Genes may explain high rate of kidney disease in African Americans
Wednesday, 21 July 2010- Two variants in a single gene may account for many cases of kidney disease in African Americans, but may also have helped their ancestors -- as well as those living in regions of present-day Africa -- resist often deadly sleeping sickness, according to US researchers.
DNA analysis among almost 400 African Americans revealed that one variant in the APOL1 gene was present in 52% of those with biopsy-proven focal segmental glomerulosclerosis (FSGS) compared with 18% of healthy African-American controls. The other variant in APOL1 was found in 23% of FSGS cases versus 15% of controls.
The findings were reported online in Science by Dr. Martin Pollak of Beth Israel Deaconess Medical Center in Boston, and colleagues, who also found that the variants may also ward off trypanosomal disease, commonly known as African sleeping sickness, even as they increase the risk of kidney disease.
The rate of kidney disease is four times greater among African Americans compared with whites. Compared with whites, blacks also have substantially higher rates of hypertension-associated kidney failure and FSGS, a specific type of injury to the kidney's filtering system that leads to kidney failure.
Pollak and colleagues noted that earlier genome-wide studies had indicated that genetic variants associated with kidney disease in African Americans were located in a region containing APOL1. The gene encodes apolipoprotein L-1. The variants associated with kidney disease were dubbed G1 and G2, both of which altered the APOL1 protein's amino acid sequence slightly.
After their initial discovery in a sample of 205 cases and 180 controls, the researchers sought validation in a second cohort of 1,030 African Americans with hypertension-associated kidney disease cases and 1,025 in good health. Individuals with one G1 or G2 allele had a slight increase in kidney disease risk (odds ratio 1.26, 95% CI 1.01 to 1.56) in the validation study.
Two alleles greatly increased the likelihood of disease (OR 7.3, 95% CI 5.6 to 9.5) compared with zero risk alleles. The increase in risk associated with two alleles versus one was also substantial (OR 5.8, 95% 4.5 to 7.5). About 46% of the cases had two risk alleles, compared with roughly 11% of controls.
Pollak and colleagues went on to analyse the prevalence of G1 and G2 in the large HapMap genomic database. They found that 40% of individuals of Nigerian Yoruba ancestry carried the G1 allele, whereas it was never found in European, Japanese, or Chinese genomes. G2 was also seen in Yoruba genomes but not in the other groups.
The high prevalence of the G1 and G2 variants in individuals of African ancestry led the researchers to suspect that these variants must also confer some type of benefit -- or else the process of natural selection would have removed it from the gene pool.
It had been reported in 2003 that APOL1 is lethal to the trypanosomes that cause African sleeping sickness. But Pollak and colleagues determined that this effect is limited to the APOL1 versions encoded by the G1 and G2 variants.
The particular species of parasitic trypanosome, T. b. rhodesiense, carried by the tsetse fly, produces a virulence factor that inactivates other forms of APOL1, but G1 and G2 alter the protein's sequence in such a way that the virulence factor can't bind to it.
"It will be interesting to determine the distribution of these mutations throughout sub-Saharan Africa," the researchers commented. "In present-day Africa, T. b. rhodesiense is found in the Eastern part of the continent, while we noted high frequency of the trypanolytic variants and the signal of positive selection in a West African population."
Of more immediate interest to US clinicians, the study's findings may help explain the high prevalence of kidney disease in African Americans. "Unraveling the molecular mechanisms by which [APOL1 variants] contribute to renal injury will be of great importance in understanding and potentially preventing renal disease in individuals of recent African ancestry," Pollak and colleagues wrote.
Source: G. Genovese, et al., "Association of trypanolytic ApoL1 variants with kidney disease in African-Americans," Science 2010; DOI: 10.1126/science.1193032.
