African-Americans are four times more likely than their white peers to develop chronic kidney disease (CKD) across their lifetime. African Americans also develop CKD as a comorbid condition much more often than individuals of European descent, even when controlled for other risk factors. Much of this increased risk correlates to increased genetic susceptibility, specifically mutations in the APOL1 gene found on chromosome 22 that are only found in individuals of African ancestry. Variants in APOL1 are associated with increased CKD risk.
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APOL1, which codes for an apolipoprotein, is bound to HDL3 and circulates in the bloodstream. However, APOL1 is also expressed in some kidney cells. Although the direct mechanism of nephron destruction is largely unknown, scientists believe it is at least in part due to the protein’s ability to induce apoptosis and cell necrosis. An individual must have two copies of the APOL1 risk variants to be at risk for kidney disease. In one study, up to 76 percent of individuals with two copies of the faulty allele also reported having some kind of precursor to CKD — glomerulosclerosis or nephrosclerosis — compared with only 12 percent with two low-risk alleles.
Much like sickle cell trait can protect its heterozygous carriers from the ill-effects of malaria, APOL1 protects against African trypanosomiasis, or African sleeping sickness, to a degree consistent with the number of risk alleles inherited. This protective function of genetic mutation is of no use to those of African descent living far from the risk of contracting trypanosomiasis. A recent study suggests that individuals of African descent who do not identify as African (i.e., Haitian and Jamaican) have similar genetic variations, but don’t know about their risk for developing CKD. To complicate matters further, although approximately 12 percent of African-Americans carry an APOL1 risk genotype, only a subset of individuals develop CKD regardless of their genetic APOL1 variant. This makes the disease quite different from sickle cell disease because it seems to develop only in individuals who have experienced what researchers call a “second hit,” requiring stress on the organism to activate a disease state.
John Sedor, MD, and John O’Toole, MD, Nephrology and Hypertension, along with Leslie Bruggeman, PhD, Inflammation and Immunity, have devoted much of their research to determining how APOL1 works in the body and how understanding the molecular basis for APOL1’s genetic association could inform treatment of CKD in the future. Currently, the clinical utility of genotyping individuals for APOL1 remains controversial, but Dr. Sedor believes that it may have the most impact in a transplantation setting.
“Outcome data show deceased donor kidneys with APOL1 high-risk genotypes have worse outcomes, independent of recipient APOL1 genotype,” he explains. “In addition, case studies and one retrospective cohort analysis suggest living kidney donors with the APOL1 risk genotype may also be at risk for progressive CKD. Fortunately the NIDDK [National Institute of Diabetes and Digestive and Kidney Diseases] has assembled the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to define the effects of variant APOL1 on living donor and allograft outcomes, which should guide us in implementing APOL1 genotyping in clinical practice.”