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Background  Among 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 Findings  We 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.    Conclusions  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.

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