Malignant Disease in Children whose Mothers had Chickenpox,Mumps, or Rubella in Pregnancy

To test the hypothesis that leukaemia may follow virus infection in pregnancy an analysis was made of deaths which occurred in a cohort of children born in 1951 and 1952 after pregnancies in which the mothers suffered virus infections—chickenpox or mumps at any stage of gestation or rubella in the first 18 weeks. All deaths which occurred between the children''s second birthday and the end of 1971 were studied.Two deaths from leukaemia occurred among the children whose mothers suffered from chickenpox, a significant excess. There were no deaths from leukaemia among the other children, but the causes of the two deaths after maternal mumps—Ewing''s tumour and Still''s disease—are noted because of their rarity.     

Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study

Background

Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.

Methods and Findings

We used data from the Shanghai Women''s Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996–2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse''s smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44–0.74) for total mortality, 0.29 (0.16–0.54) for CVD mortality, and 0.76 (0.54–1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4–5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.

Conclusions

In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern—including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake—was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention. Please see later in the article for the Editors'' Summary     

Marital and Reproductive Histories of Women With Cancer of the Breast and Their Sisters

In a study of 45 pairs of sisters—each pair including one sister with cancer of the breast and one without the disease—differences in marital and reproductive histories were observed. These differences included less frequent marriage, later marriage, fewer children, and a longer delay between date of marriage and the first pregnancy in the sisters with the disease. These findings appear to confirm presently known reproductive risk factors for cancer of the breast, but they also raise the possibility that unknown behavioral factors influencing the endocrine system may be delaying marriage and pregnancy.     

Carcinoma of the Colon and Rectum: A Perspective for Practicing Physicians,with Recommendations for Screening

Carcinoma of the colon and rectum is the most common serious type of cancer found in the United States and is second only to lung cancer among causes of death from cancer. Its cause is unknown but several environmental factors—especially low bulk, high fat diets—seem to predispose to its development. The disease is readily treatable by surgical operation if it is diagnosed early. Radiation and chemotherapy may offer some additional benefit in treating advanced disease but the response to all forms of therapy is disappointing in patients in whom disease has spread beyond the bowel wall. Colorectal cancer appears to be a very slowly progressive disease with a long asymptomatic period providing an ideal opportunity for diagnosis at an early treatable stage. Both proctosigmoidoscopy and screening specimens of stool for occult blood have been shown to be effective methods for identifying it before symptoms develop. These procedures should be done routinely in all patients over 40 years old and especially in those patients who have other risk factors such as positive family histories or hereditary conditions known to predispose to colorectal cancer.     

Integrative analysis of clinical and epigenetic biomarkers of mortality

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome‐wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow‐up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry‐stratified meta‐analysis of all‐cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10⁻⁷, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm‐based prediction models for all‐cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C‐index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P _MR = 4.1 × 10⁻⁴) and negatively associated with longevity (Beta = −1.9, P _MR = 0.02). Pathway analysis revealed that genes associated with mortality‐related CpGs are enriched for immune‐ and cancer‐related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.     

Association of Matrix Metalloproteinase-3 -1171(5A>6A) Polymorphism with Cancer Risk: A Meta-Analysis of 41 Studies

Background and Objective

Evidence has shown that matrix metalloproteinases-3 (MMP3) is important for cancer progression. Recent studies about the association between the -1171(5A>6A) polymorphism in MMP3 promoter region and cancer risk have yielded conflicting results.

Methodology/Principal Findings

We performed a meta-analysis of 41 studies including 11112 cases and 11091 controls to determine whether the -1171(5A>6A) polymorphism of MMP3 was associated with cancer risk. We assessed the strength of association and performed sub-group analyses by cancer types, ethnicity, smoking status, genotyping method, source of controls and sample size. The pooled results revealed that no significant association of the -1171(5A>6A) polymorphism with overall cancer risk in any of four models. Further sub-group analysis revealed that individuals with the 6A allele had lower risk of gastrointestinal cancer in two models: heterozygote comparison (6A/5A vs. 5A/5A: OR = 0.74, 95%CI: 0.60—0.91; I² = 1.9%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR = 0.77, 95%CI: 0.64—0.94; I² = 29.0%). Additionally, the associations were significant in Asian populations for three models: homozygote comparison (6A/6A vs. 5A/5A, OR = 0.68, 95%CI: 0.52—0.90; I² = 26.7%), heterozygote comparison (6A/5A vs. 5A/5A: OR = 0.75, 95%CI: 0.58—0.98; I² = 0.0%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR = 0.69, 95%CI: 0.54—0.88; I² = 0.5%). It was noteworthy that we had a contrary finding in non-smokers: the variant 6A/6A homozygote might statistically increase cancer risk compared with 6A/5A+5A/5A genotype (OR = 1.92, 95%CI: 1.25—2.96; I² = 72.7%).

Conclusion

This meta-analysis suggests that the -1171(5A>6A) polymorphism in MMP3 promoter region is not associated with overall cancer risk, but it may contribute to decreased cancer risk in Asian population when compared with Caucasian population and significantly reduce the risk of gastrointestinal cancer.     

Predicting death in home care users: derivation and validation of the Risk Evaluation for Support: Predictions for Elder-Life in the Community Tool (RESPECT)

BACKGROUND:Prognostication tools that report personalized mortality risk and survival could improve discussions about end-of-life and advance care planning. We sought to develop and validate a mortality risk model for older adults with diverse care needs in home care using self-reportable information — the Risk Evaluation for Support: Predictions for Elder-Life in the Community Tool (RESPECT).METHODS:Using a derivation cohort that comprised adults living in Ontario, Canada, aged 50 years and older with at least 1 Resident Assessment Instrument for Home Care (RAI-HC) record between Jan. 1, 2007, and Dec. 31, 2012, we developed a mortality risk model. The primary outcome was mortality 6 months after a RAI-HC assessment. We used proportional hazards regression with robust standard errors to account for clustering by the individual. We validated this algorithm for a second cohort of users of home care who were assessed between Jan. 1 and Dec. 31, 2013. We used Kaplan–Meier survival curves to estimate the observed risk of death at 6 months for assessment of calibration and median survival. We constructed 61 risk groups based on incremental increases in the estimated median survival of about 3 weeks among adults at high risk and 3 months among adults at lower risk.RESULTS:The derivation and validation cohorts included 435 009 and 139 388 adults, respectively. We identified a total of 122 823 deaths within 6 months of a RAI-HC assessment in the derivation cohort. The mean predicted 6-month mortality risk was 10.8% (95% confidence interval [CI] 10.7%–10.8%) and ranged from 1.54% (95% CI 1.53%–1.54%) in the lowest to 98.1% (95% CI 98.1%–98.2%) in the highest risk group. Estimated median survival spanned from 28 days (11 to 84 d at the 25th and 75th percentiles) in the highest risk group to over 8 years (1925 to 3420 d) in the lowest risk group. The algorithm had a c-statistic of 0.753 (95% CI 0.750–0.756) in our validation cohort.INTERPRETATION:The RESPECT mortality risk prediction tool that makes use of readily available information can improve the identification of palliative and end-of-life care needs in a diverse older adult population receiving home care.

Most people in high-income countries die of causes with progressive, predictable trajectories of decline.^1–4 Since 2000, the 3 leading causes of death in Canada — accounting for 55% of all deaths — have been cancer, heart disease and stroke.¹ Other leading causes of death, such as dementia and chronic lower respiratory diseases, also share signs and symptoms of senescence that are common across chronic diseases, including deterioration of physical and cognitive function, as well as an increased need for assistance.Despite the predictable nature of most deaths, many Canadian residents who are at the end of life do not receive adequate home-based supports.⁵ In Ontario — the largest province in Canada with more than 14 million residents and the setting of this study — only 40% of decedents receive formal home care, and less than 20% receive a physician home visit in their last year of life.^6,7 Even among those who had received palliative and end-of-life care, the start of service was often too close to death and failed to have a positive impact on the quality of life in those last months.⁸ The lack of available and accurate prognostic information is a key challenge. There are few existing tools that can be used to inform palliative care planning for the general population of older adults who live in the community and in people without cancer.⁹ Other barriers to accurate prognostic estimates include clinicians’ reluctance or lack of time and existing prognostication tools’ reliance on complex or specialized inputs, such as laboratory data and previous health care use. As a result, many older and frail adults do not receive timely palliative care and do not have an advance care plan.^6,10–13Our primary objective was to develop and validate a model for predicting mortality risk among the general population of community-dwelling adults with and without cancer that spans an actionable period for end-of-life planning (5 yr to imminent death). The variables included in our prognostication model — the Risk Evaluation for Support: Predictions for Elder-life in the Community Tool (RESPECT) — were prespecified to include exposures that could be self-reported by patients and their caregivers, including family members.     

Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts

Background

Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men''s smoking prevalence is among the world''s highest.

Methods and Findings

We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia''s total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.

Conclusions

Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors'' Summary     

Epithelial cell plasticity: breaking boundaries and changing landscapes

Epithelial tissues respond to a wide variety of environmental and genotoxic stresses. As an adaptive mechanism, cells can deviate from their natural paths to acquire new identities, both within and across lineages. Under extreme conditions, epithelial tissues can utilize “shape‐shifting” mechanisms whereby they alter their form and function at a tissue‐wide scale. Mounting evidence suggests that in order to acquire these alternate tissue identities, cells follow a core set of “tissue logic” principles based on developmental paradigms. Here, we review the terminology and the concepts that have been put forward to describe cell plasticity. We also provide insights into various cell intrinsic and extrinsic factors, including genetic mutations, inflammation, microbiota, and therapeutic agents that contribute to cell plasticity. Additionally, we discuss recent studies that have sought to decode the “syntax” of plasticity—i.e., the cellular and molecular principles through which cells acquire new identities in both homeostatic and malignant epithelial tissues—and how these processes can be manipulated for developing novel cancer therapeutics.     

Incidence,prevalence, mortality,disability-adjusted life years and risk factors of cancer in Australia and comparison with OECD countries, 1990–2015: findings from the Global Burden of Disease Study 2015

BackgroundComparative evidence on the burden, trend, and risk factors of cancer is limited. Using data from the Global Burden of Disease (GBD) study, we aimed to assess cancer burden – incidence, prevalence, mortality, disability-adjusted life years (DALYs) – and attributable risk factors for Australia between 1990 and 2015, and to compare them with those of 34 members of the Organisation for Economic Co-operation and Development (OECD).MethodsThe general GBD cancer estimation methods were used with data input from vital registration systems and cancer registries. A comparative risk assessment approach was used to estimate the population-attributable fractions due to risk factors.ResultsIn 2015 there were 198,880 (95% uncertainty interval [UI]: 183,908–217,365) estimated incident cancer cases and 47,562 (95% UI: 46,061–49,004) cancer deaths in Australia. Twenty-nine percent (95% UI: 28.2–29.8) of total deaths and 17.0% (95% UI: 15.0–19.1) of DALYs were caused by cancer in Australia in 2015. Cancers of the trachea, bronchus and lung, colon and rectum, and prostate were the most common causes of cancer deaths. Thirty-six percent (95% UI: 33.1–37.9) of all cancer deaths were attributable to behavioral risks. The age-standardized cancer incidence rate (ASIR) increased between 1990 and 2015, while the age-standardized cancer death rate (ASDR) decreased over the same period. In 2015, compared to 34 other OECD countries Australia ranked first (highest) and 24^th based on ASIR and ASDR, respectively.ConclusionThe incidence of cancer has increased over 25 years, and behavioral risks are responsible for a large proportion of cancer deaths. Scaling up of prevention (using strategies targeting cancer risk factors), early detection, and treatment of cancer is required to effectively address this growing health challenge.     

Goals for California Against Cancer

Assuming that present trends continue, about 30,000 persons in California will be dying from cancer each year by the early 1970''s. This expectation takes into account both changes in the size and other characteristics of the population, and changes in cancer mortality rate—increases in some sites and decreases in others, according to the 1950-1960 trends.On the other hand, if everything now known to avoid cancer deaths were actually done, conservative estimation indicates that each year at least 7,500 of the 30,000 expected cancer deaths (based on the trends of 1950-1960 and taking into account present accomplishment as well as failure) would not occur. Possibly many more deaths could be avoided.     

The blood metabolome of incident kidney cancer: A case–control study nested within the MetKid consortium

BackgroundExcess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and findingsWe assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case–control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10⁻⁸). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10⁻⁵), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some—but not all—metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., −0.17 SD change [ß_BMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10⁻⁵). BMI was also associated with increased levels of glutamate (ß_BMI: 0.12, p = 1.5 × 10⁻³). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.ConclusionsThis study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI—the principal modifiable risk factor of kidney cancer.

In a case-control study, Florence Guida and colleagues identify metabolites associated with risk of kidney cancer, and use Mendelian randomization techniques to study the role of body mass index in this relationship.     

Anti-Cancer Vaccines — A One-Hit Wonder?

Immunization against common bacterial and viral diseases has helped prevent millions of deaths worldwide. More recently, the concept of vaccination has been developed into a potentially novel strategy to treat and prevent cancer formation, progression, and spread. Over the past few years, a handful of anti-cancer vaccines have been licensed and approved for use in clinical practice, thus providing a breakthrough in the field. However, the path has not always been easy, with many hurdles that have had to be overcome in order to reach this point. Nevertheless, with more anti-cancer vaccines currently in development, there is still hope that they can eventually become routine tools used in the treatment and prevention of cancer in the future. This review will discuss in detail both types of anti-cancer vaccine presently used in clinical practice — therapeutic and preventive — before considering some of the more promising anti-cancer vaccines that are currently in development. Finally, the issue of side effects and the debate surrounding the overall cost-effectiveness of anti-cancer vaccines will be examined.     

Proportion of cancer cases and deaths attributable to lifestyle risk factors in Brazil

BackgroundLifestyle risk factors (tobacco smoking, alcohol consumption, overweight and obesity, unhealthy diet, and lack of physical activity) have been associated with increased risk of at least 20 types of cancer. We estimated the proportion of cancer cases and deaths that could be potentially avoided by eliminating or reducing lifestyle risk factors in Brazil.MethodsWe obtained the distribution of lifestyle risk factors by sex and age groups from recent representative health surveys in Brazil; relative risks from pooled analyses of prospective studies and meta-analyses; and cancer cases and deaths in 2012 from GLOBOCAN.ResultsWe found that 26.5% (114,497 cases) of all cancer cases and 33.6% (63,371 deaths) of all cancer deaths could be potentially avoided by eliminating lifestyle risk factors in Brazil. Plausible reductions in these exposures based on policy targets and cancer prevention recommendations could have potentially avoided 4.5% (19,731 cases) and 6.1% (11,480 deaths) of all cancer cases and deaths, respectively. Tobacco smoking accounted for most of the preventable cancer cases and deaths, followed by high body mass index and alcohol consumption. Larynx, lung, oropharynx, esophagus and colorectum cancer cases and deaths could be at least halved by eliminating these lifestyle risk factors.ConclusionFindings from this study may be useful to inform strategies for cancer prevention and control across Brazil.     

Genetic Factors Are Not the Major Causes of Chronic Diseases

The risk of acquiring a chronic disease is influenced by a person’s genetics (G) and exposures received during life (the ‘exposome’, E) plus their interactions (G×E). Yet, investigators use genome-wide association studies (GWAS) to characterize G while relying on self-reported information to classify E. If E and G×E dominate disease risks, this imbalance obscures important causal factors. To estimate proportions of disease risk attributable to G (plus shared exposures), published data from Western European monozygotic (MZ) twins were used to estimate population attributable fractions (PAFs) for 28 chronic diseases. Genetic PAFs ranged from 3.4% for leukemia to 48.6% for asthma with a median value of 18.5%. Cancers had the lowest PAFs (median = 8.26%) while neurological (median = 26.1%) and lung (median = 33.6%) diseases had the highest PAFs. These PAFs were then linked with Western European mortality statistics to estimate deaths attributable to G for heart disease and nine cancer types. Of 1.53 million Western European deaths in 2000, 0.25 million (16.4%) could be attributed to genetics plus shared exposures. Given the modest influences of G-related factors on the risks of chronic diseases in MZ twins, the disparity in coverage of G and E in etiological research is problematic. To discover causes of disease, GWAS should be complemented with exposome-wide association studies (EWAS) that profile chemicals in biospecimens from incident disease cases and matched controls.     

Causes of death in men with prostate cancer: Results from the Danish Prostate Cancer Registry (DAPROCAdata)

BackgroundCurrent knowledge of the validity of registry data on prostate cancer-specific death is limited. We aimed to determine the underlying cause of death among Danish men with prostate cancer, to estimate the level of misattribution of prostate cancer death, and to examine the risk of death from prostate cancer when accounting for competing risk of death.Material and methodsWe investigated a nationwide cohort of 15,878 prostate cancer patients diagnosed in 2010–2014; with 3343 deaths occurring through 2016. Blinded medical chart review was carried out for 670 deaths and compared to the national cause of death registry. Five death categories were defined: 1) prostate cancer-specific death, 2) other unspecified urological cancer death, 3) other cancer death 4) cardiovascular disease death, and 5) other causes of death. Competing risk analyses compared Cox cause-specific and Fine-Gray regression models.ResultsChart review attributed 51.2% of deaths to prostate cancer, 17.0% to cardiovascular disease, and 16.7% to other causes. The Danish Register of Causes of Death attributed 71.7% of deaths to prostate cancer when including all registered contributing causes of death, and 57.0% of deaths when including only the primary registered cause of death. The probability of death by prostate cancer was 10% at 2-year survival.ConclusionsMore than half of the deceased men in our study cohort died of their prostate cancer disease within a mean of 2.4 years of follow up. Data from the death registry is prone to misclassification, potentially overestimating the proportion of deaths from prostate cancer.     

Genetic Association Analysis of Complex Diseases Incorporating Intermediate Phenotype Information

Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24–25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs—rs1800469, rs1982072, and rs2241714—in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46×10⁻⁵, 1.18×10⁻⁵, and 6.57×10⁻⁶, respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis.     

Some Social and Forensic Aspects of Exhumation and Reinterment of Industrial Revolution Remains

The aetiological aspects of exhumed remains from two burial sites were examined using 1839 and 1879 as years of comparison. We tried to discover whether the sample of recovered remains was representative of those buried. The state of the remains varied according to the type of soil and coffin material in which they were buried. At the earlier date most deaths were caused by infectious lesions rather than degenerative ones and 76% of those who died were below employable age—whereas in 1879 the commonest causes of death were tuberculosis (“phthisis”) and bronchitis, and 42% died before they could be employed. The registration of deaths were recorded more accurately at the later date, and it was easier to build up a picture of the age, sex, and occupation of the people who died.     

Risk factors for premature death in middle aged men

The causes of premature death and the associated risk factors were analysed in a cohort of 7935 middle aged men participating in a preventive population programme in Malmö. They were screened when aged 46-48 and then followed up for 3½-8 years. Two hundred and eighteen died, of whom 181 (83%) underwent necropsy. Three major causes of death were established: cancer in 61 (28%), deaths related to consumption of alcohol in 55 (25%), and coronary heart disease in 50 (23%).Distinctly different patterns of risk factors were found to be associated with each of the three main causes of premature death. In death due to coronary heart disease smoking (p=0·0062), serum cholesterol concentration (p=0·00014), serum triglyceride concentration (p=0·00013), systolic blood pressure (p=0·000012), and diastolic blood pressure (p=0·0021) were the strongest single determinants but diastolic blood pressure ceased to be a predictive factor in a multivariate analysis whereas all the other variables could be combined in a highly predictive logistic model. In death related to consumption of alcohol equal or even stronger associations were found for serum γ glutamyltransferase activity (p<0·0001), points scored in a questionnaire screening for alcoholism (p<0·0001), and, inversely, serum cholesterol (p=0·0046) and serum creatinine (p<0·0001) concentrations both when applied independently and when combined in a logistic model. In death due to cancer significant associations were found for serum urate concentration (p=0·023) and, inversely, serum cholesterol concentration (p=0·056-0·031).Malignant diseases and diseases related to consumption of alcohol were at least as prominent as cardiovascular disorders in causing premature death in the cohort of men studied. All three types of conditions are potentially avoidable and seem to be associated with significant and distinctive patterns of risk factors. These patterns should be used, as blood pressure and serum lipid concentrations already are, to predict the risk of premature death and indicate preventive measures.