A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study

The Challenge: Cardiometabolic Disease Omics in Hispanic and Latino Populations are Unknown

Metabolites are small molecules that exert essential roles in biological processes. Small changes in metabolite levels can affect body homeostasis and can be reflected in health and disease. Studying the effect of gene variants on metabolite levels and the impact of such associations on health and disease helps understand cardiovascular and metabolic disease outcomes. Hispanic and Latino populations are at high risk for cardiometabolic diseases, although the relationship between genes, metabolites levels, and disease risk is largely unknown for this population. To address this knowledge gap, researchers used the Metabolon Global Discovery Panel to combine phenotypic data with Genome-Wide Association Study (GWAS) data from an at-risk cohort of Hispanics/Latinos.

Metabolon Insight: Metabolomic Profiling of At-risk Hispanic and Latino Populations

The study authors leveraged the Global Discovery Panel to perform metabolomic profiling of 3,926 participants in the Hispanic Community Health Study/Study of Latinos, for which GWAS data had also been produced.¹

The Solution: Co-localize Genetic Variants with Metabolites

In this study, researchers integrated metabolite measurements from fasted blood samples with co-localization analysis of genetic variants to understand the interaction of metabolites and genes in a Hispanic/Latino community, a typically underrepresented population with a unique genetic background. They analyzed a panel of 1,000 genomes and identified 640 circulating metabolites in the cohort population.

From 46 previously unreported variant-metabolites pairs, they identified a genetic association with 12 metabolites, including amino acids, lipids, cofactors and vitamins, nucleotides, and peptides. The researchers also confirmed 301 known locus-metabolite associations. Notably, they replicated their finding

Further analysis showed that the levels of five metabolites were associated with a risk of coronary heart disease (CHD) or Type 2 diabetes (T2D). For example, two variants located in or near CYP4F2 and levels of octadecanedioate and the vitamin E metabolites gamma-CEHC and gamma-CEHC glucuronide. Associated with decreased CHD risk, these metabolites may improve CHD risk prediction. Conversely, increased levels of 1-arachidonylglycerol and 1-palmitoyl-2-stearoyl-GPC were associated with increased odds of T2D.

This study also provides the very first report of an association between the gene rs2328895 (encoding the protein “Solute Carrier family 17 member 1”; SLC17A1) and decreased levels of N-acetyl tryptophan, which reduces the risk of heart failure (HF) and the prevalence of coronary heart disease (CHD). Moreover, this gene is also associated with a decreased risk of incidence of CHD in older people.

The Outcome: 46 Variant-metabolite Associations Revealed

The Global Discovery Panel enabled this research group to report 46 clinically relevant associations between gene variants and circulating metabolites in Hispanic and Latino populations, demonstrating that metabolites are integral for the functional annotation of GWAS loci. The findings highlight the impact of genetic variants on metabolite levels and, consequently, on the cardiometabolic disease risk in this unique population.