Clinical Genetic Testing for APOL1: Are we There Yet?

End-stage renal disease (ESRD) disproportionately affects African Americans, who are two to four times more likely than European Americans to develop ESRD. Two independent variants of the apolipoprotein L1 (APOL1) gene, G1 and G2, have been associated with a 7- to 10-fold greater risk of developing nondiabetic ESRD in African Americans. Those who inherit two risk variants (G1/G1, G2/G2, or G1/G2) are also more likely to develop ESRD at a younger age and to have progression of chronic kidney disease. Currently, it is not known what proportion of persons with high-risk genotypes will develop ESRD in the general population, the exact mechanism of injury for APOL1-related risk, its relation to environmental exposures, or whether patients with comorbid conditions are more likely to develop ESRD. To address the above uncertainties, research that includes assessment of APOL1 status is needed before guidelines for general testing can be endorsed. Currently, APOL1 testing has been proposed as part of kidney transplant protocols both for living donors and recipients. However, because of uncertainties regarding the clinical implications of APOL1 variants, testing could generate confusion, anxiety, or stigma. Multiple forms of evidence, including the views of community members, are needed to support responsible approaches to providing information about APOL1 status as part of clinical care or in population screening. Informed consent with subsequent counseling regarding the risks and benefits of APOL1 testing should be considered for patients at high risk.

Familial identification: population structure and relationship distinguishability.

With the expansion of offender/arrestee DNA profile databases, genetic forensic identification has become commonplace in the United States criminal justice system. Implementation of familial searching has been proposed to extend forensic identification to family members of individuals with profiles in offender/arrestee DNA databases. In familial searching, a partial genetic profile match between a database entrant and a crime scene sample is used to implicate genetic relatives of the database entrant as potential sources of the crime scene sample. In addition to concerns regarding civil liberties, familial searching poses unanswered statistical questions. In this study, we define confidence intervals on estimated likelihood ratios for familial identification. Using these confidence intervals, we consider familial searching in a structured population. We show that relatives and unrelated individuals from population samples with lower gene diversity over the loci considered are less distinguishable. We also consider cases where the most appropriate population sample for individuals considered is unknown. We find that as a less appropriate population sample, and thus allele frequency distribution, is assumed, relatives and unrelated individuals become more difficult to distinguish. In addition, we show that relationship distinguishability increases with the number of markers considered, but decreases for more distant genetic familial relationships. All of these results indicate that caution is warranted in the application of familial searching in structured populations, such as in the United States.