International HundredK+ Cohorts Consortium (IHCC)

Project Leads: Dr. David Hughes, Conway Institute, University College Dublin (UCD), Dublin, Ireland; Dr. Mazda Jenab, Section of Nutrition and Metabolism, WHO/International Agency for Research on Cancer (IARC), Lyon, France. Co-applicant: Prof Veronika Fedirko, Rollins School of Public Health, Emory University, Atlanta, GA, USA

Project Description:

Worldwide heterogeneity in cancer incidence suggests the aetiological involvement of modifiable risk factors, such as obesity (16;17). Obesity, overweight duration, and weight gain in adulthood are each associated to increased cancer risks, particularly of obesity-related cancers such as colorectal cancer (CRC)(2;10;18-20). Early life exposures appear to impact obesity in adulthood, and a concomitant influence on cancer incidence is plausible. For example, dramatic increases in CRC incidence observed at younger ages in many world regions(21), may relate to early life exposures and higher obesity rates in younger generations(22). However, this link is not established, and few studies have attempted to assess life-course obesity exposures in cancer aetiology by consideration of genetic predisposition. Both adult- and child-hood obesity have strong and partially overlapping genetic determinants, whereas those for infant obesity may be somewhat distinct (23). Diverse genetic factors for obesity through life stages infers different metabolic processes in early- versus later-life that may underlie adiposity and cancer development in adulthood. We aim to assess whether life course specific genetic markers of obesity influence CRC development.

We hypothesize that varying obesogenic inherited predisposition in early- and later-life stages will differentially impact risk of CRC and possibly earlier-onset disease. Our main objective is to explore these associations using existing genetic, anthropometric and cancer incidence data from available and relevant IHCC cohorts. Agreement to participate has been obtained from UK Biobank (UKBB), theEuropean Prospective Investigation of Cancer and Nutrition (EPIC), and the large, international Genetics and Epidemiology of CRC consortium (GECCO; which includes some IHCC cohorts); additional IHCC cohorts with pertinent data are invited to join. Using available data on SNPs robustly associated to obesity, we will construct from 4 specific genetic risk scores (GRS) for obesity in infancy, childhood, adulthood, and overlapping-childhood / adulthood. The GRS will be applied to evaluate risks for developing CRC (UKBB, full cohort analysis; GECCO, EPIC; nested case-control analyses; any other IHCC cohort with relevant data), and to assess whether the associations differ by age, sex, and select modifiable exposures (i.e. lifestyle, dietary factors; anthropometry measures across life stages). We will further test the GRS associations to explore the role of major underlying mechanisms of CRC development, i.e. metabolic dysfunction and inflammation, using existing biomarker measures (UKBB, EPIC, other applicable IHCC cohorts). The GRS will be calculated from the sum of risk alleles corresponding to obesity phenotypes in each individual and weighted by the effect size estimate of the corresponding GWAS on the phenotype. Cause specific risks for the GRS-cancer associations will be estimated using logistic regression models or Cox proportional hazard, as appropriate.

This project will add pertinent knowledge linking genetically-defined obesity and CRC development at different life stages, providing essential insight into how obesity, and its major underlying mechanisms, may drive colorectal carcinogenesis during the life-course. These findings will inform cancer control strategies and public health policies, strengthening the evidence base for “windows-of-opportunity” interventions to reduce obesity and prevent CRC. They will also provide pilot data for a larger study on obesity-related cancers and survival after cancer diagnosis.

Project Leads: Adam Butterworth, South Asian Cohorts; Andre R. Brunoni, ELSA-Brasil; Arash Etemadi, Golestan Cohort Study; Hakon Hakonarson, Children’s Hospital of Philadelphia

Project Description:

Heart disease, diabetes, and other chronic diseases often develop without symptoms, resulting in a heavy burden for both patients and healthcare systems. Affected individuals can struggle with disease management, and disease progression can lead to expensive and often debilitating health problems. Importantly, health outcomes can be significantly improved through early diagnosis and intervention. However, particularly for individuals in lower and middle income countries and minority populations in high income countries, relevant diagnostics are often unavailable.

In this pilot program, we propose a systematic approach to metabolic profiling, which represents a highly-scalable model for risk prediction and prevention. Importantly, because of its relatively low cost, metabolic profiling offers a route to individualized medicine for cohorts that have traditionally lacked the requisite infrastructure and resources to take advantage of such programs.

We proposed to use the high-throughput and cost-effective nuclear magnetic resonance (NMR) metabolomics platform from Nightingale Health (a commercial assay provider) to metabolically characterize 5,000 individuals from four diverse IHCC cohorts, intended as a seed program that can be expanded to many more cohorts across the IHCC. The platform measures 250 biomarkers including lipids (including 14 lipoprotein subclasses), particle size, apolipoproteins, fatty acids, omega-3 and -6, amino acids, ketones, chronic inflammation, fluid balance, kidney function, and glycolysis. This is far more than the handful of biomarkers by routine cholesterol tests, and offer highly stable repeatability in measurements at absolute concentrations. Because of its cost – effectiveness on a mass scale (>50,000 samples), it can be available at <$20 USD per sample – the technology represents a gateway technology for cohorts that have hitherto been left behind by the OMICS revolution.

The pilot program will involve 5,000 individuals of African, South Asian, South American, and Persian ancestry. Ultimately, we aim to scale the program to potentially millions of IHCC cohort participants. Importantly, because analyses are performed at local Nightingale clinically- accredited laboratories in Finland and the United States, local sites are not required to bear the burden of expensive equipment and maintenance – underlining the potential for scalability versus many other OMICS approaches. To this end, a key focus of the program will be to establish metabolomic workgroups on biospecimens and clinical implementation, which will develop a formal infrastructure to support and promote expansion of metabolomics work across the network.

From the perspective of the individual patient, the proposed program will facilitate early identification of disease risk through metabolic profiling, which can be effectively targeted through medication. From the population perspective, the ability to leverage low-cost OMICS to systematically track clinical outcomes can provide transformative possibilities for governments to build effective nationwide health policies informed by cuttin edge biomedical resources.

Project Leads: Dr. Paul Brennan, International Agency for Research on Cancer (IARC), Lyon, France; Dr. Mahdi Sheikh, International Agency for Research on Cancer (IARC), Lyon, France

Project Description:

The recent opioid crisis has resulted in thousands of deaths annually and billions in economic losses. Opioids are categorized into opiates (the natural/minimally-processed subgroup including opium and heroin), and pharmaceutical opioids (the semi-synthetic/synthetic subgroup). Opioid misuse has become a major public health concern in many parts of the world including North America, Australia, Europe, South America, Asia, and Africa.

The acute health hazards of opioid misuse are well characterized, but the long-term health consequences of regular use of opioids remain unknown. In the Golestan Cohort Study (a member cohort of IHCC) we showed that regular use of opiates is associated with a wide range of adverse long-term health outcomes including premature death, overall mortality, and mortality from cardiovascular, digestive, and respiratory diseases. We also showed that regular use of opiates is associated with higher risk of developing cancers in different organs of the respiratory, digestive, and urinary tracts and the central nervous system. Similar results were shown in several case-control studies that were performed by our team and other investigators. Additionally, evidence from registry data linkage studies has shown associations between regular use of pharmaceutical opioids and increased risk of several cancer types including lung, liver, and urogenital cancers. These results and the emerging evidence on the tumor promoting effects of opioids, and the experimental studies that showed the presence of opioid receptors in cancer tissues and their effects on tumor initiation and progression, along with the studies that documented chromosomal damage in association with exposure to some opioids, have raised substantial concerns on the long-term effects of using opioids.

To our knowledge, the Golestan Cohort Study represents the only prospective study that has analyzed the association between using opiates and cancer incidence and cause-specific mortality. Also, the association between using pharmaceutical opioids and mortality has been only assessed in few prospective studies, while the association between using pharmaceutical opioids and cancer incidence has not been evaluated in any large prospective cohort. With the continued worldwide crisis of opioid use, global initiatives are necessary to determine the long-term effects of using opioids.

There are also limitations that have prevented the evaluation of mortality and cancer risk in relation to opioid use. These include the fact that detailed data on opioid use have not been gathered in most cohorts, while in cohorts with opioid use data, the number of long-term opioid users is limited and therefore a single cohort often cannot provide sufficient power to evaluate cancer incidence and cause-specific mortality outcomes among opioid users. Further, the types, patterns of use, accessibility, and underlying health conditions differ among opioid users in various countries, and thus performing a single analysis in one cohort might not be generalizable to other regions. Therefore, a comprehensive consortium-based approach is needed to address this issue. We propose to conduct this within the International Hundred K+ Cohorts Consortium.

Project Leads: Jordan W. Smoller, MD, ScD, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School; Sarah Bauermeister, PhD, Department of Psychiatry, University of Oxford

Project Description:

The COVID-19 pandemic is bringing an unprecedented set of challenges that may impact the mental health of populations around the world. Whilst more than 20 million people worldwide have been infected between January-August 2020, many now fear the emergence of a secondary pandemic of mental distress and illness. The direct effects of morbidity and mortality associated with the illness, which presently has no specific treatment or vaccine, have brought suffering and bereavement often in the absence of usual family and social support, to victims and their families. First-responders and healthcare providers face overwhelming stress and trauma associated with caring for victims, compounded by inadequate protective equipment and fears for their own health. The physical distancing imposed on communities has led to drastic disruptions of social connections and community supports that are known to buffer stress. Interruptions of schooling and socialization for young people threaten long-term effects on development. Unemployment, economic downturns, and food and housing insecurity resulting from efforts to control the pandemic, such as quarantine, curfew, and lockdown measures, result in further distress in more vulnerable populations, straining resources for mental healthcare. In addition, those at risk by virtue of pre-existing mental disorders are often cut off from usual care. In a recent survey of 128 UK carehomes, 80% of those with dementia are showing an acceleration of decline (https://www.alzheimers.org.uk/). Suicide rates are expected to rise in the coming months. The unprecedented scale and scope of the pandemic and its fallout mean that the evidence-base for optimal prevention and treatment strategies is limited. All of this is occurring against a backdrop of already rising rates of psychiatric illness and suicide in many countries.

The International HundredK+ Cohorts Consortium (IHCC) provides a unique platform for addressing urgent questions about the epidemiology, impact, and treatment needs for global communities in the context of this dire situation. The IHCC brings together cohorts comprising longitudinal data from millions of individuals around the world and the participation of epidemiologists and other researchers with the expertise to address these questions. A substantial subset of these cohorts have already begun fielding surveys and other data collections efforts specifically focused on mental health, well-being and social determinants of health. This proposal, on behalf of the IHCC COVID-19 Mental Health & Behavioral Impact Scientific Working Group, aims to leverage this platform to address pressing questions related to COVID-19 and mental health by harmonizing and analyzing data from large-scale longitudinal cohorts around the world. This pilot project will provide key insights about the etiology of adverse mental health outcomes of the pandemic, identify subgroups at greatest risk, and inform strategies for preventing psychiatric sequelae.

Project Leads: Professor John Chambers, LKC School of Medicine, Nanyang Technological University, Singapore; Dr. Laura Lyman Rodriguez, Patient-Centered Outcomes Research Institute (PCORI), USA

Project Description:

Population cohorts represent powerful tools to address disease susceptibility, and to inform new strategies for disease prevention. Classically, population cohorts have been used to advance understanding of chronic diseases, which typically arise from exposures across the life course. However, population cohorts may also be valuable for investigating the behavioural, environmental, and biological factors that influence transmission, susceptibility and outcomes for infectious diseases. The latter has been highlighted by the recent COVID-19 pandemic.

Population research can be strengthened by collaboration between cohorts, with joint analysis of relevant clinical and biomarker data. Bringing data and samples together increases sample size, provides opportunities to replication testing, and enables evaluation of whether findings are generalisable.1 In addition, inclusion of people living in different settings and varied outcomes, enables investigation of a wider range of genetic and environmental exposures, as well as the interaction between them. However, the global landscape of population research, reveals that cohorts have diverse designs and conduct practices, and that there are substantial differences in the availability and utility of the materials collected.2 Harmonising, strengthening and facilitating synergy between cohorts is a key ambition of IHCC.

Taking these two factors together, the IHCC has an opportunity to bring the power of its diverse cohort representation from around the world to bear on COVID-19, as well as broader health-related research questions. Such efforts will benefit from the longitudinal design of cohorts, with extensive data collected over time in different populations, with different environmental and lifestyle influences, and the ability (existing or potential) to examine biosamples. Given the array of collection protocols, biospecimen infrastructure needs, and study designs across cohorts, a robust analysis of existing resources, practices, and needs among IHCC or IHCC-aligned cohorts is fundamental to establishing a foundation for future work to buttress sample collections and management processes. This would in turn enable IHCC to identify needs and begin to support capacity building for biospecimen-based analyses and collaborative projects within and across cohorts from diverse settings and inclusive of diverse populations and communities.
Aims

Our general aim is to promote sample documentation, facilitate sample sharing, and strengthen biosample collections, amongst cohorts aligned to the IHCC effort, and particularly with regard to cohorts that could inform on otherwise underrepresented populations around the globe. Our specific aims include:

1. Knowledge-base. Develop a community-driven resource under the IHCC umbrella, and with an initial focus on COVID-19 relevant issues to: (a) Document and disseminate current activity and (b) Collate knowledge on best practice, in the biospecimen and biomarker sphere.
2. Demonstration projects. Identify cohorts from underserved settings to strengthen biospecimen collection and establish focussed demonstration projects relevant to COVID-19 as a springboard for larger collaborative research efforts and funding applications.

Project Leads: Prof Michèle Ramsay, Sydney Brenner Institute for Molecular Bioscience (SBIMB), University of Witwatersrand (Wits)) PI of H3Africa

Project Description:

The novel coronavirus SARS-CoV-2 has swept across the world infecting millions of people. While the majority counter the effects of the virus, showing no or very mild symptoms, a minority becomes seriously ill and some die as a result of the reaction to infection. Those most vulnerable include men, the elderly and people with co-morbidities such as diabetes and hypertension. Interestingly, the progression of the pandemic in Africa has been somewhat different, with lower reported infection rates having been variably attributed to lower testing capacity, higher prior exposure to other coronaviruses and infections, and a younger population, possibly resulting in lower mortality. Genetic host susceptibility as a predisposing factor is currently under investigation worldwide. Early studies in Europeans have identified two genome-wide association signals, one on chromosome 9 at the ABO blood group locus and one on chromosome 3 potentially involving a set of 6 genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1). Among them, the causative gene could not be identified, but several have biological plausibility. SLC6A20 encodes the solute carrier family 6 member 20 transporter protein that functionally interacts with angiotensin-converting enzyme 2, which is the cell-surface receptor for SARS-CoV-2. CCR9 and CXCR6 are involved in immune responses to viral infections. The international COVID-19 Host Genomics Consortium (https://www.covid19hg.org/) replicated the chromosome 3 association. Rare monogenic susceptibility to severe COVID-19 in younger men has been described in two families, one of whom originated in Somalia. The affected men had loss of function mutations in the TLR7 gene on the X-chromosome. They were deficient in TLR7 and had impaired innate immune responses to the viral infection, with poor upregulation of IRF7, IFNB1, and ISG15 gene expression. Genetic host susceptibility studies in African populations have the potential to identify novel associations and to contribute biological insights into COVID-19 morbidity and mortality.

This application is aligned with the scientific priorities of the IHCC as follows: It is an important response to the coronavirus disease (COVID-19) as it is unfolding in Africa, with an initial focus on South Africa, but with potential expansion to the continent. Host response to the viral infection can be considered a complex trait which is showing important regional differences in disease prevalence and progression. The intention is to leverage existing studies in Africa with health data, where the investigators are planning to investigate the epidemiology of the COVID-19 pandemic in their longitudinal cohorts. Some cohorts already have biospecimens and some already have DNA and genome-wide genotyping data. This project would therefore lead to the enhancement of existing cohorts and expanding their capabilities for genomic data-related research.

We therefore propose this as a pilot study for the “Novel corona virus host susceptibility study in South Africa (COVIGen-SA)” project with the intention of expanding it to additional African participants, cohorts and countries. The pilot study will specifically focus on hospitalised COVID-19 cases in different hospitals and research projects in and around Johannesburg, Gauteng.