Genetic risk factors for Mesoamerican nephropathy

Abstract

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 ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 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.

Keywords: Mesoamerican; OPCML; genetics; kidney disease.

Fig. 1.

Estimating the effect of Native American ancestry on MeN risk. (A) Increase in odds ratio (OR) for each additional 1% Native American ancestry for Discovery, Replication, and Combined datasets. In the combined dataset, each 10% increase (e.g., from 30 to 40%) in percent Native American ancestry translates into a ~1.5 fold increase in the OR of MeN. There was no heterogeneity between discovery and replication cohorts (P = 0.38). CI = confidence interval. (B) To assess for nonlinear effects of fraction Native American ancestry, the study population was divided into five evenly sized intervals by fraction Native American ancestry. The group with the lowest (0.24 to 0.38) Native American ancestry was the referent. With increasing Native American ancestry, group 2 OR was 1.92 (1.17 to 3.16; P = 0.01); group 3 OR, 2.99 (1.79 to 5.01; P = 0.00002); group 4 OR, 6.11 (3.01 to 12.39; P = 2.6 × 10⁻⁷); and group 5 OR, 6.25 (1.88 to 20.81; P = 0.0017).

Fig. 2.

Urine osmolality and kidney function in active sugarcane workers (controls) with and without the OPCML protective variant. (A) Urine osmolality was higher in apparently healthy, active (control) participants with the OPCML protective allele (mean 793 ± 62 mOsm, n = 8) than in noncarriers (573 ± 253 mOsm, n = 188) (P = 0.003, Mann–Whitney test). All individuals tested had either zero or 1 protective allele. (B) Serum creatinine, the standard biochemical measure of kidney function, did not differ statistically between control participants with (0.79 ± 0.09 mg/dL, n = 8) and without (0.86 ± 0.13 mg/dL, n = 188) the OPCML protective allele (P > 0.05). (C and D) There was no significant relationship between serum creatinine and urine osmolality in either workers with (C) or without (D) the OPCML protective allele (trendlines shown). These data suggest that the increased urinary concentration in carriers of the OPCML protective allele is not due to better preserved renal function.

Fig. 3.

Opcml knockout mice exhibit disease-relevant physiological differences in response to volume challenges and heat stress. (A) Opcml deletion protects against body weight loss after water restriction and fasting (WRF) for 12 h. (B) Opcml deletion protects against body weight loss after furosemide (50 mg/kg) challenge at the beginning of an 8 h water restriction and fast. (C) Opcml deletion protects against body weight loss after a 3 d intermittent heat challenge. (D) Longitudinal core body temperature measurements collected over 2 d by continuous telemetry under baseline conditions at 23 °C followed by (E). 3 d of intermittent heat exposure. In Zeitgeber time (ZT), ZT 0-12 is the light/low activity phase and ZT 12-23 is the dark/high activity phase. (F) Baseline and maximum core body temperature during intermittent heat stress. Opcml^−/− peak temperature was 1.1 °C/2°F lower than Opcml^+/+ mice. Summary statistical data for heat stress experiments are located in SI Appendix, Fig. S7. Peak temperature is lowest in Opcml^−/−mice. Opcml^+/+: Wild-type; Opcml^+/−: heterozygote; Opcml^−/−: Opcml homozygous null.