Apolipoprotein L1 Gene Testing Comes of Age.

Abstract

The landscape in nephrology changed dramatically in 2010 with the discovery of genetic association between two coding renal-risk variants (RRVs) in the apo L1 gene ( APOL1 ) and CKD (1). The APOL1 G1 and G2 nephropathy-associated variants arose <10,000 years ago and are present almost exclusively in individuals with recent African ancestry, those with similar genetic makeup to populations currently residing in Africa. The frequencies of these variants rapidly increased, likely due to positive selection for protection afforded from Trypanosoma brucei rhodesiense infection, a parasite causing African sleeping sickness. Due to the trans-Atlantic slave trade, approximately 39% of African Americans possess one APOL1 RRV and 13% possess two. In contrast, hemoglobin S ( HbS ) gene variants are also common in African Americans; however, <8% inherit one or two HbS variants. Ancestry-based variation in APOL1 contributes to the excess risk of ESKD in African Americans, more rapid failure of transplanted kidneys from African American deceased donors, and higher rates of nephropathy in African American living-kidney donors (2,3). The kidney disease historically attributed to hypertension in nondiabetic African Americans with low-level proteinuria also proved to be APOL1 associated, with biopsy findings including solidified glomerulosclerosis and thyroidization-type tubular atrophy (4). In addition, the APOL1 spectrum of kidney disease includes FSGS, HIV-associated nephropathy (HIVAN), severe lupus nephritis, and sickle cell nephropathy (5). APOL1 RRVs are associated with nephropathy in individuals with recent African ancestry residing in the United States, Africa, Europe, South America, and the Caribbean. Beyond genetic association, APOL1 RRVs were shown to directly cause kidney disease in a transgenic mouse model (6). Recent studies show that APOL1 kidney risk variants do not associate with cardiovascular disease (7,8). Despite the evidence that APOL1 risk variants lead to kidney disease, the precise pathogenic mechanisms are not known. Data suggest a toxic gain …