Genetic risk factors for Mesoamerican nephropathy

Area of Science:

• Nephrology
• Genetics
• Environmental Health

Background:

• Mesoamerican nephropathy (MeN) is a progressive kidney disease affecting agricultural workers on Central America's Pacific coast.
• While environmental factors are implicated, a genetic component is suspected due to the disease's prevalence in specific populations without typical risk factors.

Purpose of the Study:

• To investigate the potential genetic contributions to Mesoamerican nephropathy.
• To identify genetic variants associated with MeN risk and protective factors.

Main Methods:

• A genome-wide association study (GWAS) was conducted, comparing individuals with MeN to those with normal kidney function.
• Candidate gene variants, specifically in the OPCML gene, were analyzed for association with MeN.
• Functional studies using OPCML knock-out mice were performed to understand the gene's role in physiological processes.

Main Results:

• Native American ancestry was significantly associated with an increased risk of MeN.
• Specific variants in the OPCML gene were associated with a sixfold reduced odds of MeN (OR = 0.16, P = 4 × 10^-8).
• Individuals with protective OPCML variants exhibited enhanced urine osmolality, suggesting improved hypovolemia defense, and OPCML was implicated in fluid and temperature regulation in mice.

Conclusions:

• Heritable differences in sensitivity to heat stress and dehydration likely contribute to MeN.
• The OPCML gene plays a role in regulating fluid balance and may offer protection against MeN through enhanced hydration regulation.