Genomic and environmental risk factors for cardiometabolic disease in Africans

 Principal investigator

CRUN: Halidou Tinto

Wits university: Michele Ramsay

AWI-Gen is the Africa Wits-INDEPTH partnership for Genomic Studies, a NIH funded and university supported Collaborative Center of the Human Heredity and Health in Africa (H3Africa) Consortium. It is a strategic partnership between the University of the Witwatersrand, Johannesburg (Wits), and the International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH). AWI-Gen examines genomic and environmental factors that interact with individual physiology and behaviors to influence body composition, body fat distribution and cardiometabolic disease and risk in African populations, with the aim to provide insights and evidence toward effective prevention, treatment and intervention strategies.

Empirical, validated African data to inform modeling, projections and policy remain scant and widening health inequalities are evident within and between countries, despite global improvements in age-standardized mortality and morbidity. AWI-Gen Phase 1 is a population based cross-sectional study with a research platform of over 12,045 participants 40-60 years from Burkina Faso, Ghana, Kenya and South Africa that addresses these disparities. Our four-year partnership has successfully generated epi-demographic, environmental, health history, behavioral, anthropometric, physiological and genetic data across a range of rapidly transitioning African settings.

The AWI-Gen Collaborative Center provides a unique resource to examine genetic associations and gene-environment interactions that will contribute to Afrocentric risk prediction models and African-appropriate Mendelian Randomization instruments, and exploit their potential to improve personal and population health – while strengthening regional research capacity.

Our overall goal is to establish the genomic contribution to cardiometabolic disease and risk at a time when multiple interacting transitions, in the presence of high background HIV or malaria prevalence, are driving a rapid escalation in CMD across the African continent. To deepen our understanding of CMD and risk in African populations, we aim to extend data collection and develop a population-based ‘super’ cohort (from harmonized cohorts across geographic settings) that is well-suited to examining progression among middle-aged and older persons. We have developed four closely linked research projects: (1)

Genetic association studies to elucidate functional pathways involved in determining body composition and risk for CMD by detecting pivotal genomic and environmental contributors.

(2) Building an analytic resource of bioinformatics analysis tools appropriate for African populations, including genetic risk determination, Mendelian Randomization instruments and gene-environment interaction algorithms. (3) Examining changes over the menopausal transition in body composition and CMD risk factors, and evaluating the resulting risk from physiological, genetic and epigenetic perspectives. (4) Examining the microbiome in older adults and its relationship to obesity, diabetes and glucose tolerance, and CMD risks arising from the menopausal transition.

We hypothesize that there are African-specific gene-environment interactions that are key drivers of the health transitions unfolding across the continent, and that environmentally influenced epigenetic and microbiome changes play an important role. HIV and malaria will be considered in our models as they may have critical influences. Our emphasis on women in AWI-Gen Phase 2 is informed by the increasing prevalence of obesity and associated morbidities in women, especially in regions farther along an epidemiological transition path. Genomic research in Africa has the unique potential to harness the lower levels of linkage disequilibrium in African genomes for fine mapping of associated loci to identify causal genes and variants, and guide functional analysis in candidate regions. Our first project provides the foundation for the development of cohorts in west-east-south Africa to examine the distinct and interacting influences of genetic variation, environmental, social and demographic factors, personal behaviors, and proximal risk factors on body composition and susceptibility to CMD. This will be the first multi-ethnic study in sub-Saharan Africa to address a critical shortfall in understanding at a time when the force of transitions is driving the rise in cardiometabolic conditions. We expect findings to be highly relevant in our continental context and to contribute insights far more widely.

The long-term objective of AWI-Gen is to establish a set of large longitudinal cohorts to generate research platforms based on population sampling of older adults from rural and urban settings in west-east-south Africa to explore genetic susceptibility and gene-environment interactions that are driving the increase in cardiometabolic diseases (CMD) in Africa (Ramsay et al. 2016, in press, attached an Appendix). This renewal application is a proposal to develop AWI-Gen Phase 2 to collect data on the same participants at a second time point after approximately 5 years and to pursue specific research aims to advance the goals of the H3Africa Consortium. The resource will be an excellent comparative data set for meta-analyses and for trans-ethnic studies in a global environment where Africa has till recently, been represented by African Americans and the African diaspora (Popejoy & Fullerton, 2016).

Aim 1: To expand genomic association studies from our previous focus on body composition to additional phenotypes and sub-phenotypes, to perform in silico replication studies with other African and non-African cohorts. To perform fine mapping and in silico functional analysis and to work with collaborators to do functional laboratory-based and animal studies.

Aim 2: To deepen an understanding of genome architecture and population structure in sub-Saharan populations and to modify and develop tools to study African populations more effectively (including admixture analysis, genetic risk assessment and Mendelian Randomization).

Aim 3: To strengthen genomic and bioinformatics research capacity at our six study centers and our Wits core by cross-hosting students and researchers, by holding workshops, training sessions, and scientist research visits, and publishing and widely disseminating our findings.

Aim 4: To work with colleagues in AWI-Gen and H3Africa to develop multiple community engagement strategies and a feasible approach to feedback of results to participating communities.

Aim 5: To share our data and biospecimens according to the policies of the H3Africa

Consortium in order to enhance their value and impact.

Aim 6: To strengthen partnerships with additional INDEPTH Centers and their collaborators and with the Health & Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI) study, as well as several other studies.