR = 1.34, 95% CI = 1.01–1.78; P = 0.042 by additive model analysis; OR = 1.47, 95% CI = 1.04–2.07, P = 0.028 by dominant model analysis), showed an association with an increased risk of gastric cancer.ConclusionsThese results indicate the importance of four gastric cancer susceptibility polymorphisms of IL-10, NOC3L, PSCA and MTRR in the Chinese Han population, which could be used in the determination of gastric cancer risk in clinical practice.     

Influence of ABCB1 genetic variants in breast cancer treatment outcomes

BackgroundTransportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C > T, 2677G > T/A, 3435C > T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity.MethodResponse to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2–4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2.ResultsIn response evaluation, 1236C > T polymorphism was significantly associated with treatment response for CT genotype [OR = 5.17(1.3–20.2), P = 0.018] and in dominant model (CC vs CT + TT) [OR = 4.63(1.25–17.0), P = 0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2–4 tocxicity [OR 1.48(1.00–2.20), P = 0.049] and the association was also significant in the recessive model [OR 1.88(1.05–3.39), P = 0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2–4 toxicity. In meta analysis, no overall association was found.ConclusionIn our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.     

Association of physical activity and polymorphisms in FGFR2 and DNA methylation related genes with breast cancer risk

PurposePhysical activity, a protective factor for breast cancer, increases the level of DNA methylation. Fibroblast growth factor receptor 2 (FGFR2), a confirmed breast cancer susceptibility gene, is predisposed to be methylated. Therefore, DNA methylation related genes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and DNA methyltransferase (DNMT), together with physical activity and FGFR2, may interact with each other to effect breast cancer risk.MethodsA total of 839 incident breast cancer cases and 863 age-matched controls from Guangzhou, China were included in this study. We used questionnaires to assess physical activity in metabolic equivalent (MET)-h/week/year and a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform to ascertain genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models.ResultsExercise activity and FGFR2 rs2981582 were confirmed to be associated with breast cancer risk, and were found to significantly interact (P for multiplicative and additive interactions = 0.045 and 0.021, respectively). Women who had CT/TT genotypes of FGFR2 rs2981582 and experienced exercise activity <3 MET-h/week/year had significantly increased risk (OR = 3.15, 95% CI = 2.28–4.35) compared to women with CC genotype and ≥3 MET-h/week/year. There was also a significant interaction between FGFR2 rs2981582 and MTHFR rs1801133 on breast cancer risk (P for multiplicative and additive interactions = 0.039 and 0.023, respectively).ConclusionWe found both a gene–environment (FGFR2-exercise activity) and a gene–gene (FGFR2–MTHFR) interaction on breast cancer risk. Our results suggest that environmental factors, such as physical activity, may be able to counteract genetic susceptibility to breast cancer.     

The influence of a TNF gene polymorphism on the severity of rheumatoid arthritis in the Brazilian Amazon

PurposeThe aim of this study was to investigate the influence of the TNF -308 G/A polymorphism in the promoter region of the tumor necrosis factor-α gene on the susceptibility and severity of rheumatoid arthritis (RA) in individuals from the Brazilian Amazon.MethodsA total of 323 individuals—192 healthy controls without arthritis and 131 individuals suffering from arthritis—were genotyped for this polymorphism using a methodology based on PCR-RFLP.ResultsThe frequency of the A allele (TNF2) in rheumatoid arthritis sufferers was not significantly higher than in the controls (p = 0.926; OR = 0.97; confidence interval 0.54–1.76). However, using a logistic regression model, when the patients were stratified according to whether the manifestations were preponderantly articular or systemic, there was a strong association between the TNF2 allele and systemic arthritis (p = 0.001; OR = 5.89; confidence interval = 1.98–17.5) as well as the use of anti-TNF immunotherapy (p = 0.023; OR = 1.10; confidence interval = 1.00–1.14). The main factors that were found to influence the risk of extra-articular disease were age greater than or equal to 60 years (p = 0.008; OR = 4.06; confidence interval = 1.45–11.38), disease duration greater than 10 years (p = 0.031; OR = 3.10; confidence interval = 1.11–8.63) and positive rheumatoid factor (p = 0.035; OR = 2.07; confidence interval = 1.05–4.09).ConclusionsThese results suggest that the TNF2 allele is associated with the more serious forms of the disease in individuals from the Brazilian Amazon but not with a risk for developing RA.     

Polymorphisms of the DNA repair gene MGMT and risk and progression of head and neck cancer

Methylating agents are involved in carcinogenesis, and the DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) removes methyl group from O⁶-methylguanine. Genetic variation in DNA repair genes has been shown to contribute to susceptibility to squamous cell carcinoma of the head and neck (SCCHN). We hypothesize that MGMT polymorphisms are associated with risk of SCCHN. In a hospital-based case–control study of 721 patients with SCCHN and 1234 cancer-free controls frequency-matched by age, sex and ethnicity, we genotyped four MGMT polymorphisms, two in exon 3, 16195C > T and 16286C > T and two in the promoter region, 45996G > T and 46346C > A. We found that none of these polymorphisms alone had a significant effect on risk of SCCHN. However, when these four polymorphisms were evaluated together by the number of putative risk genotypes (i.e. 16195CC, 16286CC, 45996GT + TT, and 46346CA + AA), a statistically significantly increased risk of SCCHN was associated with the combined genotypes with three to four risk genotypes, compared with those with zero to two risk genotypes (adjusted odds ratio (OR) = 1.27; 95% confidence interval (CI) = 1.05–1.53). This increased risk was also more pronounced among young subjects (OR = 1.81; 95% CI = 1.11–2.96), men (OR = 1.24; 95% CI = 1.00–1.55), ever smokers (OR = 1.25; 95% = 1.01–1.56), ever drinkers (OR = 1.29; 95% CI = 1.04–1.60), patients with oropharyngeal cancer (OR = 1.45; 95% CI = 1.12–1.87), and oropharyngeal cancer with regional lymph node metastasis (OR = 1.52; 95% CI = 1.16–1.89). In conclusion, our results suggest that any one of MGMT variants may not have a substantial effect on SCCHN risk, but a joint effect of several MGMT variants may contribute to risk and progression of SCCHN, particularly for oropharyngeal cancer, in non-Hispanic whites.     

Community-acquired infections and their association with myeloid malignancies

Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown. Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n = 8489), CML (n = 3626) diagnosed 1992–2005; MDS (n = 3072) and MPNs (n = 2001) diagnosed 2001–2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality. Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14–1.26], 1.25 [95% CI: 1.16–1.36]), influenza (ORs 1.16 [95% CI: 1.07–1.25], 1.29 [95% CI: 1.16–1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06–1.21], 1.22 [95% CI: 1.11–1.35]), pneumonia (ORs 1.28 [95% CI: 1.21–1.36], 1.52 [95% CI: 1.40–1.66]), sinusitis (ORs 1.23 [95% CI: 1.16–1.30], 1.25 [95% CI: 1.15–1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07–1.18], 1.26 [95% CI: 1.17–1.36]). Cellulitis (OR 1.51 [95% CI: 1.39–1.64]), herpes zoster (OR 1.31 [95% CI: 1.14–1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17–1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12–1.31]), pneumonia (OR 1.49 [95% CI: 1.37–1.62]), sinusitis (OR 1.19 [95% CI: 1.09–1.29]) and cellulitis (OR 1.43 [95% CI: 1.32–1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21–1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded. Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.     

Association between periodontitis and common variants in the promoter of the interleukin-6 gene

We recently reported an association between interleukin-6 (IL6) polymorphisms (SNPs) and haplotypes and aggressive periodontitis (AgP). The aim of this study was to investigate this association in a larger cohort of subjects, affected by either aggressive or chronic periodontitis. Five IL6 SNPs were analyzed in 765 subjects (167 generalized aggressive periodontitis, 57 localized aggressive, 310 chronic periodontitis and 231 periodontally healthy). Among Caucasians (n = 454) there were moderate associations for ?1363T allele (p = 0.011) and for ?174GG and ?1363GG genotypes with diagnosis of periodontitis (respectively, p = 0.044, OR = 1.6, 95% CI = 1.0–2.4, and p = 0.017, OR = 1.8, 95% CI = 1.1–2.8, adjusted for age, gender and smoking). Haplotypes containing the ?174G>C, ?1363G>T and ?1480C>G polymorphisms were associated with diagnosis of periodontitis (p = 0.02). Subgroup analysis by disease phenotype showed associations for the localized AgP (LAgP) group and ?1480C>G and ?6106A>T SNPs (p = 0.007 and 0.010, respectively). Among Caucasians the genotypes IL6 ?1480 CC and ?6106 TT increased the adjusted OR for LAgP (OR = 3.09 and 2.27, respectively). This study supports the hypothesis that IL6 polymorphisms and haplotypes are moderately associated with periodontitis, possibly acting through influencing tissue levels of IL6. This association is stronger for LAgP than for other periodontal disease phenotypes.