Pharmacogenetic testing's promise, problems, and pitfalls

In 2019, Dr. Carl Bryce wrote a Diagnostic Tests review in American Family Physician about the allopurinol hypersensitivity assay, "a blood test to detect the presence of a human leukocyte antigen B [HLA-B] genetic variant that increases the risk of life-threatening, severe cutaneous reactions in patients taking allopurinol." According to this article and a rapid evidence review of gout, testing was recommended for Korean adults with stage 3 or higher chronic kidney disease and all adults of Han Chinese or Thai descent, who have a higher frequency of the variant, prior to initiating allopurinol. In 2020, the American College of Rheumatology (ACR) simplified and broadened this testing recommendation to "people of Southeast Asian and African American descent."

Though pharmacogenetic testing holds promise for improving clinical decision-making, a recent JAMA Viewpoint contended that race-based testing recommendations are problematic. Even a racially homogenous European country such as Switzerland exhibits wide genetic diversity in the frequency of the HLA-B*58:01 allele, with one city (Basel) actually having a higher frequency than the U.S. African American population. Further examination of the ACR's race-based guidance reveals additional complexities and contradictions:

The ACR guideline cites Han Chinese, Korean, and Thai as examples of Southeast Asian descent, even though China and Korea are not typically considered Southeast Asian countries. The guideline then states that screening is cost-effective in Asian populations generally. However, Japan is in Asia, but the allele frequency of HLA-B*5801 in Japan is even lower than that of White individuals in the US, who are not recommended for screening. In addition, the recommendation to screen all African American patients in the US before prescribing allopurinol belies wide-ranging HLA-B*5801 variation across Africa, where reported HLA-B*5801 frequencies, based on small sample sizes, range from 1% (comparable with White individuals in the US) to 10% (comparable with Thailand).

In an AFP editorial published online last month, Dr. Bonzo Reddick took aim at a related issue: the use of diagnostic and clinical prediction tools that, like pharmacogenetic tests, incorrectly utilize race as a proxy for genetic differences. These include the atherosclerotic cardiovascular disease (ASCVD) Pooled Cohort risk calculator, equations for glomerular filtration rate (GFR), a calculator for predicting the likelihood of a successful vaginal birth after cesarean delivery, and pulmonary function testing "correction factors" for Black and Asian patients.

Recognizing that "claims about pharmacogenetic testing ... are inconsistently supported by scientific evidence, and most tests have not been examined by the U.S. Food and Drug Administration [FDA]," Drs. Wendy Rubinstein and Michael Pacanowski shared the FDA's perspective on what clinicians need to know in the July issue of AFP. In a table of selected pharmacogenetic associations, they summarized known and potential gene-drug interactions and recommendations for clinical practice, when applicable. In a Diagnostic Tests review in the same issue, Dr. Natasha Pyzocha evaluated GeneSight Psychotropic, an expensive test panel that analyses 12 genes with possible interactions with 57 neuropsychiatric medications. Dr. Pyzocha concluded that while this test may help patients who have had multiple unsuccessful trials of therapy, "because only a small population of patients are expected to have genetic phenotypes that would necessitate medication changes, ... routine genetic testing is not recommended," and "choosing antidepressants based on health history and symptoms should still be the standard initial approach."