Genetically determined metabolite variation identifies a heat related pathway in workers at risk of Mesoamerican Nephropathy

Mesoamerican nephropathy (MeN), a regional chronic kidney disease of unknown etiology (CKDu) in Central America, is a leading cause of death among young agricultural workers and other manual laborers. MeN has both strong environmental and genetic components. Genetically-determined variability in urine metabolite concentrations may provide insight into causal factors driving kidney injury in MeN. We investigated the associations between nucleotide variants and levels of 93 urine metabolites in 313 Nicaraguan workers with normal renal function from an area with exceptionally high MeN prevalence. Of genetically-influenced urinary metabolites, one of the strongest relationships was between genetic variants in AGXT2 and metabolites on a pathway related to brown fat differentiation and thermogenesis. Nicaraguans at risk of MeN had higher urinary levels of one of these metabolites, ß-aminoisobutyrate, compared to similar workers in the Mediterranean. Longitudinal studies will be needed to determine the effect of these metabolites on development of MeN. Our study illustrates how genetics could be useful for understanding factors such as heat stress and energy metabolism in populations at risk for CKDu.