Genetic risk factors for Mesoamerican nephropathy

• 成果类型: Article
• 署名作者: Friedman, David J.; Leone, Dominick A.; Amador, Juan Jose; Kupferman, Joseph; Francey, Lauren J.; Lopez-Pilarte, Damaris; Lau, Jorge; Delgado, Iris; Yih, W. Katherine; Salinas, Alejandro; Wang, Minxian; Genovese, Giulio; Shah, Shrijal; Kelly, Jessica; Tattersfield, Calum F.; Raines, Nathan H.; Amador, Magaly; Dias, Leny; Pitsillides, Achilleas; Rubio, Oriana Ramirez-; Amador, Alda G.; Cortopassi, Marissa; Applebaum, Katie M.; Alper, Seth L.; Banks, Alex S.; Mcclean, Michael D.; Leibler, Jessica H.; Scammell, Madeleine K.; Dupuis, Josee; Brooks, Daniel R.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Boston University; Harvard University; Harvard Medical School; Harvard Pilgrim Health Care; Boston University; ISGlobal; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; George Washington University; Boston University; McGill University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9262
• DOI: 10.1073/pnas.2404848121
• 发表日期: 2024-12-03
• 关键词: chronic kidney-disease; genotype imputation; ng108-15 cells; association; stratification; mechanisms; inference; selection; protein; opioids

摘要

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 OPCML gene, which encodes a protein that binds opioid receptors, that were associated with similar to sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 x 10(-8)). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML 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.