Perspective: Young Workers at Higher Risk for Carcinogen Exposures.

Young workers, those under the age of 25, are considered a vulnerable working population, primarily due to their increased risk of injury. In this study we investigate if young workers may also be at an increased risk for occupational exposure to carcinogens. Using the 2006 and 2016 Canadian Census of Population and previously obtained CAREX Canada data, this study aimed to identify sectors and occupations that have high proportions of young workers and where potential exists for exposure to known and suspected carcinogens. Key groups where young workers are likely at a higher risk for occupational exposure to carcinogens were identified. Our work shows that young workers in construction, outdoor occupations, and farming are key groups that warrant further investigation. These specific groups are highlighted because of the large number of young workers employed in these sectors/situations, the high number of possible carcinogen exposures, and the potential for higher risk behavior patterns that typically occur in these types of jobs. While there is no data available to develop carcinogen exposure estimates specific to young workers, it is our perspective that young workers are likely at a higher risk for occupational exposure to carcinogens. Our findings identify opportunities to improve the occupational health and safety for this vulnerable population, particularly for young construction workers, farm workers, and outdoor workers.

A scoping review of risk factors and transmission routes associated with human giardiasis outbreaks in high-income settings.

The flagellated pathogen Giardia duodenalis is one of the leading causes of parasitic gastrointestinal illness worldwide. In many higher income countries, such as the United Kingdom, the disease is often perceived as being travel-related, likely leading to the under-reporting of sporadic cases and outbreaks. A summary of the literature describing outbreaks and risk factors in higher income countries is necessary to improve our understanding of this pathogen and identify existing knowledge gaps. Initial literature searches were carried out in September 2016 and updated at regular intervals until November 2021, using appropriate search terms in Medline, Embase and PubMed databases. A total of 75 papers met the inclusion criteria, revealing that the consumption of contaminated water and contact with young children of diaper-wearing age were the most common transmission routes leading to outbreaks of giardiasis. Of the ten studies where food was primarily associated with outbreaks, food handlers accounted for eight of these. Another reported transmission route was direct contact with fecal material, which was reported in six studies as the primary transmission route. Travel-associated giardiasis was considered the sole transmission route in two studies, whereas multiple transmission routes contributed to giardiasis outbreaks in eleven studies. The evidence around zoonotic transmission was less clear and hampered by the lack of robust and regularly applied parasite molecular typing techniques. This literature review summarizes the findings of Giardia outbreak investigations and epidemiological studies in high-income countries. Transmission routes are identified and discussed to highlight the associated risk factors. These data also indicate gaps in our current knowledge that include the need for robust, in-depth molecular studies and have underscored the importance of water as a transmission route for Giardia cysts. These future molecular studies will improve our understanding of Giardia epidemiology and transmission pathways in higher income countries to prevent spread of this significantly under-reported pathogen.

Cancer and the Environment projects with four First Nations organizations: working together to address concerns about carcinogens in the environment.

SETTING: For First Nations people, human health and well-being are interconnected with a healthy environment. First Nations organizations commonly raise concerns regarding carcinogens in the environment; however, few case studies are available as guidance for working in a participatory and respectful way to help assess and address these concerns. INTERVENTION: Through four community-led pilot projects executed over two years, we collaborated with 15 participants from four First Nations organizations across four provinces to identify concerns related to environmental carcinogens and to address those concerns through an integrated knowledge translation (KT) approach. We co-developed and implemented strategic KT plans for each pilot project, and conducted evaluation surveys and interviews with participants at multiple time points to assess process, progress, barriers and facilitators, and impact. OUTCOMES: The activities and outputs of the pilot projects are available at www.carexcanada.ca . Participants identified 18 concerns, and we co-developed 24 knowledge products. Tailored fact sheets for communities and briefing notes for leadership were deemed most useful; interactive maps were deemed less useful. Evaluation indicated that the collaborative projects were effective in addressing the concerns raised regarding exposures to carcinogens. IMPLICATIONS: The participant-led approach and multi-year funding to support capacity enhancement and face-to-face engagement were facilitators to project success. However, participants did face important barriers to collaborate which should be considered in future projects of this kind: the most important being a lack of resources (people and time), given competing and often more urgent priorities.

RéSUMé: LIEU: Pour les Premiers Peuples, la santé et le bien-être humains sont indissociables de la santé de l'environnement. Les organismes des Premières Nations se disent souvent préoccupés par les cancérogènes présents dans l'environnement, mais peu d'études de cas sont disponibles pour apprendre à travailler de façon participative et respectueuse à évaluer ces préoccupations et à y répondre. INTERVENTION: Dans le cadre de quatre projets pilotes de proximité menés sur une période de deux ans, nous avons collaboré avec 15 participants, issus de quatre organismes des Premières Nations dans quatre provinces, à cerner leurs préoccupations liées aux cancérogènes dans l'environnement et à y répondre selon une démarche intégrée d'application des connaissances. Nous avons conjointement élaboré et mis en œuvre des plans stratégiques d'application des connaissances pour chaque projet pilote et mené des sondages d'évaluation et des entretiens avec les participants à plusieurs reprises pour évaluer le processus, les progrès accomplis, les éléments favorables et défavorables et les impacts des projets. RéSULTATS: Les activités et les extrants des projets pilotes sont présentés sur le site www.carexcanada.ca . Les participants ont exprimé 18 motifs de préoccupation, et nous avons élaboré avec eux 24 produits du savoir. Les fiches d'information adaptées à chaque communauté et les notes d'information pour les dirigeants ont été jugées très utiles, mais les cartes interactives un peu moins. Selon l'évaluation, les projets collaboratifs ont réussi à répondre aux préoccupations soulevées quant à l'exposition aux cancérogènes. CONSéQUENCES: La démarche axée sur les participants et le financement pluriannuel consacré au renforcement des capacités et aux contacts directs ont été des éléments favorables à la réussite des projets. Par contre, les participants ont fait face à d'importants obstacles à la collaboration dont il faudrait tenir compte dans les futurs projets de la sorte, le principal obstacle étant le manque de ressources (personnes et temps), étant donné l'existence de priorités concurrentes et souvent plus urgentes.

Barriers and facilitators for the safe handling of antineoplastic drugs.

INTRODUCTION: Antineoplastic drugs are widely used in the treatment of cancer. However, some are known carcinogens and reproductive toxins, and incidental low-level exposure to workers is a health concern. CAREX Canada estimated that approximately 75,000 Canadians are exposed to antineoplastic drugs in workplace settings. While policies and guidelines on safe handling of antineoplastic drugs are available, evidence suggests that compliance is low. In this paper, we identify barriers and facilitators for safe handling of antineoplastic drugs in workplace settings. METHODS: We utilized a unique method to study public policy which involved compiling policy levers, developing a logic model, conducting a literature review, and contextualizing data through a deliberative process with stakeholders to explore in-depth contextual factors and experiences for the safe handling of antineoplastic drugs. RESULTS: The most common barriers identified in the literature were: poor training (46%), poor safety culture (41%), and inconsistent policies (36%). The most common facilitators were: adequate safety training (41%), leadership support (23%), and consistent policies (21%). Several of these factors are intertwined and while this means one barrier can cause other barriers, it also allows healthcare employers to mitigate these barriers by implementing small but meaningful changes in the workplace. CONCLUSION: The combination of barriers and facilitators identified in our review highlight the importance of creating work environments where safety is a priority for the safe handling of antineoplastic drugs. The results of this study will assist policy makers and managers in identifying gaps and enhancing strategies that reduce occupational exposure to antineoplastic drugs.

Screening-level assessment of cancer risk associated with ambient air exposure in Aamjiwnaang First Nation.

The manuscript reports findings from a screening-level assessment of cancer risk from outdoor air in Aamjiwnaang First Nation. Ambient air pollution can contribute to cardiovascular/respiratory diseases, and certain types of cancer. Certain communities may be at higher risk to the negative health impacts due to their geographical proximity to pollution sources. Outdoor air concentrations were mapped and the Lifetime Excess Cancer Risks (LECR) associated with long-term exposure to known carcinogens were estimated. LECR results for both benzene and 1,3-butadiene were above one per million. The LECR for benzene was 6.4 per million when the Health Canada slope factor was applied and 12.0 when using the US EPA. For 1,3-butadiene the LECR estimate was 8.8 per million. This work provides a better understanding of environmental exposures and potential associated cancer risks for residents in the Aamjiwnaang community and highlights the need for further air monitoring and a more detailed risk assessment.

Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.

BACKGROUND: The objective of this study was to investigate the relation of severe COVID-19 to prior drug prescribing. METHODS: Severe cases were defined by entry to critical care or fatal outcome. For this matched case-control study (REACT-SCOT), all 4251 cases of severe COVID-19 in Scotland since the start of the epidemic were matched for age, sex and primary care practice to 36,738 controls from the population register. Records were linked to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. RESULTS: Severe COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in a care home, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.8, 13.3), and in those without any of the conditions designated as conferring increased risk of COVID-19. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19 and these associations were present in those without any of the designated risk conditions. The fraction of cases in the population attributable to exposure to these drug classes was 38%. The largest effect was for antipsychotic agents: rate ratio 4.18 (3.42, 5.11). Other drug classes with large effects included proton pump inhibitors (rate ratio 2.20 (1.72, 2.83) for = 2 defined daily doses/day), opioids (3.66 (2.68, 5.01) for = 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates and were stronger with recent than with non-recent exposure. CONCLUSIONS: Severe COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression, or dyskinesia; have anticholinergic effects; or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Measures to reduce the burden of mortality and morbidity from COVID-19 should include reinforcing existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy. REGISTRATION: ENCEPP number EUPAS35558.

An update on the incidence of human giardiasis in Scotland, 2011-2018.

BACKGROUND: Giardia duodenalis is one of the most common parasites in the UK to cause diarrhoeal illness. Giardiasis is likely to be significantly under-reported in the UK as laboratory testing is largely based on examining stool samples from individuals with a recent travel history. This results in the majority of locally-acquired cases going undetected. To increase awareness of giardiasis, we describe data gathered from cases reported within Scotland during 2011-2018. METHODS: All of the 21 Scottish National Health Service (NHS) diagnostic microbiology laboratories performed microscopy examination to detect Giardia cysts in stools, from mostly travel-related cases. The exception was one laboratory that implemented an antigen-based enzyme immunoassay in 2015. This resulted in every submitted stool being tested for Giardia. Laboratory-confirmed cases of giardiasis were reported to Health Protection Scotland (HPS) via the Electronic Communication of Surveillance in Scotland (ECOSS) during the eight-year period. Data for calculating the incidence per 100,000 of the population were obtained from the National Records of Scotland mid-2018 population estimates in Scotland. RESULTS: A total of 1631 Scottish cases were reported during 2011-2018 (8-year mean: 204; range: 166-269). National Health Service Grampian, Borders and Lothian reported the highest incidence of Giardia (9.8, 7.5 and 6.7 per 100,000, respectively), all of which were above the Scottish mean incidence (3.8 per 100,000). Following the implementation of antigen testing in NHS Grampian during 2015, reports significantly increased 3.6-fold (P = 0.005). The highest incidence of giardiasis occurred in the 20-49 years age group (mean 5.4 per 100,000). Of interest, the mean incidence of giardiasis was significantly higher in males than in females (4.8 versus 3.1 per 100,000, respectively; P < 0.0001). CONCLUSIONS: This report highlights the need to capture enhanced information on every laboratory-confirmed case of giardiasis to gain a better understanding of the local sources and transmission pathways occurring in Scotland. In addition, implementing sensitive, automated technologies across UK NHS diagnostic microbiology laboratories to permit the efficient, routine testing of every submitted stool for Giardia, should be encouraged to ensure all cases are identified and treated appropriately.

Hepatitis A-2017 an unusual year in Scotland.

BACKGROUND: The number of cases of acute hepatitis A reported in Scotland each year is small, and the majority of cases have been associated with travel to endemic regions. However, in early 2017, in the midst of ongoing outbreaks of hepatitis A among MSM in Europe, there was a sharp rise in the number of cases reported to Health Protection Scotland. OBJECTIVES: The initial aim of this study was to investigate the reason for the observed increase in cases of hepatitis A at the start of 2017. As cases continued for the remainder of the year, these cases were typed to determine whether these cases were linked to each other, or other outbreaks. STUDY DESIGN: The study population consisted of 42 hepatitis A infected patients with no obvious source of infection. The patient samples were collected between January and December 2017. The VP1/2 A region was amplified and sequenced. RESULTS: The majority of samples typed as genotype 1 A (n = 17) or genotype 1B (n = 15). Within genotype 1 A, fifteen samples had strains (VRD_521_2016 or RIVM_HAV16_090) associated with ongoing outbreaks of hepatitis A in MSM in Europe. Within genotype 1B, there were four clusters of infections, with identical cases in geographically distinct regions with no identified epidemiological link. CONCLUSIONS: Molecular typing proved useful, as it allowed public health to identify clusters, establish links with other outbreaks and compare Scottish strains with those reported elsewhere.

BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004).

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a significant risk of recurrence despite adjuvant intravesical therapy. OBJECTIVE: To determine whether celecoxib, a cyclo-oxygenase 2 inhibitor, reduces the risk of recurrence in NMIBC patients receiving standard treatment. DESIGN, SETTING, AND PARTICIPANTS: BOXIT (CRUK/07/004, ISRCTN84681538) is a double-blinded, phase III, randomised controlled trial. Patients aged ≥18 yr with intermediate- or high-risk NMIBC were accrued across 51 UK centres between 1 November 2007 and 23 July 2012. INTERVENTION: Patients were randomised (1:1) to celecoxib 200mg twice daily or placebo for 2 yr. Patients with intermediate-risk NMIBC were recommended to receive six weekly mitomycin C instillations; high-risk NMIBC cases received six weekly bacillus Calmette-Guérin and maintenance therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was time to disease recurrence. Analysis was by intention to treat. RESULTS AND LIMITATIONS: A total of 472 patients were randomised (236:236). With median follow-up of 44 mo (interquartile range: 36-57), 3-yr recurrence-free rate (95% confidence interval) was as follows: celecoxib 68% (61-74%) versus placebo 64% (57-70%; hazard ratio [HR] 0.82 [0.60-1.12], p=0.2). There was no difference in high-risk (HR 0.77 [0.52-1.15], p=0.2) or intermediate-risk (HR 0.90 [0.55-1.48], p=0.7) NMIBC. Subgroup analysis suggested that time to recurrence was longer in pT1 NMIBC patients treated with celecoxib compared with those receiving placebo (HR 0.53 [0.30-0.94], interaction test p=0.04). The 3-yr progression rates in high-risk patients were low: 10% (6.5-17%) and 9.7% (6.0-15%) in celecoxib and placebo arms, respectively. Incidence of serious cardiovascular events was higher in celecoxib (5.2%) than in placebo (1.7%) group (difference +3.4% [-0.3% to 7.2%], p=0.07). CONCLUSIONS: BOXIT did not show that celecoxib reduces the risk of recurrence in intermediate- or high-risk NMIBC, although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib. PATIENT SUMMARY: Celecoxib was not shown to reduce the risk of recurrence in intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC), although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib.

Priority Setting for Occupational Cancer Prevention.

BACKGROUND: Selecting priority occupational carcinogens is important for cancer prevention efforts; however, standardized selection methods are not available. The objective of this paper was to describe the methods used by CAREX Canada in 2015 to establish priorities for preventing occupational cancer, with a focus on exposure estimation and descriptive profiles. METHODS: Four criteria were used in an expert assessment process to guide carcinogen prioritization: (1) the likelihood of presence and/or use in Canadian workplaces; (2) toxicity of the substance (strength of evidence for carcinogenicity and other health effects); (3) feasibility of producing a carcinogen profile and/or an occupational estimate; and (4) special interest from the public/scientific community. Carcinogens were ranked as high, medium or low priority based on specific conditions regarding these criteria, and stakeholder input was incorporated. Priorities were set separately for the creation of new carcinogen profiles and for new occupational exposure estimates. RESULTS: Overall, 246 agents were reviewed for inclusion in the occupational priorities list. For carcinogen profile generation, 103 were prioritized (11 high, 33 medium, and 59 low priority), and 36 carcinogens were deemed priorities for occupational exposure estimation (13 high, 17 medium, and 6 low priority). CONCLUSION: Prioritizing and ranking occupational carcinogens is required for a variety of purposes, including research, resource allocation at different jurisdictional levels, calculations of occupational cancer burden, and planning of CAREX-type projects in different countries. This paper outlines how this process was achieved in Canada; this may provide a model for other countries and jurisdictions as a part of occupational cancer prevention efforts.

Tuberculosis in healthcare workers, Scotland.

In an attempt to explore healthcare worker acquisition of tuberculosis infection, we conducted population-based surveillance of all cases recorded as healthcare workers reported to Enhanced Surveillance of Mycobacterial Infection from 2000 to 2015. Over the study period, the mean incidence rate of tuberculosis among all healthcare workers was 15.4 per 100,000 healthcare workers. However, the incidence rate of tuberculosis amongst those healthcare workers born outside the UK was 164.8 per 100,000 compared with 5.0 per 100,000 UK-born healthcare workers. Fifty-seven per cent of all non-UK-born healthcare workers were diagnosed within five years of their arrival in the UK and would have been new entrants to the NHS. An effective new entrant occupational health screening programme for latent tuberculosis infection may have prevented some of these active cases of infection.

Insidious Risk of Severe Mycobacterium chimaera Infection in Cardiac Surgery Patients.

BACKGROUND: An urgent UK investigation was launched to assess risk of invasive Mycobacterium chimaera infection in cardiothoracic surgery and a possible association with cardiopulmonary bypass heater-cooler units following alerts in Switzerland and The Netherlands. METHODS: Parallel investigations were pursued: (1) identification of cardiopulmonary bypass-associated M. chimaera infection through national laboratory and hospital admissions data linkage; (2) cohort study to assess patient risk; (3) microbiological and aerobiological investigations of heater-coolers in situ and under controlled laboratory conditions; and (4) whole-genome sequencing of clinical and environmental isolates. RESULTS: Eighteen probable cases of cardiopulmonary bypass-associated M. chimaera infection were identified; all except one occurred in adults. Patients had undergone valve replacement in 11 hospitals between 2007 and 2015, a median of 19 months prior to onset (range, 3 months to 5 years). Risk to patients increased after 2010 from <0.2 to 1.65 per 10000 person-years in 2013, a 9-fold rise for infections within 2 years of surgery (rate ratio, 9.08 [95% CI, 1.81-87.76]). Endocarditis was the most common presentation (n = 11). To date, 9 patients have died. Investigations identified aerosol release through breaches in heater-cooler tanks. Mycobacterium chimaera and other pathogens were recovered from water and air samples. Phylogenetic analysis found close clustering of strains from probable cases. CONCLUSIONS: We identified low but escalating risk of severe M. chimaera infection associated with heater-coolers with cases in a quarter of cardiothoracic centers. Our investigations strengthen etiological evidence for the role of heater-coolers in transmission and raise the possibility of an ongoing, international point-source outbreak. Active management of heater-coolers and heightened clinical awareness are imperative given the consequences of infection.

Outbreak of Neisseria meningitidis capsular group W among scouts returning from the World Scout Jamboree, Japan, 2015.

The 23rd World Scout Jamboree was held in Japan from 28 July to 8 August 2015 and was attended by over 33,000 scouts from 162 countries. An outbreak of invasive meningococcal disease capsular group W was investigated among participants, with four confirmed cases identified in Scotland, who were all associated with one particular scout unit, and two confirmed cases in Sweden; molecular testing showed the same strain to be responsible for illness in both countries. The report describes the public health action taken to prevent further cases and the different decisions reached with respect to how wide to extend the offer of chemoprophylaxis in the two countries; in Scotland, chemoprophylaxis was offered to the unit of 40 participants to which the four cases belonged and to other close contacts of cases, while in Sweden chemoprophylaxis was offered to all those returning from the Jamboree. The report also describes the international collaboration and communication required to investigate and manage such multinational outbreaks in a timely manner.

The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls.

AIMS: Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A(1), the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear. METHODS AND RESULTS: Case-control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA(1) than to HDL-C. The ratio apoB/apoA(1) was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8-9.2)] and varied little with age. The ratio apoB/apoA(1) was substantially more informative about risk (chi(1)(2) = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (chi(1)(2) = 407, 334, 204, and 105, respectively). Given apoB and apoA(1), the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA(1) and pre-onset HDL-C with risk in such retrospective case-control studies. CONCLUSION: Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.

Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-alpha (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.

Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'.

BACKGROUND: Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position -148 in the beta-fibrinogen gene promoter (beta - 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question. METHODS: Genotyping and measurement of blood fibrinogen concentration were carried out in 4,685 cases of confirmed MI and 3,460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12,220 coronary disease cases and 18,716 controls was conducted. RESULTS: Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case-control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14-1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A(1) ratio, this risk ratio fell to 1.03 (95% CI 1.00-1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96-1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95-1.04) per allele in the meta-analysis. CONCLUSIONS: Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk.

Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E epsilon2/epsilon3/epsilon4 genotype.

Results from two small studies, involving a total of only 174 cases, have suggested that the increased risk of coronary heart disease conferred by cigarette smoking is substantially affected by genotype at the apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism. We have established APOE genotypes in 4484 patients with acute myocardial infarction diagnosed before the age of 55 years for male and 65 years for female patients, and in 5757 controls with no history of cardiovascular disease. On average, the hazard ratio for myocardial infarction was 1.17 (95% CI 1.09-1.25; p<0.00001) per stepwise change from epsilon3/2 to epsilon3/3 to epsilon3/4 genotype. Among individuals in this study with known cigarette smoking status, the hazard ratio for myocardial infarction in smokers versus non-smokers was 4.6 (4.2-5.1). There was, however, no significant difference between the smoker/non-smoker hazard ratios for those with different APOE genotypes (chi2(2)=0.69; p=0.7). When differences in risk between different genotypes are not extreme (as with this APOE polymorphism), reliable assessment of hypothesised gene-environment interactions will often require the study of many thousands of disease cases.