A genetic variant has recently reached genome-wide significance for association with TNF-inhibitor response in rheumatoid arthritis patients. Here we undertake a replication study in a UK Caucasian population to test for association with TNF-inhibitor response.

The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population.

Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2-33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96-23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90-75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83-40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.

Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.

To determine the projected impact of a multigene pharmacogenetic (PGx) test on medication prescribing.

Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region.

The application of pharmacogenomics could meaningfully contribute toward medicines optimization within primary care. This review identified 13 studies describing eight implementation models utilizing a multi-gene pharmacogenomic panel within a primary care or community setting. These were small feasibility studies (n <200). They demonstrated importance and feasibility of pre-test counseling, the role of the pharmacist, data integration into the electronic medical record and point-of-care clinical decision support systems (CDSS). Findings were considered alongside existing primary care prescribing practices and implementation frameworks to demonstrate how issues may be addressed by existing nationalized healthcare and primary care infrastructure. Development of point-of-care CDSS should be prioritized; establishing clinical leadership, education programs, defining practitioner roles and responsibilities and addressing commissioning issues will also be crucial.

Aim: Numerous drugs are being widely prescribed for COVID-19 treatment without any direct evidence for the drug safety/efficacy in patients across diverse ethnic populations. Materials & methods: We analyzed whole genomes of 1029 Indian individuals (IndiGen) to understand the extent of drug-gene (pharmacogenetic), drug-drug and drug-drug-gene interactions associated with COVID-19 therapy in the Indian population. Results: We identified 30 clinically significant pharmacogenetic variants and 73 predicted deleterious pharmacogenetic variants. COVID-19-associated pharmacogenes were substantially overlapped with those of metabolic disorder therapeutics. CYP3A4, ABCB1 and ALB are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four CYP inhibitor drugs. Conclusion: Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.

Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.

Background:Plasmodium vivax malaria is endemic in Madagascar, where populations have genetic inheritance from Southeast Asia and East Africa. Primaquine, a drug of choice for vivax malaria, is metabolized principally via CYP2D6. CYP2D6 variation was characterized by locus-specific gene sequencing and was compared with TaqMan™ genotype data. Materials & methods: Long-range PCR amplicons were generated from 96 Malagasy samples and subjected to next-generation sequencing. Results: The authors observed high concordance between TaqMan™-based CYP2D6 genotype calls and the base calls from sequencing. In addition, there are new variants and haplotypes present in the Malagasy. Conclusion: Sequencing unique admixed populations provides more detailed and accurate insights regarding CYP2D6 variability, which may help optimize primaquine treatment across human genetic diversity.

Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.