African-Americans (AA) have higher rates of kidney disease than Americans of Caucasian ethnicity. Two years ago the MHY9 (non-muscle myosin heavy chain 9) locus on chromosome 22 has been associated with glomerulosclerosis and non-diabetic end stage renal disease in AA and in Hispanic Americans. How MYH9 could predispose to glomerulosclerosis on a molecular level remained unknown and speculative. However MHY9 appeared to be a plausible candidate since it can cause a human syndrome - May-Hegglin anomaly(MHA; OMIM 155100) - which includes kidney disease (interstitial nephritis). Nate blogged about this here and here.Last week Martin Pollak and colleagues reported in Science that two independent variants in the nearby APOL1 (Apolipoprotein L-1) gene were responsible for the increased risk of renal disease disease and not the MHY9 gene. APOL1 is only ~20kb upstream of MYH9, however there is a strong recombination hot spot between the two genes, thus the entire effect of this locus on kidney disease in AA appears to be due to APOL1 based on strong statistical evidence.
AA with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) were associated with two independent sequence variants in the APOL1 gene {FSGS odds ratio was 10.5 [95% confidence interval (CI) 6.0 to 18.4] and H-ESKD odds ratio was 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. Trypanosoma can cause sleeping sickness and these variants can protect carriers from sleeping sickness.
The authors conclude/speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African-Americans. The mechanism of how APOl1, which is a soluble factor in human serum traveling with HDL particles, can predispose to kidney disease is unknown.
Interestingly , it is also should be noted that another paper, that was published in the same week, showed the distribution of the same APOL1 variant most associated with kidney disease risk in different African populations. It was showed that this variant is more prevalent in western compared to northeast African populations and completely absent in Ethiopia, consistent with the reported protection from forms of kidney disease known to be associated with the APOL1 variants (and also the absent of trypanosoma in Ethiopia highland).
ReplyDeleteTzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K. (Jul 2010). "Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene." Human Genetics.