Genetic risk factors for Mesoamerican nephropathy
Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the <i>OPCML</i> gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; <i>P</i> = 4 × 10<sup>-8</sup>). Sugarcane workers with the protective <i>OPCML</i> variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with <i>Opcml</i> knock-out mice revealed roles for <i>OPCML</i> in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America.
Authors
- Alejandro José Salinas
- Minxian Wang (ORCID: https://orcid.org/0000-0002-3753-508X)
- Giulio Genovese (ORCID: https://orcid.org/0000-0003-3066-5575)
- Daniel R. Brooks (ORCID: https://orcid.org/0000-0001-6220-6889)
- Achilleas Pitsillides (ORCID: https://orcid.org/0000-0002-2658-1566)
- Marcos Amador (ORCID: https://orcid.org/0000-0003-0477-4751)
- David J. Friedman (ORCID: https://orcid.org/0000-0002-0301-9298)
- Dominick Leone (ORCID: https://orcid.org/0000-0002-6401-2292)
- Seth L. Alper (ORCID: https://orcid.org/0000-0002-6228-2512)
- Leny Dias
- Jorge Luis Lau
- Nathan H. Raines (ORCID: https://orcid.org/0000-0003-3297-9447)
- Marissa Cortopassi
- Jason Kelly
- Shrijal S. Shah (ORCID: https://orcid.org/0000-0001-5594-7507)
- Jessica H. Leibler (ORCID: https://orcid.org/0000-0002-0605-0928)
- Ana Amador (ORCID: https://orcid.org/0000-0002-1040-2359)
- Michael D. McClean (ORCID: https://orcid.org/0000-0002-3902-8823)
- Josée Dupuis (ORCID: https://orcid.org/0000-0003-2871-3603)
- Iris Delgado (ORCID: https://orcid.org/0000-0002-7021-3357)
- Lauren J. Francey (ORCID: https://orcid.org/0000-0002-9700-2277)
- Calum F. Tattersfield
- Madeleine K. Scammell (ORCID: https://orcid.org/0000-0003-3836-083X)
- Juan José Amador (ORCID: https://orcid.org/0000-0003-4538-6368)
- Joseph Kupferman
- Oriana Ramírez‐Rubio (ORCID: https://orcid.org/0000-0002-8332-3264)
- Katie M. Applebaum (ORCID: https://orcid.org/0000-0001-5006-8888)
- W. Katherine Yih (ORCID: https://orcid.org/0000-0001-5084-2052)
- Damaris López-Pilarte
- Alex S. Banks
Institutions
- Broad Institute (US)
- Boston University (US)
- Milken Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- George Washington University (US)
- Harvard Pilgrim Health Care (US)
- Barcelona Institute for Global Health (ES)
- McGill University (CA)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1073/pnas.2404848121
- Citations
- 11
- Primary Topic
- Digestive system and related health
- Type
- article
- Field-Weighted Citation Impact
- 6.05
Funders
- Satellite Healthcare
- Ministerio de Salud
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases