Gene: APOL1 at 22q12.3
Methodology: Bi-directional sequence analysis of exon 6 of APOL1.
Analytical and Clinical Sensitivity: See Below
Non-Diabetic Nephropathy is a name given to a variety of kidney diseases without diabetes mellitus as the underlying cause. The natural history of renal disease begins with an initial kidney injury. The subsequent clinical manifestations can vary from asymptomatic hematuria to dialysis-dependent renal failure. As renal dysfunction progresses, patients experience symptoms including hypertension, anemia, hyperkalemia, volume overload, metabolic acidosis, and bone disease. End stage renal disease (ESRD) is manifest by uremia, which can include symptoms of anorexia, lethargy, nausea and vomiting, uremic pericarditis, seizures, muscle cramps, and coma.
African Americans have a 4 to 5 times higher rate of ESRD than European Americans. In this population, the locus on chromosome 22 that contains APOL1 confers nearly all of the increased risk for nondiabetic nephropathy. Specifically, two sequence variants in the APOL1 gene are strongly associated with focal segmental glomerulosclerosis (FSGS; odds ratio = 10.5) and hypertension attributed end stage renal disease (H-ESRD; odds ratio = 7.3), sickle cell nephropathy, and HIV nephropathy. In addition, preliminary clinical studies suggest that transplanted kidneys with two APOL1 risk alleles have shorter graft survival than donor kidneys with zero or one APOL1 risk alleles.
APOL1 encodes the Apolipoprotein L1 protein, a component of HDL. The same variants of APOL1 that confer kidney disease risk encode the Apolipoprotein L1 protein that has been show to be toxic to the trypanosome responsible for African sleeping sickness, Trypanosoma brucei rhodesiense.
The two APOL1 nephropathy risk variants are denoted G1, which is composed of two nonsynonymous coding variants that are in complete linkage disequilibrium, and G2, a six base pair deletion. The G1 and G2 alleles are mutually exclusive. There is no difference in risk of kidney disease when individuals with no risk alleles are compared to those with one risk allele. Two risk alleles, either G1/G1, G2/G2, or G1/G2 are required to confer additional risk of kidney disease. Therefore, this pattern supports a recessive model of inheritance.
Sequencing of exon 6 of APOL1 has over 99% sensitivity to detect the risk variants.
Bi-directional sequence analysis of exon 6 of APOL1.
This assay is greater than 99.9% accurate in detecting mutations in the sequence analyzed. According to published data, the APOL1 G1 and G2 alleles are responsible for the increased risk of kidney disease seen in African Americans when compared to European Americans.
U.S. Renal Data System: USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, MD, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Disease, 2009
Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR. 2010. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 13;329(5993):841-5. (PMID 20647424)
Freedman BI, Kopp JB, Langefeld CD, Genovese G, Friedman DJ, Nelson GW, Winkler CA, Bowden DW, Pollak MR. 2010. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J Am Soc Nephrol. 21(9):1422-6. (PMID: 20688934)
Friedman DJ, Pollak MR. 2011. Genetics of kidney failure and the evolving story of APOL1. J Clin Invest. 1;121(9):3367-74 (PMID: 21881214)
Ashley-Koch AE, Okocha EC, Garrett ME, Soldano K, De Castro LM, Jonassaint JC, Orringer EP, Eckman JR, Telen MJ. 2011. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br J Haematol. 155(3):386-94. (PMID: 21910715)
Friedman DJ, Kozlitina J, Genovese G, Jog P, Pollak MR. 2011. Population-based Risk Assessment of APOL1 on Renal Disease. J Am Soc Nephrol. (PMID: 21997396)
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