APOL1 Genotyping
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Background
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.
Read More...The two APOL1 nephropathy risk variants are denoted G1 and G2. The G1 allele is composed of two nonsynonymous coding variants that are in complete linkage disequilibrium. The G2 allele is a six base pair deletion. The G1 and G2 alleles are mutually exclusive and there is no difference in risk of kidney disease when individuals with no risk alleles (G0) are compared to those with one risk allele. Two risk alleles—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.
Epidemiology
- High prevalence of APOL1 risk alleles in African-Americans, though absent in those of Ethiopian descent.
- The allele frequency for G1 (Ser342Gly/Ile384Met) is approximately 21% in African-Americans.
- The allele frequency for G2 (Asn388_Tyr389del) is approximately 13% in African-Americans.
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Approximately 12% of African-Americans have two APOL1 risk alleles.
Inheritance Pattern
- Autosomal recessive
- The presence of two risk alleles confers a 7 to 30 fold increased risk of developing kidney disease, when compared to those with low risk APOL1 alleles
Gene Information
| Gene | Protein | OMIM# | Locus |
| APOL1 | Apolipoprotein L1 | 603743 | 22q12.3 |
Testing Strategy
This test is indicated for:
- African-Americans with a clinical risk or family history of kidney disease
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African-Americans being evaluated as living kidney donor
Test Outcomes
- The presence of two risk alleles confirms that the patient is at increased risk for developing kidney disease
- The presence of no or one risk allele confirms that the patient is not at an increased risk for developing kidney disease
Methodology
This test is performed by Sanger sequencing of exon 6 of APOL1. This test does not detect large deletions or variants in other coding exons or non-coding regions that could affect gene expression.
Analytical and Clinical Sensitivity
This assay is greater than 99.9% accurate in detecting variants in the sequence analyzed.
