Important genetic link found for FSGS in African Americans

Genome-wide association studies have previously shown a strong signal between a region residing on chromosome 22 centered on MYH9 and African Americans with FSGS and hypertension attributed end-stage kidney disease (H-ESKD). On July 15, 2010, Science released online a publication revealing a strong association between the same but expanded interval containing a nearby gene encoding for apolipoprotein L-1 (APOL1) in a similar group of patients.

The investigators, led by Dr. Martin Pollak, the chief of the Division of Nephrology at Boston's Beth Israel Deaconess Medical Center, reasoned that because no causal mutations have been identified in MYH9, other alleles ought to be considered. Furthermore, recent selection pressures in Africans could lead to longer patterns of linkage disequilibrium (LD). More, but previously unavailable, data from African individuals whose DNA were sequenced in the 1000 Genomes Project (www.1000genomes.org) was used to identify polymorphisms that showed large frequency differences between Africans and Europeans.

An initial association analysis was done comparing 205 African-American sporadic cases with biopsy proven FSGS to 180 African-American controls. The strongest signals were found in the last exon of APOL1. More specifically, two closely spaced alleles that are in perfect LD (i.e. no recombination events) showed the strongest association. This two-allele haplotype termed “G1” consisted of the non-synonymous coding variants rs73885319 (S342G) and rs60910145 (I384M). Logistic regression analysis to control for G1 led to the identification of a second strong association with a 6 base pair deletion in APOL1 termed G2.

Logistic regression analysis was also performed to control for both G1 and G2 but no other significant associations were found and controlling for MYH9 failed to eliminate the APOL1 signal. However, G1 and G2 are in strong LD with variants in MYH9, explaining previously reported associations of MYH9 with kidney disease.

The investigators also conclude a recessive pattern of inheritance. Individuals carrying no or one risk allele had no differences in FSGS risk (OR = 1.04, CI 0.63-2.13). Individuals, however, with two risk alleles had a ten time greater risk of disease compared to subjects with no or one risk allele (OR = 10.5, CI 6.0-18.4).

A similar analysis was replicated in a larger cohort of 1030 African-American cases with H-ESKD and 1025 geographically matched African-American controls. The same strong association for G1 and G2 emerged with a P value of 10^-63 and was 35 orders of magnitude stronger than for MYH9 SNPs. The inheritance pattern was once again consistent with a recessive model. Two risk alleles versus zero or one risk allele yielded an odds ratio of 7.3 (CI 5.6-9.5) and 5.8 (CI 4.5-7.5), respectively.

Comparison of the frequencies of G1 and G2 in the different HapMap ancestral populations yielded interesting results. G1 was present in approximately 40% of Yoruban African chromosomes and G2 was detected in 3 Yoruban subjects. Conversely, G1 and G2 was not found in Europeans, Japanese or Chinese individuals. This led investigators to speculate that the high frequency of these disease-associated variants in Yoruba and African-Americans may be due to a selective advantage in Africa.

ApoL1 is the trypanolytic factor in human serum that confers resistance to the Trypanosoma brucei brucei parasite. T. brucei brucei has evolved into two additional subspecies, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, both of which inhibit ApoL1 anti-trypanosomal activity. In vitro assays presented in the paper show that G1 and G2 ApoL1 variants lysed Trypanosoma brucei rhodesiense.

In summary, the investigators show that variants in APOL1, a gene that resides in an expanded interval that contains MYH9, are associated with FSGS and H-ESKD in African Americans. No association is found for MYH9. Disease-associated variants in APOL1 termed G1 and G2 occur in high frequency in African and African American populations but not other ancestral groups, suggesting it may confer a selection advantage, a model similar to sickle cell anemia. Indeed, the authors show that ApoL1 proteins bearing these variations kill trypanosome subspecies resistant to wildtype ApoL1.

At the very least, the results reported in this paper suggest that other kidney disease risk alleles in African Americans other than MYH9 need to be considered. The speculation on the selective advantage conferred by this sequence variation in ApoL1 is an interesting one. Importantly, however, how it contributes to the pathogenesis of kidney disease needs yet to be determined and should be the focus of further investigation.

Moumita Barua, MD FRCPC

Post doctoral research fellow

Beth Israel Deaconess Medical Center

Boston