European Case-control Study Research Articles

Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis

While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼ 90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable. We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥ 0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.

Algebraic Methods for Studying Interactions Between Epidemiological Variables

Background Independence models among variables is one of the most relevant topics in epidemiology, particularly in molecular epidemiology for the study of gene-gene and gene-environment interactions. They have been studied using three main kinds of analysis: regression analysis, data mining approaches and Bayesian model selection. Recently, methods of algebraic statistics have been extensively used for applications to biology. In this paper we present a synthetic, but complete description of independence models in algebraic statistics and a new method of analyzing interactions, that is equivalent to the correction by Markov bases of the Fisher’s exact test. Methods We identified the suitable algebraic independence model for describing the dependence of two genetic variables from the occurrence of cancer and exploited the theory of toric varieties and Grobner basis for developing an exact independence test based on the Diaconis-Sturmfels algorithm. We implemented it in a Maple routine and we applied it to the study of gene-gene interaction in Gen-Air, an European case-control study. We computed the p-value for each pair of genetic variables interacting with disease status and we compared our results with the standard asymptotic chi-square test. Results We found an association among COMT Val158Met, APE1 Asp148Glu and bladder cancer (p-value: 0.009). We also found the interaction among TP53 Arg72Pro, GSTP1 Ile105Val and lung cancer (p-value: 0.00035). Leukaemia was observed to significantly interact with the pairs ERCC2 Lys751Gln and RAD51 172 G > T (p-value 0.0072), ERCC2 Lys751Gln and LIG4 Thr9Ile (p-value: 0.0095) and APE1 Asp148Glu and GSTP1 Ala114Val (p-value: 0.0036). Conclusion Taking advantage of results from theoretical and computational algebra, the method we propose was more selective than other methods in detecting new interactions, and nevertheless its results were consistent with previous epidemiological and functional findings. It also helped us in controlling the multiple comparison problem. In the light of our results, we believe that the epidemiologic study of interactions can benefit of algebraic methods based on properties of toric varieties and Grobner bases.

A comprehensive study of polymorphisms in the ABCB1, ABCC2, ABCG2, NR1I2 genes and lymphoma risk

Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular "xenosensors" like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2 and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the four genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European case-control study (EpiLymph) using the Illumina GoldenGate™ assay technology. Carriers of the SNP rs6857600 minor allele in ABCG2 was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p < 0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p = 0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL.

Antenatal screening forToxoplasma gondiiinfection at a tertiary care hospital in Riyadh, Saudi Arabia

BACKGROUND AND OBJECTIVES:Congenital toxoplasmosis is associated with significant morbidity and mortality. This study investigates the prevalence of toxoplasmosis among pregnant women.DESIGN AND SETTING:A retrospective study at King Khalid University Hospital, Riyadh from September 2009 to August 2010.PATIENTS AND METHODS:Laboratory data of 2176 pregnant women screened for Toxoplasma gondii in the antenatal care unit were assessed during the study period. The mean (SD) age of the women and the duration of pregnancy were 25 (7.3) years and 18 (7.7) weeks, respectively. Data were extracted for the presence or absence of anti-T gondii immunoglobulin G (IgG) and IgM antibodies.RESULTS:Of 2176 sera tested, 1351 (62%) did not show any evidence of exposure to T gondii. The remaining 825 (38%) samples tested positive for anti-T gondii IgG antibodies, and none was found to have anti-T gondii IgM antibodies in the serum. These data reveal that a significantly high number of women in the antenatal care unit at King Khalid University Hospital in Riyadh had been exposed to T gondii.CONCLUSION:A high prevalence of toxoplasmosis among pregnant women warrants multicenter community-based investigations for assessment of T gondii infection and identification of risk factors for transmission of toxoplasmosis in general, and particularly during pregnancy.

Challenges in defining and classifying the preterm birth syndrome

In 2009, the Global Alliance to Prevent Prematurity and Stillbirth Conference charged the authors to propose a new comprehensive, consistent, and uniform classification system for preterm birth. This first article reviews issues related to measurement of gestational age, clinical vs etiologic phenotypes, inclusion vs exclusion of multifetal and stillborn infants, and separation vs combination of pathways to preterm birth. The second article proposes answers to the questions raised here, and the third demonstrates how the proposed system might work in practice.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in ADH1B (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by DSM-IV criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio of 0.34, 95% confidence interval 0.24, 0.48) for alcohol dependence, with genome-wide significance (6.6 × 10−10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24 hour period (lifetime), with p = 3×10−13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults and demonstrated a significant protective effect. This variant has the strongest effect on risk for alcohol dependence of any tested in European populations.

The Case-Population Study Design

The case-population approach or population-based case-cohort approach is derived from the case-control design and consists of comparing past exposure to a given risk factor in subjects presenting a given disease or symptom (cases) with the exposure rate to this factor in the whole cohort or in the source population of cases. In the same way as the case-control approach, the case-population approach measures the disproportionality of exposure between cases of a given disease and their source population expressed in the form of an odds ratio approximating the ratio of the risks in exposed and not-exposed populations (relative risk). The aim of this study was to (i) present the case-population principle design in a way understandable for non-statisticians; (ii) propose the easiest way of using it for pharmacovigilance purposes (mainly alerting and hypothesis testing); (iii) propose simple formulae for computing an odds ratio and its confidence interval; (iv) apply the approach to several practical and published examples; and (v) discuss its pros and cons in the context of real life. The approach used is derived from that comparing two rates expressed as person-time denominators. It allows easy computation of an odds ratio and its confidence interval under several hypotheses. Results obtained with the case-population approach were compared with those of case-control studies published in the literature. Relevance and limits of the proposed approach are illustrated by examples taken from published pharmacoepidemiological studies. The odds ratio (OR) reported in a European case-control study on centrally acting appetite suppressants and primary pulmonary hypertension was 23.1 (95% CI 6.9, 77.7) versus 31 (95% CI 16.2, 59.2) using the case-population approach. In the European case-control studies SCAR (Severe Cutaneous Adverse Reactions) and EuroSCAR on the risk of toxic epidermal necrolysis associated with the use of medicines, the OR for cotrimoxazole was 160 and 102, respectively, versus 44.4 using the case-population approach. Similarly, these two case-control studies found ORs of 12 and 72 for carbamazepine versus 24.4 using the case-population approach, 8.7 and 16 for phenobarbital versus 21.9, 12 for piroxicam (analysed in the SCAR study only) versus 14.5, and 5.5 and 18 for allopurinol versus 3.4 using the case-population approach. Being based on the estimate derived from sales statistics of the total exposure time in the source population of cases, the method can be used even when there is no information about the actual number of exposed subjects in this population. Although the case-population approach suffers from limitations stemming from its main advantage, i.e. impossibility to control possible confounders and to quantify the strength of associations due to the absence of an ad hoc control group, it is particularly useful to use in routine practice, mainly for purposes of signal generation and hypothesis testing in drug surveillance.

Dietary acrylamide and risk of prostate cancer

Acrylamide has been designated by IARC as a "probable human carcinogen." High levels are formed during cooking of many commonly consumed foods including French fries, potato chips, breakfast cereal and coffee. Two prospective cohort studies and two case-control studies in Europe found no association between acrylamide intake and prostate cancer. We examined this association in a large prospective cohort of 47,896 US men in the Health Professionals' Follow-up Study, using updated dietary acrylamide intake from food frequency questionnaires in 1986, 1990, 1994, 1998 and 2002. From 1986 through 2006, we documented 5025 cases of prostate cancer, and 642 lethal cancers. We used Cox proportional hazards models to assess the association between acrylamide intake from diet and prostate cancer risk overall as well as risk of advanced or lethal cancer. Acrylamide intake ranged from a mean of 10.5 mcg/day in the lowest quintile to 40.1 mcg/day in the highest quintile; coffee and potato products were largest contributors to intake. The multivariate-adjusted relative risk of prostate cancer was 1.02 (95% confidence interval: 0.92-1.13) for the highest versus lowest quintile of acrylamide intake (p-value for trend = 0.90). Results were similar when restricted to never smokers and to men who had prostate-specific antigen (PSA) tests. There was no significant association for dietary acrylamide and risk of lethal, advanced or high-grade disease, or for different latency periods ranging from 0-4 years to 12-16 years. We found no evidence that acrylamide intake, within the range of US diets, is associated with increased risk of prostate cancer.

Genome-wide association study of HPV seropositivity

High-risk α mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas β cutaneous HPV types (e.g. HPV8) have been implicated in non-melanoma skin cancer. Although antibodies against the capsid protein L1 of HPV are considered as markers of cumulative exposure, not all infected persons seroconvert. To identify common genetic variants that influence HPV seroconversion, we performed a two-stage genome-wide association study. Genome-wide genotyping of 316 015 single nucleotide polymorphisms was carried out using the Illumina HumanHap300 BeadChip in 4811 subjects from a central European case-control study of lung, head and neck and kidney cancer that had serology data available on 13 HPV types. Only one association met genome-wide significance criteria, namely that between HPV8 seropositivity and rs9357152 [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.24-1.50 for the minor allele G; P=1.2 × 10(-10)], a common genetic variant (minor allele frequency=0.33) located within the major histocompatibility complex (MHC) II region at 6p21.32. This association was subsequently replicated in an independent set of 2344 subjects from a Latin American case-control study of head and neck cancer (OR=1.35, 95% CI=1.18-1.56, P=2.2 × 10(-5)), yielding P=1.3 × 10(-14) in the combined analysis (P-heterogeneity=0.87). No heterogeneity was noted by cancer status (controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a proof of principle that genetic variation plays a role in antibody reactivity to HPV infection.

Lung cancer risk among cooks and kitchen workers in a pooled analysis of case-control studies in Europe and Canada

ObjectivesSeveral epidemiologic studies indicate an increased risk of lung cancer among cooks but it is not known whether this is caused by cigarette smoking or by occupational exposure to carcinogens....

Lung cancer risk in painters: results from the SYNERGY pooled analysis

ObjectivesThe International Agency for Research on Cancer identified “occupational exposure as a painter” as a cause of lung cancer. Identifying the specific causative agent(s) has been difficult since painters are...

Lung cancer risk among hairdressers in SYNERGY – pooled analysis from case-control studies in Europe and Canada

ObjectivesMost cohort studies show an increased risk of lung cancer among hairdressers. We investigated the risk of lung cancer among hairdressers and barbers in a large pooled dataset, while controlling...

Occupation and risk of upper aerodigestive tract cancer: The ARCAGE study

We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry.

Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006

Inflammatory bowel disease (IBD) frequently affects women during their reproductive years. Pregnancy outcome in women with IBD is well described, particularly in retrospective studies. To evaluate the pregnancy outcome in patients with IBD in a prospective European multicentre case-control study. Inflammatory bowel disease pregnant women from 12 European countries were enrolled between January 2003 and December 2006 and matched (1:1) to non-IBD pregnant controls by age at conception and number of previous pregnancies. Data on pregnancy and newborn outcome, disease activity and therapy were prospectively collected every third month using a standard questionnaire. Logistic regression analysis with odds ratio was used for statistical analyses. P value<0.05 was considered significant. A total of 332 pregnant women with IBD were included: 145 with Crohn's disease (CD) and 187 with ulcerative colitis (UC). Median age (range) at conception was 31 years (15-40) in CD and 31 (19-42) in UC patients. No statistically significant differences in frequency of abortions, preterm deliveries, caesarean sections, congenital abnormalities and birth weight were observed comparing CD and UC women with their non-IBD controls. In CD, older age was associated with congenital abnormalities and preterm delivery; smoking increased the risk of preterm delivery. For UC, older age and active disease were associated with low birth weight; while older age and combination therapy were risk factors for preterm delivery. In this prospective case-control study, women with either Crohn's disease or ulcerative colitis have a similar pregnancy outcome when compared with a population of non-inflammatory bowel disease pregnant women.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe

Objective To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome.Design Case-control study.Setting Five European countries.Participants 104 patients with Guillain-Barré syndrome and its variant Miller-Fisher syndrome...

Radon, Smoking and Lung Cancer Risk: Results of a Joint Analysis of Three European Case-Control Studies Among Uranium Miners

A combined analysis of three case-control studies nested in three European uranium miner cohorts was performed to study the joint effects of radon exposure and smoking on lung cancer death risk. Occupational history and exposure data were available from the cohorts. Smoking information was reconstructed using self-administered questionnaires and occupational medical archives. Linear excess relative risk models adjusted for smoking were used to estimate the lung cancer risk associated with radon exposure. The study includes 1046 lung cancer cases and 2492 controls with detailed radon exposure data and smoking status. The ERR/WLM adjusted for smoking is equal to 0.008 (95% CI: 0.004-0.014). Time since exposure is shown to be a major modifier of the relationship between radon exposure and lung cancer risk. Fitting geometric mixture models yielded arguments in favor of a sub-multiplicative interaction between radon and smoking. This combined study is the largest case-control study to investigate the joint effects of radon and smoking on lung cancer risk among miners. The results confirm that the lung carcinogenic effect of radon persists even when smoking is adjusted for, with arguments in favor of a sub-multiplicative interaction between radon and smoking.

−251 T/A polymorphism of the interleukin-8 gene and cancer risk: a HuGE review and meta-analysis based on 42 case–control studies

The -251T/A (rs4073), a single nucleotide polymorphism, has been identified in the promoter region of the interleukin-8 (IL-8) gene. It's presence could influence the production of IL-8 protein by regulating the transcriptional activity of the gene. A large number of studies have been performed to evaluate the role of -251T/A polymorphism on various cancers, with inconsistent results being reported. In this paper, we summarized 13,189 cases and 16,828 controls from 42 case-control studies and attempted to assess the susceptibility of -251T/A polymorphism to cancers by a comprehensive meta-analysis. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analysis were also performed. Results showed that the carriers of the -251A allele had about a 12-21% increased risk for the reviewed cancer, in total. The carriers of -251A had an elevated risk to breast cancer, gastric cancer and nasopharyngeal cancer and a reduced risk to prostate cancer, but no evidence was found to indicate that the -251A allele predisposed its carriers to colorectal and lung cancers. When stratified separately by 'racial descent' and 'study design', it was found that the carriers of the -251A allele among the African group, Asian group and hospital-based case-control study group were at a higher risk for cancer, but not in European group and population-based case-control study. These results show that -251A allele is susceptible in the development of low-penetrance cancers.

Risk factors for chronic kidney disease among human immunodeficiency virus-infected patients: A European case control study

Renal dysfunction is a common complication in human immunodeficiency virus (HIV)-infected patients and can be attributed to direct viral damage, comorbidities or drug toxicity. The aim of this study was to assess cross-sectional correlates of renal damage in a contemporary European cohort of patients. We performed a case-control study from our cohort of 750 HIV-infected adults over a period of 5 months. We assessed renal damage by either proteinuria (≥+ on urine dipstick), reduced creatinine clearance (< 60 ml/min) or reduced estimated glomerular filtration rate (eGFR) of < 60 ml/ min/1.73 m2. The characteristics of cases and controls were compared in analysis and in multivariate logistic regression models with stepwise selection. Approximately 50% of the screened 106 patients had a qualifying abnormality. Altogether, we identified 55 cases with 110 age- and gender-matched controls. Mean eGFR was 90.7 (4.8) for cases vs. 106.1 (2.3) ml/min/1.73 m2 for controls (p = 0.001). Cases had a longer duration of HIV infection, more complex regimen, longer exposure to antiretroviral therapy and a more frequent diagnosis of acquired immune-deficiency syndrome (AIDS) and hepatitis C virus (HCV) infection. In the logistic multivariate model, renal damage remained significantly associated with longer known duration of HIV infection (OR 2.88, 95% CI: 1.28 - 6.46, p = 0.01), AIDS defining condition (OR 1.09 95% CI: 1.03 - 1.16, p = 0.002) female gender (OR 2.01, 95% CI: 0.96 - 4.18, p = 0.06), and HCV infection (OR 2.12, 95% CI: 0.99 - 4.52, p = 0.05). Duration, antiretroviral regimen and coincidental HCV impacted the frequency of renal abnormalities in our patients.

Abstract 1875: Lung cancer risk among hairdressers in SYNERGY – pooled analysis from case-control studies in Europe and Canada with detailed smoking data

Abstract “Occupational exposure as a hairdresser or barber” was classified as probably carcinogenic to humans by the International Agency for Research on Cancer in volume 99 (2010). Small increases in lung cancer risk (20-40%) are found in most cohort studies but without adequate adjustment for smoking. Studies in Scandinavia and the USA show a higher prevalence of smokers among hairdressers than in the general population. The SYNERGY project has pooled information on lifetime work histories (ISCO-68) and tobacco smoking from 13479 cases and 16350 controls, including 20% women, from 11 case-control studies in 12 European countries and Canada. The original studies were conducted between 1985 and 2005. Odds ratios (OR) for lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, cigarette pack-years and time since quitting smoking. Less than 1% of the study population had ever worked as hairdresser or barber (0.89% of cases and 0.74% of controls). Hairdressers and barbers experienced a slight increase in lung cancer risk OR 1.16 (95%CI 0.90-1.49), which disappeared after adjusting for smoking OR 0.97 (95%CI 0.73-1.30). Results by duration of employment showed highest risks in hairdressers with short employment. Results were similar by gender, histology of lung cancer, and for women hairdressers. We observed a slight and non-significant increase in risk for male barbers, particularly in barbers with the longest employment and after adjustment for smoking. We could not detect an association between having worked as hairdresser or barber and increased lung cancer risk overall after adjusting for smoking. However, among male barbers we observed an increasing risk with increasing duration, although non-significant, after adjusting for tobacco smoking. Final results will include several more studies, and thereby increase the precision of our effect estimates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1875. doi:10.1158/1538-7445.AM2011-1875

Association of JAK‐STAT pathway related genes with lymphoma risk: results of a European case–control study (EpiLymph)

Previous studies have suggested an important role for the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway in tumour development. Therefore, we explored genetic variants in JAK-STAT pathway associated genes with lymphoma risk. In samples of the EpiLymph case-control study we genotyped 1536 single nucleotide polymorphisms (SNPs) using GoldenGate BeadArray™ Technology (Illumina, San Diego, CA, USA). Here, we report the associations between selected SNPs and haplotypes of the JAK-STAT pathway and risk of Hodgkin lymphoma (HL), B-cell non-Hodgkin lymphoma (B-NHL) and most frequent B-NHL subtypes. Among 210 relevant JAK-STAT pathway-related SNPs, polymorphisms in nine genes (BMF, IFNG, IL12A, SOCS1, STAT1, STAT3, STAT5A, STAT6, TP63) were significantly associated with lymphoma risk. At a study-wise significance level, we obtained a risk reduction of 28% among carriers of the heterozygous genotype of the STAT3 variant (rs1053023) for B-NHL. For six other variants within the STAT3 gene we observed an inverse association with different lymphoma subtypes. A reduced risk for HL was observed for the heterozygous genotype of the STAT6 SNP (rs324011). This is an explorative investigation to examine associations between JAK-STAT signalling related genes and lymphoma risk. The results implicate a relevant role of certain pathway-related genes in lymphomagenesis, but still need to be approved by independent studies.