Epidemiological Studies Of Association Research Articles

Meta-analysis of epidemiological studies of association of two polymorphisms in the interleukin-10 gene promoter and colorectal cancer risk

In order to make a comprehensive assessment of the potential association between two genetic variants in the IL-10 gene promoter, -1082 A>G (rs1800896) and -592 C>A (rs1800872), and colorectal cancer (CRC) risk, we conduced a meta-analysis of seven epidemiological studies, which included 1469 colorectal cancer cases and 2566 controls. Neither of the two polymorphisms had any association with increased CRC risk in overall population [for rs1800896: odds ratio (OR) = 0.90, 95% confidence interval (95%CI) = 0.76-1.06 in the dominant model and for rs1800872: OR = 1.06, 95%CI = 0.91-1.23 in the dominant model]. In subgroup analysis of the rs1800896 polymorphism, the results did not change when the analyses were restricted to individual studies, or those fulfilling Hardy-Weinberg equilibrium, or according to the source of controls. For rs1800872, however, when stratifying by the source of controls, the A allele had a significant increased risk of CRC among studies with population-based controls in the codominant model (AC vs CC: OR = 1.30, 95%CI = 1.04-1.63) and dominant model (AA/AC vs CC: OR = 1.25, 95% CI = 1.01-1.55). Based on this meta-analysis, we conclude that the IL-10 rs1800872 polymorphism could be a risk factor for CRC development among European populations. However, we found no association between the IL-10 rs1800896 polymorphism and CRC risk. Further studies, either with larger sample size or involving other SNPs and haplotypes of the IL-10 gene, are necessary to clarify the contribution of IL-10 genetic variations in colorectal carcinogenesis.

Are Migraine and Bipolar Disorders Comorbid Phenomena?

Clinical, epidemiological, and, recently, genome-wide linkage and genome-wide association studies suggest migraine and bipolar disorder are comorbid phenomena. The objective of this study was to determine whether there is also evidence that this comorbidity exists by virtue of there being a positive relationship between the prescription of medications used to treat migraine and mood-stabilizing agents using the National Norwegian Prescription Database. Data allowing ascertainment of the concurrence of prescriptions for migraine and mood-stabilizing agents were gleaned from the Norwegian Prescription Database for calendar year 2006, covering the total population (N = 4,640,219). Results were obtained using logistic regression analyses and were expressed by odds ratios (ORs). A total of 81,225 persons (1.8% of the population) received medications for migraine and 19,517 (0.45%) received a mood-stabilizing agent for a bipolar disorder; 843 persons received both types of medications. The OR expressing the relationship between the concurrent use of both categories of medications was 2.55 (95% confidence interval [CI], 2.38-2.73, P < 0.001, z score = 26.44), significant for all mood stabilizers (lithium: OR = 1.82 [95% CI, 1.58-2.10], P < 0.001, z score = 8.31; carbamazepine: OR = 2.48 [95% CI, 2.01-3.06], P < 0.001, z score = 8.42; valproic acid: OR = 2.26 [95% CI, 1.89-2.70], P < 0.001, z score = 8.96; and lamotrigine: OR = 3.50 [95% CI, 3.14-3.90], P < 0.001, z score = 22.68). The association was significantly higher for men (OR = 3.16 [95% CI, 2.74-3.66], P < 0.001, z score = 15.53) than for women (OR = 2.21 [95% CI, 2.04-2.39], P < 0.001, z score = 19.61) and was most pronounced in younger age groups and for lamotrigine. There was a strong positive association between the prescription of medications used to treat migraine and mood-stabilizing agents. This is compatible with the hypothesis that migraine and bipolar disorders are associated with one another.

Vitamin D and its emerging role in immunopathology

In recent years, there has been an increased recognition that vitamin D is not only a risk factor for poor musculoskeletal health but also a possible important contributor in the development of different autoimmune diseases. This has been linked to multiple immunosuppressive properties of vitamin D. Vitamin D has got pleiotropic effects and this reflects the wide spread presence of vitamin D receptors (VDRs) throughout the body. Currently, there is much ongoing research with regard to its emerging role in immunopathology. VDR has not only been found in tissues involved in calcium homeostasis but also in a variety of cell lines involved primarily in immune regulation, e.g., mononuclear cells, dendritic cells, antigen-presenting cells, and activated B lymphocytes and CD4+ T cells. There have been several reports linking the presence of low vitamin D to various autoimmune diseases. However, for autoimmune/inflammatory disease outcomes, firm conclusions regarding cause and effect cannot be based on epidemiological association studies, and prospective, long-term, well-designed studies, including large intervention trials, are needed across all life stages. In this paper, we will describe the evidence base for this potential role of vitamin D in different aspects of autoimmune diseases. Because of the enormous breadth of this emerging field, our aim in this review is not to provide an exhaustive list of all literature pertinent to vitamin D and immunopathology. Instead, we will frame the reasons and rationale behind the development of several immunoregulatory activities for 1,25(OH)2D3.

EXPOSURE TO AIR POLLUTION FROM TRAFFIC AND CHILDHOOD ASTHMA IN THE SWEDISH BIRTH COHORT BAMSE

Background and Aims: Epidemiological studies of the association between traffic-related air pollution and long-term effects on the development of childhood airway disease have shown inconsistent re...

Role of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension

That elevated heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in healthy people as well as in patients with cardiac diseases is supported by numerous epidemiological association studies.1–4 Increased HR has been recognized as a negative prognostic factor independent of many other clinical parameters that can influence the HR, including physical activity scores, left ventricular function, or use of β-blockers. Thus, HR appears to satisfy all epidemiological criteria for being considered as a true risk factor, and its predictive value for cardiovascular disease appeared to be as strong as that of most important cardiovascular risk factors. This is particularly true for the results obtained in hypertensive patients. Elevated HR is a common feature among hypertensive individuals.1 Among the young hypertensive subjects participating in the HARVEST study, >15% had a baseline resting HR ≥85 bpm and 27% had a HR ≥80 bpm.5 According to the Tensiopulse study, which evaluated 38 145 patients cared for by 2000 general practitioners all across Italy, >30% of the hypertensive patients had a resting HR ≥80 bpm.6 In a large French population, untreated hypertensive subjects had approximately a 6-bpm faster HR than normotensive individuals.7 Elevated HR is frequently associated with high blood pressure (BP) and metabolic disturbances and increases the risk of new onset hypertension and diabetes.1 Many experimental data obtained both in animals and in human beings support the importance of HR as a true risk factor for atherosclerosis and cardiovascular disease, providing convincing evidence for this pathogenetic mechanism.1–3 The pathogenetic connection between HR and cardiovascular disease has been discussed in several reports1–3,8,9 and is beyond the scope of this review. ### High HR as a Precursor of Hypertension, Obesity, and Diabetes Numerous studies have demonstrated that tachycardia is frequently associated with hypertension in …

The evaporation of positive genetic association findings. When time has come to go

Time and distance can often be quite helpful to create a new overall picture. This is especially true in genetic epidemiological association studies which describe a relationship between a genetic variation in a gene region with a phenotype or outcome of interest such as cardiovascular disease. These association studies became extremely popular during the last five years which can be seen not only by the number of these studies but also by the fact that they found their way into major high-impact journals on a regular basis. To a large extent this success is caused by two facts: first, genome-wide association studies (GWAS) using an hypothesis-free approach by searching the entire genome for genetic variation associated with various outcomes and phenotypes have detected a large number of genes [ 1 Ioannidis J.P. Thomas G. Daly M.J. Validating, augmenting and refining genome-wide association signals. Nat Rev Genet. 2009; 10: 318-329 Crossref PubMed Scopus (309) Google Scholar , 2 Kronenberg F. Genome-wide association studies in aging-related processes such as diabetes mellitus, atherosclerosis and cancer. Exp Gerontol. 2008; 43: 39-43 Crossref PubMed Scopus (35) Google Scholar ] and second by the steep learning curve geneticists have made over the last decade by pairing up with epidemiologists to adopt the high standards in place in that discipline. This has resulted in improved study designs and selection of cases and controls, a higher awareness of possible biases, controlling for confounders and better-powered studies. However, the power of genetic association studies is still often quite low. After harvesting the few low-hanging fruits it became clear that the expected effect sizes of genetic variations on complex phenotypes are low, requiring studies with large sample sizes. By the pressure of higher standards, genetic association studies with 17 cases and six and a half controls in which the controls are even from another galaxy are no longer publishable (with few exceptions). Instead more and more large and appropriately designed studies become available which, however, are often still underpowered to detect the small effects we expect from single polymorphisms on the outcomes. Therefore, meta-analysis of the available evidence which makes use of the already published and unpublished studies enters the scene. These studies need time in the sense that only time creates the large number of studies which then finally enter the meta-analysis. And they create distance by presenting an overview which results either in confirmation of previously claimed associations or in an evaporation of initial positive findings (“winners curse”). Two meta-analyses of this kind entered this issue of Atherosclerosis.

Smoking and Congenital Heart Disease: The Epidemiological and Biological Link

Cigarette smoking is a powerful human germ cell mutagen and teratogen. Congenital heart defects (CHD) is the most prevalent of all birth defects and leading cause of death in the first year of life. The purpose of this article is to review the epidemiology of the impact of cigarette smoking on CHD risk as well as to discuss the potential biological mechanisms of smoking-mediated abnormal cardiac development. Although epidemiological studies of association between parental smoking and CHD are limited, biological evidence support the concept that cigarette smoking may substantially contribute to the aetiology of CHD through induction of either male and female germ-cell mutation or interference with epigenetic pathways. Further research is needed to better define the relationship between parental smoking and the risk of heart defects as well as to assess parental-fetal gene-smoking interactions.

Emerging Research on Equol and Cancer1–

Mechanisms of action of equol described using in vitro studies suggest possible effects of this compound in relation to cancer risk. However, experimental data are lacking with regard to the effects of S-(-)-equol (a gut bacterial product of daidzein), racemic equol, or even daidzein on tumorigenesis in vivo. Rodent studies, using racemic equol or daidzein in equol-producing animals, suggest that equol exposure does not stimulate mammary tumor growth, but there is little evidence that it is protective either. Racemic equol has been shown to inhibit skin carcinogenesis in hairless mice. Epidemiologic studies of associations between urinary or plasma isoflavone concentrations and breast cancer risk in women have reported no association nor increased risk associated with higher equol measures in low-soy–consuming populations but have reported a trend toward decreased cancer risk with increased equol in Asian populations. These population-based differences have been reported for prostate cancer too. Several studies in Asian men report lower equol concentrations or a lower prevalence of equol-producers among men with prostate cancer compared with controls, whereas studies in European populations report no association. Studies using intermediate biomarkers of cancer risk and susceptibility in humans also have examined the effects the equol-producer phenotype in relation to soy intake with varying results. Overall, the role of equol in relation to cancer remains unclear. With the availability of R- and S-equol, animal studies of carcinogenesis and human intervention studies addressing effects of the equol enantiomers on intermediate biomarkers may help to ascertain the role of equol in cancer risk. J. Nutr. 140: 1369S–1372S, 2010.

Meta-analysis of epidemiological studies of association of P53 codon 72 polymorphism with bladder cancer

Although there have been many studies investigating a possible association between p53 codon 72 polymorphism and risk of bladder cancer, the results have been inconsistent. We conducted a meta-analysis of six epidemiological studies, which included 597 bladder cancer cases and 731 controls. Patients with bladder cancer had a significantly lower frequency of Pro/Arg [odds ratio (OR) = 0.80, 95% confidence interval (CI) = 0.64-0.99], when compared to controls. Stratifying for race, we found that among Caucasians, patients with bladder cancer had a significantly higher frequency of Arg/Arg (OR = 1.64, 95%CI = 1.18-2.28) and a lower frequency of Pro/Arg (OR = 0.62, 95%CI = 0.44-0.86), compared to controls. Stratifying various studies by the stage of bladder cancer, we found that invasive bladder cancers had a significantly lower frequency of Arg/Arg (OR = 0.58, 95%CI = 0.36-0.93) and a higher frequency of Pro/Arg (OR = 0.62, 95%CI = 0.44-0.86) than did non-invasive bladder cancers. No significant association was found between this genotype and human papilloma virus. Based on our meta-analysis, we suggest that p53 codon 72 polymorphism is associated with bladder cancer and that genotypic distribution of this polymorphism varies with the stage of bladder cancer.

The Mitochondrial A10398G Polymorphism, Interaction with Alcohol Consumption, and Breast Cancer Risk

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.

Obstructive Sleep Apnea and Cardiovascular Disease: A Perspective and Future Directions

Data from animal and human studies provide a biological plausibility to the notion that obstructive sleep apnea activates pathways that lead to insulin resistance, atherosclerosis and hypertension. Sleep apnea thus activates the same pathways as does obesity. That obstructive sleep apnea is a risk factor for cardiovascular disease is supported by epidemiological association studies. Longitudinal cohort studies also provide evidence that patients with untreated severe sleep apnea have an increased rate of cardiovascular events. But these studies, while highly suggestive, do not provide the evidence needed to convince the skeptic. This would only be obtained by randomized treatment trials with hard cardiovascular endpoints such as cardiac events and deaths. While such studies are in the planning stages, they will be challenging. There are issues about randomizing individuals with severe sleep apnea and excessive sleepiness into no therapy, since they are at known increased risk for car crashes. Thus, lack of therapy puts others on the road at risk as well as the subject with sleep apnea. There is, moreover, the concern that treating obstructive sleep apnea in very obese individuals will have little impact, since any effect of therapy for OSA will be overwhelmed by the effects of obesity itself. Data from randomized treatment trials for cardiovascular endpoints will likely not be available for many years. In the interim, physicians need to consider how to treat such patients. It is proposed that given that CPAP treatment for obstructive sleep apnea is highly effective and essentially totally safe, and that the evidence is suggestive that sleep apnea is a risk factor for cardiovascular disease, then we propose all patients with severe sleep apnea should be treated to reduce cardiovascular risk.

Paraoxonase and Coronary Heart Disease Risk

Organophosphates were first synthesized in the 1930s as insecticides1 and were subsequently shown to have direct neurotoxic effects in mammals, as well. The neurotoxicity is derived from their ability to inhibit acetylcholinesterase by covalently modifying the active-site serine group in the enzyme. Mazur2 first demonstrated the presence of an organophosphate-hydrolyzing enzyme in mammalian tissue, an observation that ultimately led to the identification of a human paraoxonase in serum in 1953.3 Paraoxonase—so named because of its ability to hydrolyze the toxic metabolite of parathion, paraoxon—was also shown early after its identification to manifest arylesterase activity, an effect that was underappreciated until the enzyme was found to play a role in modulating vascular oxidant stress many years later. Article see p 147 The paraoxonase story is a good example of the power of language to mislead. There is no teleological reason for mammals to have evolved an enzyme that can hydrolyze synthetic organophosphates; yet, paraoxonase was isolated in an effort to understand the endogenous metabolism of these exogenous neurotoxins. The enzymatic activity for which the enzyme is named is screened by using synthetic substrates without regard for the native substrate or its role in human (patho)biology. This focus on one aspect of the enzyme’s function, overemphasized by its denotation, delayed an appreciation of other potential—and perhaps more relevant—roles. In 1991, Mackness et al4 showed that paraoxonase …

Preface

Preface

Differential oxidative stress response in young children and the elderly following exposure to PM2.5

The mechanism of the adverse health effects of ambient particulate matter on humans has not been well-investigated despite many epidemiologic association studies. Measurement of personal exposure to particulate pollutants and relevant biological effect markers are necessary in order to investigate the mechanism of adverse health effects, particularly in fragile populations considered to be more susceptible to the effects of pollutants. We measured personal exposure to PM(2.5) and examined oxidative stress using urinary malondialdehyde three times in 51 preschoolers and 38 elderly subjects. A linear mixed-effects model was used to estimate PM(2.5) effects on urinary MDA levels. Average personal exposure of the children and elderly to PM(2.5) was 80.5 +/- 29.9 and 20.7 +/- 12.7 mug/m(3), respectively. Mean urinary MDA level in the children and the elderly was 3.6 +/- 1.9 and 4.0 +/- 1.6 mumol/g creatinine. For elderly subjects the PM(2.5) level was significantly associated with urinary MDA after adjusting for age, sex, BMI, passive smoking, day-care facility site, alcohol consumption, cigarette smoking, and medical history (heart disease, hypertension and bronchial asthma). However, there was no significant relationship for children. The elderly were more susceptible than young children to oxidative stress as a result of ambient exposure to PM(2.5). Identification of oxidative stress induced by PM(2.5) explains the mechanism of adverse health effects such as cardiovascular or respiratory diseases, particularly in the elderly.

Mining data, gathering variables and recombining information: the flexible architecture of epidemiological studies

Since the second half of the twentieth century, biomedical research has made increasing use of epidemiological methods to establish empirical evidence on a population level. This paper is about practices with data in epidemiological research, based on a case study in Denmark. I propose an epistemology of record linkage that invites exploration of epidemiological studies as heterogeneous assemblages. Focusing on data collecting, sampling and linkage, I examine how data organisation and processing become productive beyond the context of their collection. The case study looks at how a local population database established in 1976 to investigate possibilities for the prevention of cardiovascular disease is used thirty years later to test hypotheses on the aetiology of breast cancer. For two breast cancer investigations based on the same core data set, I follow the underlying record linkage practice and describe how research objects such as molecular markers become relevant with respect to public health through information networking. Epidemiological association studies function as tools that performatively enrol different contexts into statistical risk estimation, thereby configuring options for research as well as for clinical testing and public health policy.

Reporting of human genome epidemiology (HuGE) association studies: an empirical assessment.

BackgroundSeveral thousand human genome epidemiology association studies are published every year investigating the relationship between common genetic variants and diverse phenotypes. Transparent reporting of study methods and results allows readers to better assess the validity of study findings. Here, we document reporting practices of human genome epidemiology studies.MethodsArticles were randomly selected from a continuously updated database of human genome epidemiology association studies to be representative of genetic epidemiology literature. The main analysis evaluated 315 articles published in 2001–2003. For a comparative update, we evaluated 28 more recent articles published in 2006, focusing on issues that were poorly reported in 2001–2003.ResultsDuring both time periods, most studies comprised relatively small study populations and examined one or more genetic variants within a single gene. Articles were inconsistent in reporting the data needed to assess selection bias and the methods used to minimize misclassification (of the genotype, outcome, and environmental exposure) or to identify population stratification. Statistical power, the use of unrelated study participants, and the use of replicate samples were reported more often in articles published during 2006 when compared with the earlier sample.ConclusionWe conclude that many items needed to assess error and bias in human genome epidemiology association studies are not consistently reported. Although some improvements were seen over time, reporting guidelines and online supplemental material may help enhance the transparency of this literature.

The role of testosterone in the pathogenesis of prostate cancer

Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.

An interlaboratory study of perfluorinated alkyl compound levels in human plasma

We conducted an interlaboratory study which differed from the typical study of this type because of its emphasis on comparing intralaboratory variability in results. We sent specimens to six laboratories experienced in the analysis of perfluorinated alkyl compounds in blood matrices and that use stringent procedures to control and assure accuracy and precision. Each received an identical set of 60 plasma specimens that were analyzed in six completely independent batches. Split specimens were included so that within- and between-batch coefficients of variation could be calculated. All laboratories used liquid chromatography–tandem mass spectrometry (LC–MS/MS). The concentrations of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS) measured in the specimens in general showed a high level of agreement, although in some cases the agreement was only moderate. The average within- and between-batch coefficient of variation for PFOS was 9.1% and 9.3%; for PFOA was 14.5% and 14.5%; and for PFHxS was 14.5% and 17.0%. The recent availability of labeled internal standards, among other advances, has facilitated improvement in the accuracy and precision of the assays. Considering the degree of between-subject variation in levels among people in background-exposed populations, the results indicate that biomarker-based epidemiologic studies of associations with health could have reasonable precision.

Genetic contributions to preterm birth: Implications from epidemiological and genetic association studies

Infants born before term (<37 weeks) have an increased risk of neonatal mortality as well as other health problems. The increasing rate of preterm birth in recent decades, despite improvements in health care, creates an impetus to better understand and prevent this disorder. Preterm birth likely depends on a number of interacting factors, including genetic, epigenetic, and environmental risk factors. Genetic studies may identify markers, which more accurately predict preterm birth than currently known risk factors, or novel proteins and/or pathways involved in the disorder. This review summarizes epidemiological and genetic studies to date, emphasizing the complexity of genetic influences on birth timing. While several candidate genes have been reportedly associated with the disorder, inconsistency across studies has been problematic. More systematic and unbiased genetic approaches are needed for future studies to examine the genetic etiology of human birth timing thoroughly.

High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort

Background: Epidemiologic studies of associations between folate intake and breast cancer are inconclusive, but folate and other plant food nutrients appear protective in women at elevated risk.Objective: The objective was to examine the association between folate intake and the incidence of postmenopausal breast cancer.Design: This prospective study included all women aged ≥50 y (n = 11699) from the Malmö Diet and Cancer cohort. The mean follow-up time was 9.5 y. We used a modified diet-history method to collect nutrient intake data. At the end of follow-up, 392 incident invasive breast cancer cases were verified. We used proportional hazard regression to calculate hazard ratios (HRs).Results: Compared with the lowest quintile, the incidence of invasive breast cancer was reduced in the highest quintile of dietary folate intake (HR: 0.56; 95% CI: 0.35, 0.90; P for trend = 0.02); total folate intake, including supplements (HR: 0.56; 95% CI: 0.34, 0.91; P for trend = 0.006); and dietary folate equivalents (HR: 0.59; 95% CI: 0.36, 0.97; P for trend = 0.01).Conclusion: A high folate intake was associated with a lower incidence of postmenopausal breast cancer in this cohort.