APOL1 Null Alleles from a Rural Village in India Do Not Correlate with Glomerulosclerosis

Duncan B Johnstone,Lawrence B Holzman,Rajaram Powar,Deepak Nihalani,H Omer Ikizler,Yogendra Singh Rathore,Vasant Zare,Vijay Shegokar,Ashish Ashish,Leena Mallik,Maria Pia Rastaldi

doi:10.1371/journal.pone.0051546

Duncan B Johnstone, Lawrence B Holzman + Show 9 more

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https://doi.org/10.1371/journal.pone.0051546

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Abstract

BackgroundAmong African-Americans, genome wide association revealed a strong correlation between the G1 and G2 alleles of APOL1 (apolipoproteinL1, also called trypanolytic factor) and kidney diseases including focal and segmental glomerulosclerosis, HIV-associated nephropathy and hypertensive nephrosclerosis. In the prevailing hypothesis, heterozygous APOL1 G1 and G2 alleles increase resistance against Trypanosoma that cause African sleeping sickness, resulting in positive selection of these alleles, but when homozygous the G1 and G2 alleles predispose to glomerulosclerosis. While efforts are underway to screen patients for G1 and G2 alleles and to better understand “APOL1 glomerulopathy,” no data prove that these APOL1 sequence variants cause glomerulosclerosis. G1 and G2 correlate best with glomerulosclerosis as recessive alleles, which suggests a loss of function mutation for which proof of causality is commonly tested with homozygous null alleles. This test cannot be performed in rodents as the APOL gene cluster evolved only in primates. However, there is a homozygous APOL1 null human being who lives in a village in rural India. This individual and his family offer a unique opportunity to test causality between APOL1 null alleles and glomerulosclerosis.Methods and FindingsWe obtained clinical data, blood and urine from this APOL1 null patient and 50 related villagers. Based on measurements of blood pressure, BUN, creatinine, albuminuria, genotyping and immunoblotting, this APOL1 null individual does not have glomerulosclerosis, nor do his relatives who carry APOL1 null alleles.ConclusionsThis small study cannot provide definitive conclusions but the absence of glomerulosclerosis in this unique population is consistent with the possibility that African-American glomerulosclerosis is caused, not by loss of APOL1 function, but by other mechanisms including a subtle gain of function or by the “genetic hitchhiking” of deleterious mutations in a gene linked to APOL1 G1 and G2.

Highlights

This small study cannot provide definitive conclusions but the absence of glomerulosclerosis in this unique population is consistent with the possibility that African-American glomerulosclerosis is caused, not by loss of APOL1 function, but by other mechanisms including a subtle gain of function or by the ‘‘genetic hitchhiking’’ of deleterious mutations in a gene linked to APOL1 G1 and G2
Compared to European-Americans, African-Americans have a 3–4 fold higher rate of incident and prevalent end-stage kidney disease, including a higher rate of diabetic nephropathy, focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), and the ill-defined entity of ‘‘hypertensive nephrosclerosis [1].’’ Using mapping by admixture linkage disequilibrium, two groups in 2008 reported that FSGS, HIVAN and hypertensive nephrosclerosis in African-Americans correlate with single nucleotide polymorphisms (SNPs) on Chromosome 22q within the gene MYH9, which encodes non-muscle myosin heavy chain 2A [2,3]
Both groups found that African-American glomerulosclerosis correlates more strongly with the G1 and G2 alleles of APOL1, which lies immediately centromeric to MYH9 [12,13]

Summary

Introduction

Compared to European-Americans, African-Americans have a 3–4 fold higher rate of incident and prevalent end-stage kidney disease, including a higher rate of diabetic nephropathy, focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), and the ill-defined entity of ‘‘hypertensive nephrosclerosis [1].’’ Using mapping by admixture linkage disequilibrium, two groups in 2008 reported that FSGS, HIVAN and hypertensive nephrosclerosis in African-Americans correlate with single nucleotide polymorphisms (SNPs) on Chromosome 22q within the gene MYH9, which encodes non-muscle myosin heavy chain 2A [2,3]. Analysis of the worldwide distribution of MYH9 polymorphisms demonstrated that the high allele frequency of the MYH9 ’’risk haplotype’’ among AfricanAmericans and West Africans could be accounted for by linkage with a nearby site of selection, such as within APOL1 [15] Based on these and other data, APOL1 supplanted MYH9 as the candidate disease gene for glomerulosclerosis and hypertensive nephrosclerosis among African-Americans. APOL1 may not be the gene responsible for African-American glomerulosclerosis at this locus on Chr22 While this is an initial caveat of all discoveries from genome wide association studies due to linkage [18], such caution is not currently stressed amidst the momentum of APOL1-glomerulopathy. This individual and his family offer a unique opportunity to test causality between APOL1 null alleles and glomerulosclerosis

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