European Case-control Study Research Articles

New gene variants associated with venous thrombosis: a replication study in White and Black Americans

We evaluated 10 single-nucleotide polymorphisms (SNPs) identified in three European case-control studies as risk factors for venous thrombosis. We sought to replicate the positive findings from this report among Whites and to evaluate the association of these SNPs with venous thrombosis for the first time among Blacks. These SNPs were evaluated in a case-control study of deep vein thrombosis and pulmonary embolism that included 1076 cases and 1239 controls. About 50% of subjects were African Americans. We measured plasma factor (F) XI on a subset of subjects. Among Whites, positive findings for rs13146272 in the CYP4V2 gene, for rs3087505 in the KLKB1 gene and for rs3756008 and rs2036914 in the F11 gene were found. We did not find significant associations for rs2227589 in the SERPINC1 gene and for rs1613662 in the GP6 gene. Among Blacks, rs2036914 in F11 and rs670659 in RGS7 were related to venous thrombosis, but the study had limited statistical power for many SNPs. Among Blacks, plasma FXI was related to two SNPs and the OR relating to the 90th percentile of the control distribution of plasma FXI was 2.6 (95% CI, 1.4, 5.0). Our study supports the finding that genetic variants in the F11 gene are risk factors for venous thrombosis among both Whites and Blacks, although the findings in Blacks require confirmation. A meta-analysis of five case-control studies indicates that rs2227589 in the SERPINC1 gene, rs13146272 in the CYP4V2 gene and rs1613662 in the GP6 gene are risk factors for venous thrombosis among Whites.

Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph

Using EpiLymph case-control data, we found that chronic lymphocytic leukemia patients were more likely to have abnormal reactive serological patterns to Epstein Barr virus than controls. Here, we aimed to assess whether this association is modified by genetic variants. We examined 1,305 Single Nucleotide Polymorphisms from 300 selected genes related to various pathways in 240 cases and 513 controls from five European centers. In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed. The strong interactions observed may be indicative of a specific pathway in cancer genesis. Confirmation of these results is warranted.

Kaposi sarcoma (KS)-associated herpesvirus microRNA sequence analysis and KS risk in a European AIDS-KS case control study.

We recently identified polymorphisms in Kaposi sarcoma-associated herpesvirus (KSHV)-encoded microRNA (miRNA) sequences from clinical subjects. Here, we examine whether any of these may contribute to KS risk in a European AIDS-KS case-control study. KSHV load in peripheral blood was determined by real-time quantitative polymerase chain reaction. Samples that had detectable viral loads were used to amplify the 2.8-kb miRNA encoding region plus a 646-bp fragment of the K12/T0.7 gene. Additionally, we characterized an 840-bp fragment of the K1 gene to determine KSHV subtypes. KSHV DNA was detected in peripheral blood mononuclear cells of 49.6% of case patients and 6.8% of controls, and viral loads tended to be higher in case patients. Sequences from the miRNA-encoding regions were conserved overall, but distinct polymorphisms were detected, some of which occurred in primary miRNAs, pre-miRNAs, or mature miRNAs. Patients with KS were more likely to have detectable viral loads than were controls without disease. Despite high conservation in KSHV miRNA-encoded sequences, polymorphisms were observed, including some that have been reported elsewhere. Some polymorphisms could affect mature miRNA processing and appear to be associated with KS risk.

Gene-nutrition interactions that modify the risk of upper aero-digestive tract cancer. Screening results of a European multi-center case-control study

Gene-nutrition interactions that modify the risk of upper aero-digestive tract cancer. Screening results of a European multi-center case-control study

Cigarette smoking and lung cancer – Risk estimates for the major histological types from a pooled analysis of European case-control studies

Cigarette smoking and lung cancer – Risk estimates for the major histological types from a pooled analysis of European case-control studies

Abstract 3777: Diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada

Abstract Introduction: Diesel-motor exhaust (DME) is classified by IARC as probably carcinogenic to humans. The epidemiological evidence is evaluated as limited since many studies lack adequate information on tobacco smoking and only few studies reported on exposure-response relationships. Our objective is to investigate the risk of lung cancer following occupational exposure to DME, while controlling for smoking and potential occupational confounders. Methods: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from more than 13300 cases and 16300 controls from case-control studies conducted in 12 European countries and Canada. A job exposure matrix based on ISCO codes, assigning no (0), low (1) or high (2) exposure to DME was applied to determine level of exposure to DME. Cumulative exposure was defined as: ∑(level2 * duration). Odds ratios (OR) of lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, pack-years and time since quitting smoking, and ever employment in a “Group A” job, i.e. occupations with established lung cancer risk. Results: Workers exposed to low levels of occupational DME exposure had an increased risk of lung cancer after 40 years of exposure OR 1.31 (95% CI 1.14-1.51), while workers exposed to high DME levels experienced a similar risk already after short duration (<10 years) OR 1.29, 95% CI 1.15-1.46. Cumulative DME exposure showed a significant exposure-response trend (p-value <0.000) with an OR of 1.31 (95% CI 1.20-1.44) in the highest quartile. These results were similar in workers never employed in “Group A“ jobs, lending support to the assumption that confounding due to other occupational exposures was not responsible for the observed risk. Analyses in sub-populations of women and never-smokers also indicated an increased risk of lung cancer following occupational DME exposure. Conclusion: Our results indicate that occupational exposure to DME is associated with an increased risk of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3777.

Penetrance of NOD2/CARD15 genetic variants in the general population

In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater risk. However, the importance of these genetic variants if identified in particular individuals within the general population is unknown. We undertook this study to estimate the penetrance of these variants in the general population. We genotyped 43,596 individuals from the Danish general population followed between January 1976 and July 2007. Using a logistic regression model, we estimated the risk of Crohn disease in relation to variants of the NOD2/CARD15 gene in the general population. Penetrance was calculated as the fraction of participants in whom Crohn disease was diagnosed before age 50 years. In the general population, 89% of participants were noncarriers of the genetic variants of interest (n = 38,594), 11% were heterozygotes (n = 4838), and 0.4% were compound heterozygotes or homozygotes (n = 164). For Crohn disease, multifactorially adjusted odds ratios were 1.2 (95% confidence interval [CI] 0.8-1.9) for heterozygotes and 3.3 (95% CI 0.8-13.6) for compound heterozygotes and homozygotes combined, relative to noncarriers. Only 2 compound heterozygotes received a diagnosis of Crohn disease, and this disease was not diagnosed in any of the homozygotes. The penetrance at age 50 years of NOD2/CARD15 genetic variants of Crohn disease was 0.30% (95% CI 0.29%-0.31%) for heterozygotes and 1.5% (95% CI 1.4%-1.6%) for compound heterozygotes and homozygotes. The penetrance of NOD2/CARD15 genetic variants in relation to risk of Crohn disease for this Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are identified.

Active and Involuntary Tobacco Smoking and Upper Aerodigestive Tract Cancer Risks in a Multicenter Case-Control Study

Several important issues for the established association between tobacco smoking and upper aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large-scale case-control study in Europe. Analysis was done on 2,103 UADT squamous cell carcinoma cases and 2,221 controls in the Alcohol-Related Cancers and Genetic Susceptibility in Europe project, a multicenter case-control study in 10 European countries. Unconditional logistic regression was done to obtain odds ratios (OR) and 95% confidence intervals (95% CI). Compared with never tobacco smoking, current smoking was associated with UADT cancer risks (OR, 6.72; 95% CI, 5.45-8.30 for overall; OR, 5.83; 95% CI, 4.50-7.54 for oral cavity and oropharynx; OR, 12.19; 95% CI, 8.29-17.92 for hypopharynx and larynx; and OR, 4.17; 95% CI, 2.45-7.10 for esophagus). Among never drinkers, dose-response relationships with tobacco smoking pack-years were observed for hypopharyngeal and laryngeal cancers (P(trend) = 0.010) but not for oral cavity and oropharyngeal cancers (P(trend) = 0.282). Among never smokers, ever exposure to involuntary smoking was associated with an increased risk of UADT cancers (OR, 1.60; 95% CI, 1.04-2.46). Our results corroborate that tobacco smoking may play a stronger role in the development of hypopharyngeal and laryngeal cancers than that of oral cavity and oropharyngeal cancers among never drinkers and that involuntary smoking is an important risk factor for UADT cancers. Public health interventions to reduce involuntary smoking exposure could help reduce UADT cancer incidence.

“I-MOVE” towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe, 2008-9

Within I-MOVE (European programme to monitor seasonal and pandemic influenza vaccine effectiveness (IVE)) five countries conducted IVE pilot case-control studies in 2008-9. One hundred and sixty sentinel general practitioners (GP) swabbed all elderly consulting for influenza-like illness (ILI). Influenza confirmed cases were compared to influenza negative controls. We conducted a pooled analysis to obtain a summary IVE in the age group of >or=65 years. We measured IVE in each study and assessed heterogeneity between studies qualitatively and using the I2 index. We used a one-stage pooled model with study as a fixed effect. We adjusted estimates for age-group, sex, chronic diseases, smoking, functional status, previous influenza vaccinations and previous hospitalisations. The pooled analysis included 138 cases and 189 test-negative controls. There was no statistical heterogeneity (I2=0) between studies but ILI case definition, previous hospitalisations and functional status were slightly different. The adjusted IVE was 59.1% (95% CI: 15.3-80.3%). IVE was 65.4% (95% CI: 15.6-85.8%) in the 65-74, 59.6% (95% CI: -72.6 -90.6%) in the age group of >or=75 and 56.4% (95% CI: -0.2-81.3%) for A(H3). Pooled analysis is feasible among European studies. The variables definitions need further standardisation. Larger sample sizes are needed to achieve greater precision for subgroup analysis. For 2009-10, I-MOVE will extend the study to obtain early IVE estimates in groups targeted for pandemic H1N1 influenza vaccination.

Apolipoprotein E/C1 Locus Variants Modify Renal Cell Carcinoma Risk

Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in 777 Caucasian RCC cases and 1,035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615 controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the U.S. study were within a regulatory region of the APOE promoter. The OR for rs8106822 A>G variant was 1.22(AG) and 1.41(GG) (P(trend) = 0.01) in the European study, 1.05(AG) and 1.51(GG) (P(trend) = 0.03) in the U.S. study, and 1.15(AG) and 1.44(GG) (P(trend) = 0.001) among 1,485 cases and 1,639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR, 0.87(TG); OR, 0.71(TT); P(trend) = 0.02), the U.S. (OR, 0.68(TG); OR, 0.71(TT); P(trend) = 0.02), and both studies combined (OR(TG), 0.79; OR(TT), 0.71; P(trend) = 0.001), as was the G-G haplotype (r(2) = 0.64; P= 4.7 x 10(-4)). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE protein in vitro and is in linkage disequilibrium with key known variants defining the e2, e3, and e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.

Homocysteine increases the risk associated with hyperlipidaemia

The European Concerted Action Project 'Homocysteine and Vascular Disease' showed that an elevated homocysteine is associated with a substantially increased risk of cardiovascular disease, and particularly when combined with other factors such as smoking, hypertension and hypercholesterolaemia. The purpose of this study was to examine the potential interactions between homocysteine and individual lipid subfractions. In addition, it was hypothesized that HDL cholesterol may protect against hyperhomocysteinaemia because HDL cholesterol is associated with the enzyme paroxonase, which reduces oxidization of homocysteine to the harmful metabolite, homocysteine thiolactonase. Data from a multicentre European case-control study (750 cases and 800 controls) were used for analysis. The risks of vascular disease associated with homocysteine, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apoprotein A1 and apoprotein B were established. The effect of elevated homocysteine on the cardiovascular risk associated with each lipid subfraction was then examined. As expected, homocysteine, total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B were associated with cardiovascular risk. HDL cholesterol was inversely related to risk. Homocysteine increased the risk associated with all lipid measures. In contrast, a low plasma cholesterol does not seem to confer protection against the risk associated with a raised plasma homocysteine. Hyperhomocysteinaemia is associated with an increased risk at all levels of HDL cholesterol, conversely, in those with elevated homocysteine HDL cholesterol levels result in reduced risk. In general, the increased cardiovascular risk associated with elevated homocysteine is evident across the spectrum cholesterol subfraction levels.

Medical history and risk of lymphoma: results of a European case–control study (EPILYMPH)

Lymphomas are a heterogeneous group of immune-cell malignancies. Immunology-related conditions are among the few factors for which consistent evidence exists relating them to lymphoma risk. We used the data from the European case-control study Epilymph on 2,362 lymphoma cases and 2,458 controls to investigate associations between a medical history of infectious and non-infectious diseases with overall and subentity-specific lymphoma risk. As key results, we observed an increased odds ratio (OR) for self-reported infections with hepatitis B virus (HBV, OR = 1.91, 95% CL = 1.24-2.94) and a null result for rheumatoid arthritis. Additionally, we found an increased OR for infectious mononucleosis (OR = 1.68, 95% CL = 1.14-2.48), an inverse association to frequency of sickness in childhood (OR = 0.68, 95% CL = 0.55-0.84), and-as casual finding-an increased OR with acetaminophen intake (OR = 2.29, 95% CL = 1.49-3.51). Our results are consistent with the current knowledge about the association with mononucleosis as indicator of Epstein-Barr-virus infection, suggest serological study of the association to HBV infection and do not support the view of a positive association between rheumatoid arthritis and lymphoma risk.

Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases.

Work related perceived stress and muscle activity during standardized computer work among female computer users

The current study investigated the associations between work-related perceived stress and surface electromyographic (sEMG) parameters (muscle activity and muscle rest) during standardized simulated computer work (typing, editing, precision, and Stroop tasks). It was part of the European case-control study, NEW (Neuromuscular assessment in the Elderly Worker). The present cross-sectional study was based on a questionnaire survey and sEMG measurements among Danish and Swedish female computer users aged 45 or older (n=49). The results show associations between work-related perceived stress and trapezius muscle activity and rest during standardized simulated computer work, and provide partial empirical support for the hypothesized pathway of stress induced muscle activity in the association between an adverse psychosocial work environment and musculoskeletal symptoms in the neck and shoulder.

Abstract A89: Association of genes involved in lipid metabolism-peroxidation and risk of renal cancer in the Central European Renal Cancer Case-Control Study

Abstract A89 Recent descriptive studies have reported increases in kidney cancer incidence since the 1970s in the United States and globally. Lipid peroxidation has been suggested as a unifying mechanistic pathway by which several known risk factors including obesity, hypertension, and chemicals directly damage cells of the proximal renal tubules and induce renal carcinogenesis. This study investigated the association between renal cell cancer (RCC) risk and variation in genes that modify the effects of lipid peroxidation, inflammation, and oxidative stress. We conducted a case-control study of RCC (987 cases and 1298 controls) from Central and Eastern Europe and analyzed genomic DNA for 635 single nucleotide polymorphisms (SNPs) thirty-eight candidate genes using an Illumina Oligo Pool-All (OPA). First, the minimum p-value permutation test (MINP) was used to identify genes that remained significant with an FDR&amp;lt;5%. Subsequently, a haplotype-based sliding window analysis of three consecutive SNPs was used to identify chromosome regions of interest that remained significant at a FDR&amp;lt;5%. Six genes were selected for in-depth analysis after multiple testing correction of the single marker associations: APOE, GPX4, NOS2A and PTGS2. The overall gene-level p-values for these genes were 0.017, 0.020, 0.055 and 0.069 using the MINP test, respectively. The minimum FDR-adjusted p-values in a sliding window haplotype analysis were 0.0005, 0.0007, 0.0002 and 1.09x10-5, respectively. For these regions, age-, sex- and center-adjusted haplotype relative risks were computed using the HaploStats package in R. After adjustment, a strong signal centered around the promoter region of APOE gene (rs405509) remained significantly associated with decreased risk of RCC compared to persons homozygous for the referent haplotype (OR=0.73 95% CI:0.59-0.91); global p=0.001). A second haplotype window spanning from IVS7+11 to IVS12-52 of the NOS2A gene that was significantly associated with increased risk (OR=1.36 (95% CI:1.05-1.78); p-global p-0.006). Additional haplotype windows spanning the trans-membrane and tyrosine kinase domains of INSR (rs28601) and intron 2 of LEPR (rs970467) genes also were investigated further (FDR-adjusted p &amp;lt;0.05). After adjustment in Haplostats, two additional high risk haplotypes were identified that were significantly associated with risk. To our knowledge this is the first and largest study of RCC conducted to evaluate these genes in relation to RCC. Although replication and fine mapping studies will be required to confirm these findings, this study supports the hypothesis variation in genes influencing lipid metabolism/peroxidation may increase susceptibility to sporadic kidney cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A89.

Alcohol drinking and the risk of upper aero digestive tract cancer: European multicenter case-control study ARCAGE

The aim of the research was to determine the satisfaction of patients diagnosed with colorectal cancer, with the actual bowel preparation prior to surgery, and the effectiveness of bowel emptying according to the protocol of a single procedure proposed by the authors. We studied two approaches of nurses to patients during mechanical bowel preparation. The first approach was connected with bowel emptying prior to planned surgery (according to the standard procedure of surgical wards), and the second one according to the protocol proposed by the authors. Data on patient satisfaction with the preoperative preparation were acquired using a questionnaire of our own design. The questionnaire was comprised of 26 questions compiled using the Likert scale. The reliability of the questionnaire was examined using the Cronbach alpha coefficient, and the resulting value was 0.906. Several statistical methods were used in the research: Chi-square test, F-test, Student's t-test, Mann–Whitney test, significance α = 0.05 and Cramer V coefficient. The examined issue was verified in the Slovak Republic and the Czech Republic in surgery clinics at the F.D. Roosevelt Teaching Hospital with Policlinic Banska Bystrica, the Teaching Hospital Brno, University Hospital Martin, and T. Bata Regional Hospital Zlin.It was found that our suggested protocol for bowel preparation, which focuses on patient satisfaction in the preparation process for surgery and efficient bowel emptying, is assessed more positively by patients and surgeons than the traditional standard procedure for bowel emptying. We recommended the proposed protocol be put into practice as a standard part of nursing documentation for patients being prepared for colon surgery at the Surgery Clinic II of the Slovak Medical University, F.D. Roosevelt Teaching Hospital with Policlinic Banska Bystrica.

A case‐control study of the relation between plasma selenium and asthma in European populations: a GA2LEN project*

There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

The relation between paracetamol use and asthma: a GA2LEN European case-control study

Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.

Exposure to ultraviolet radiation and risk of malignant lymphoma and multiple myeloma--a multicentre European case-control study

Three recent studies have reported a decreased risk of non-Hodgkin lymphoma (NHL) for high ultraviolet (UV) radiation exposure. We conducted a multicentre case-control study during 1998-2004 in France, Germany, Ireland, Italy and Spain, comprising 1518 cases of NHL, 268 cases of Hodgkin lymphoma, 242 cases of multiple myeloma and 2124 population or hospital controls. We collected information on sensitivity to sun and personal exposure to UV radiation in childhood and adulthood via interview, and assessed occupational exposure to UV radiation from the occupational history. The risk of Hodgkin and NHL was increased for increasing skin sensitivity to the sun [odds ratio (OR) for no suntan vs very brown 2.35, 95% CI 0.94-5.87 and 1.39, 95% CI 1.03-1.87, respectively]. The risk of diffuse large B-cell lymphoma was reduced for increasing adult personal (OR for highest vs lowest quartile of exposure in free days 0.62, 95% CI 0.44-0.87) and for occupational exposure to UV radiation (OR for highest vs lowest exposure tertile 0.63, 95% CI 0.37-1.04). The risk of multiple myeloma was increased for personal exposure to UV radiation during adulthood (OR for highest vs lowest quartile of exposure in free days 1.49, 95% CI 0.88-2.50). A protective effect was observed for use of sun lamps for diffuse large B-cell lymphoma (OR for 25+ times vs never 0.63, 95% CI 0.38-1.03). The hypothesis of a protective effect of UV radiation on lymphoma is supported by our results. The underlying mechanisms might differ from those operating in skin carcinogenesis. The increased risk of multiple myeloma is worth replication.

Genetic Analysis of Krüppel-Like Zinc Finger 11 Variants in 5864 Danish Individuals: Potential Effect on Insulin Resistance and Modified Signal Transducer and Activator of Transcription-3 Binding by Promoter Variant −1659G&amp;gt;C

The transcription factor Krüppel-like zinc finger 11 (KLF11) has been suggested to contribute to genetic risk of type 2 diabetes (T2D). Our previous results showed that four KLF11 variants, in strong linkage disequilibrium (LD block including +185 A>G/Gln62Arg and -1659 G>C) were associated with T2D in a north European case-control study. Here we further analyzed these variants for T2D association in a general Danish population and assess their possible effect on gene function. We genotyped Gln62Arg variant, representative for the LD block, in 5864 subjects of the INTER99 study to assess association to T2D and glucose metabolism-related quantitative traits. We studied effects of LD-block variants on KLF11 function and in particular, the effect of -1659G>C on transcriptional regulation of KLF11 using EMSA, chromatin immunoprecipitation, gene reporter assays, and small interfering RNA transfection. We could not confirm T2D association of the KLF11 LD block, however, in glucose-tolerant subjects; it was significantly associated with higher fasting serum insulin and C-peptide levels and increased homeostasis model assessment insulin resistance indexes (P = 0.00004, P = 0.006, and P = 0.00002, respectively). In addition, binding of signal transducer and activator of transcription (STAT)-3 to the wild-type (-1659G>C) allele stimulated gene transcription, whereas STAT3 did not bind onto the mutant allele. We showed that KLF11 may interfere with glucose homeostasis in a Danish general population and that STAT3-mediated up-regulation of KLF11 transcription was impaired by the -1659G>C variant. Overall, KLF11 variants may have a deleterious effect on insulin sensitivity, although that may not be sufficient to lead to T2D.