How 196,000 Spanish participants are helping to decode heart disease risk

How 196,000 Spanish participants are helping to decode heart disease risk

Researchers are bringing together 35 Spanish population cohorts to find out why some people are more vulnerable to heart disease and how precision medicine can change the odds.

In a recent study published in the European Journal of Epidemiology, researchers summarize theCOllaborative cOHortsREASSEMBEDDATA to study mEchanisms andLonmmIchronic illnessASES (Cordelia) study, its proposed contributions to cardiovascular science and its methodology. The study collects data from 35 independent Spanish population cohorts (n = 196,632, mean age = 52 years, 54% female) to unravel the variables that contribute to cardiovascular disease in this ethnic group.

The study aims to conduct the largest cardiovascular disease (CVD)-centric genome-wide association study (GWAS) in southern Europe, with the aim of improving the prediction and understanding of CVD rather than direct mitigation in the region. Cordelia represents a significant step forward in medicine's understanding of CVD risk factors and has the potential to lead advances in precision medicine across southern Europe.

background

Atherosclerotic cardiovascular diseases (ASCVDs) are age-related chronic diseases caused by cholesterol, fats and other insoluble substances coating the lining of artery walls, eventually leading to reduced or even stopped blood flow. While the wonders of modern science have helped curb incidence and mortality rates worldwide, they have also extended human lifespans, inadvertently contributing to an aging world and the resulting increase in absolute ASCVD cases.

Decades of research have attempted to unravel the risk factors that contribute to the genesis of ASCVD and have so far observed that genetic, environmental and socioeconomic factors all contribute to the disease and must be closely monitored. While healthy lifestyles may mitigate ASCVD risk, risk factors exhibit a curious locally divergent feature where variables that strongly predict ASCVD prevalence in one region may not necessarily play an important role in ASCVD prevalence elsewhere.

"...justifies the creation of large population cohorts in certain regions of the world. Very few large cohorts are available in southern European and Mediterranean populations. In Spain, the recently launched Impact Precision Medicine initiative is the only cohort study of its kind, recruiting approximately 200,000 participants by 2028 and completing 10 years of follow-up by 2038."

Southern Europe is a highly understandable population through the lens of ASCVD risk (few studies have samples from the region) and GWAS (sparse representation in GWAS databases). Given the inadequacies of current predictive models in predicting ASCVD risk in southern European populations, it is essential to create a GWAS-focused ASCVD cohort in the region.

About Cordelia

The Cordelia study aims to address this need through comprehensive assessment of ASCVD risk factors (environmental, clinical, socioeconomic, genetic, etc.) in southern European populations by combining data from 35 pre-existing Spanish cohorts. The goal is also to conduct the largest ASCVD-centered GWAs in the region and use these data to generate polygenic risk scores for at-risk populations to predict their 10-year incidence probability for contracting ASCVDs.

"Cordelia also aims to identify subgroups of the population according to their genetic predisposition to diseases that would best benefit from available pharmacological treatments and lifestyle modifications. All previous findings are stratified by sex, which may increase the relevance of sex differences in ASCVD, which may lead to more accurate and effective prevention strategies."

methodology

The 35 Spanish cohorts from the Cordelia dataset cumulatively include 196,632 participants between 18 and 84 years old. DNA samples represented 60% of participants, serum/plasma samples represented 50%, and genotype data were already available for five cohorts, each genotyped using different platforms and reference genomes. For the remaining cohorts, standardization of genotyping will be performed using the Axiom™ Spain Biobank Array-2 to facilitate data harmonization.

All participants received questionnaires (World Health Organization [WHO] standardized surveys) that included a personalized code, date of study, age, gender, region of residence, and civil status. These variables were synthesized to include the administrative variables/demographics of the Cordelia study.

Clinical outcomes were assessed using event-based follow-up over periods ranging from 5 to 30 years, depending on the cohort, with each medical emergency (or CVD event) reported using the International Classification of Diseases (ICD-10 and ICD-9). Data sets will be further linked to those of the official Spanish National Institute of Statistics' mortality register and the Spanish hospital, and the data sets will be discharged and facilitate future comparisons of fatal and non-fatal events.

In addition, all participants underwent clinical assessments, with follow-up data collected over time primarily for investigative purposes, rather than repeated full risk factor measurement for all participants. These assessments included blood tests (after overnight fasting) and questionnaires to record recent health behaviors (sleep, exercise, smoking status, etc.).

It is important to note that while there are multiple data points, such as:

In addition, the Cordelia team developed harmonized algorithms for conditions such as hypertension and diabetes to ensure consistency across cohorts, as definitions and measurement approaches sometimes varied over the study's 30-year recruitment window.

Preliminary findings

So far the study has found that participants are 52 years old (average), 54% are female and 96% were born in Spain. The cohort is relatively well educated, with 20% having received a university degree. Encouragingly, 52% of participants had never smoked, but 24% reported consistent current smoking.

It should be made clear that this paper is the first joint publication of the Cordelia Meta-Cohort. Previous scientific publications have used data from the individual cohorts now integrated into Cordelia, rather than the new, harmonized meta-dataset itself. These publications often used data from the individual cohorts now integrated into Cordelia, reflecting the broad utility and scientific impact of the resource.

Conclusions

The Cordelia study shows promise as the next step in Southern Europe's fight against ASCVD. Once completed, it will comprise the largest ASCVD cohort in the region and the most comprehensive and detailed GWAs for individuals of Southern European descent in the world. The project's detailed data collection methods facilitate research in non-ASCVD-related areas such as Covid-19, cancer and sleep.

“By integrating comprehensive clinical, environmental, genetic and socioeconomic data, Cordelia demonstrates how large-scale collaborative research can advance precision medicine.”

However, researchers caution that the Cordelia study faces several limitations. Data came from cohorts that used different recruitment methods, time periods, and variable definitions, resulting in heterogeneity in the data set. Not all variables were collected in the same way - some data are self-reported and recruitment strategies differ (including population-based, hospital-based and worker cohorts).

DNA and biological samples represented only a subset of participants (60% and 50%, respectively). The power to detect associations for rare genetic variants is limited and the cohort may not be fully representative of the broader Spanish or southern European populations.

The Cordelia team has implemented statistical and methodological approaches to address these issues (e.g., harmonization and mixed effects models), but these challenges should be considered when interpreting the study's results.

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