Exploratory Genome Sequence Analysis of Candidate Genes Identified Three Loci Potentially Related to Mefloquine Side Effects

BACKGROUND: Despite effectiveness as a once-weekly antimalarial prophylaxis, mefloquine has fallen out of favor due to its neuropsychiatric side effects. While possible genetic susceptibilities have been identified in preliminary studies, pharmacogenomic testing guidance is not available for mefloquine. METHODS: Volunteers with a history of mefloquine exposure were recruited to a cross-sectional case-control study. Pharmacogenomic analysis was performed on 7 candidate genes of interest with 16 missense variants including ORM1, MTHFR, MDR1, PYK2, HT2A, ADA, and ADORA2A. RESULTS: Fifty participants enrolled including those who had mefloquine exposure and chronic adverse effects (AEs) lasting 6 months or longer (n = 23); with subsequent AEs less than 6 months (n = 12); no AEs (n = 8); and a control group with a history of post-traumatic stress disorder (PTSD) but no mefloquine exposure (n = 7). Psychometric testing showed that mefloquine users with AEs lasting 6 months or more and PTSD patients who had not used mefloquine reported more evidence of sleep impairment, balance and equilibrium disorders, and lower levels of psychological well-being than mefloquine users who reported without AEs or with AEs but lasted less than 6 months. The ADORA2A gene was found to carry a higher burden of variation among volunteers exposed to mefloquine with AEs compared to those who did not. The variant rs141942830 within ADORA2A was observed to be higher among cases compared to the reference allele frequency listed in the gnomAD database but was found to not be significantly enriched. In addition, MTFHR gene was found to be enriched for variation in volunteers with long-term side effects compared to those with short-term or no side effects. CONCLUSIONS: Volunteers who reported long-term adverse events after exposure to mefloquine had excess rare variation within the ADORA2A gene compared to those without adverse events and those with short term adverse events. The ADORA2A rs141942830 was identified as a new variant of interest, as it was elevated but not significantly enriched among cases of long-term AEs, compared to the population frequency reported by gnomAD. These non-silent variants may serve as mediators to alternate pathways for signal transduction or drug metabolism.