BACKGROUND: Genetic polymorphisms are known to play a crucial role in the development of osteoporosis. Vitamin D3 regulates bone homeostasis through the vitamin D receptor (VDR). Reduced VDR activity increases osteoporosis risk. Study Design: A case-control study.
METHODS: This case-control study investigated the potential association between six single-nucleotide polymorphisms (SNPs) within the VDR gene (rs11568820, rs4516035, rs2228570, rs1544410, rs7975232, and rs731236) and the occurrence of osteoporosis in Kerman province. The genotypes of the SNPs were analyzed using polymerase chain reaction-restriction fragment length polymorphism, tetra primer amplification refractory mutation system-PCR, and sequencing in two groups of osteoporosis patients (n=40) and controls (n=42). Additionally, the levels of calcium and vitamin D3 in the serum of the patients were measured, and the in silico analysis of the VDR structure and interaction was performed using I-TASSER, ProSA, PROCHECK, GeneMANIA, GTEx, and GPS 6.0.
RESULTS: None of the patients exhibited calcium or vitamin D3 deficiencies. Among the six SNPs, only the T allele in rs4516035, which leads to a shorter variant called VDRA, showed a significant association with susceptibility to osteoporosis (odds ratio=3.061, P=0.007). The in silico analysis demonstrated that the 3D structure, expression, and post-transcriptional modification of VDRA are distinct from those of the more extended variant, VDRB1. VDRB1 is upregulated in sun-exposed skin, and its interactions with its partners differ from those of VDRA.
CONCLUSIONS: Despite adequate vitamin D levels, the VDRA variant, which has lower activity, could increase the predisposition to osteoporosis in the studied population. These findings clarify the importance of genetic screening for personalized medicine and the effectiveness of prevention and treatment strategies.

BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.
OBJECTIVE: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).
METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.
RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).
CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

BACKGROUND: Hypothyroidism is a common endocrine disorder that exerts a substantial influence on people all over the world. Levothyroxine (LT-4) is the drug of choice for the treatment of hypothyroidism and the starting oral dose is typically ranging from 1.5 to 1.7 µg/kg/day. The target is to achieve an optimum serum TSH level of 0.4-4.0 mIU/L; hence, the dose is titrated accordingly. Once the LT-4 dose is adjusted to obtain the target TSH level, it usually remains stable for a long period of time in most cases. However, some of the patients require frequent dose adjustments and some of them require unusually high doses. Therefore, the aim of this study is to determine the association of pharmacogenomic, clinical and behavioural factors with the oral levothyroxine (LT-4) dose requirement of hypothyroid patients in Sri Lanka.
METHODS: This study will be conducted as a matched case-control study and will involve primary hypothyroid patients who visit the diabetes and endocrinology clinic at the National Hospital, Kandy, Sri Lanka. We will recruit a total of 292 cases and select 292 controls from the clinic who are matched in terms of age, sex and Body Mass Index (BMI). An interviewer-administered questionnaire will be used to collect data from the participants (n = 584). Of the 584 patients, blood samples will be collected from a sub-sample (n = 150) for DNA extraction. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) will be performed for single nucleotide polymorphisms (SNP) analysis.
CONCLUSIONS: Frequent dose adjustments of levothyroxine cause a serious economic burden to the healthcare system. By identifying the root causes of the variations in LT-4 dosage, a more comprehensive comprehension of hypothyroidism and its management can be attained in Sri Lanka. Furthermore, upon identification of a positive association/correlation between genetic polymorphisms and the LT-4 dose, SNP profiles can be used as a possible genetic marker for dose adjustment determination in future patients.

The case discussion demonstrates the benefit of using Pharmacogenomic (PGx) results to aid in the selection of antidepressant therapy and improve response to treatment. Nearly half of patients diagnosed with major depressive disorder fail initial therapy and may require multiple trials of antidepressants. Genetic variation in several metabolic enzymes contribute to the variable response to antidepressant therapy. PGx testing provides an opportunity to inform antidepressant selection and optimize therapeutic outcomes, while minimizing risk of adverse events. A 79-year-old female who had been experiencing a suboptimal response to escitalopram following dose escalation over a period of three years was referred for a PGx consultation. A clinical pharmacist assessed significant drug-gene, drug-drug, and drug-drug-gene interactions, and relevant clinical information to recommend alternative antidepressant therapy, which resulted in mood improvement.

UNASSIGNED: Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables.
UNASSIGNED: Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to ≥3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment.
UNASSIGNED: We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma.
UNASSIGNED: Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceived SAMS, but the findings have to be confirmed in larger studies.

Lack of equitable representation of global genetic diversity has hampered the implementation of genomic medicine in under-represented populations, including those on the African continent. Data from the multi-national Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study suggest that genotype guidance for prescriptions reduced the incidence of clinically relevant adverse drug reactions (ADRs) by 30%. In this study, hospital dispensary trends from a tertiary South African (SA) hospital (Steve Biko Academic Hospital; SBAH) were compared with the drugs monitored in the PREPARE study. Dispensary data on 29 drugs from the PREPARE study accounted for ~10% of total prescriptions and ~9% of the total expenditure at SBAH. VigiLyze data from the South African Health Products Regulatory Authority were interrogated for local ADRs related to these drugs; 27 were listed as being suspected, concomitant, or interacting in ADR reports. Furthermore, a comparison of pharmacogene allele frequencies between African and European populations was used to frame the potential impact of pre-emptive pharmacogenetic screening in SA. Enumerating the benefit of pre-emptive pharmacogenetic screening in SA will only be possible once we initiate its full application. However, regional genomic diversity, disease burden, and first-line treatment options could be harnessed to target stratified PGx today.

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Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here, we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary health care system.
We performed a query of psychiatry service note text in our electronic health record using 71 predefined PGx terms. Patients who underwent combinatorial PGx testing were identified, and documentation of test results was analyzed. Prescription data following testing were examined for the frequency of prescriptions influenced by genes on the panel along with the medical specialties involved.
A total of 341 patients received combinatorial PGx testing, and documentation of results was found to be absent or incomplete for 198 patients (58%). The predominant method of documentation was through portable document formats uploaded to the electronic health record\'s \"Media\" section. Among patients with at least 1 year of follow-up, a large majority (194/228, 85%) received orders for medications affected by the tested genes, including 132 of 228 (58%) patients receiving at least 1 non-psychiatric medication influenced by the test results.
Results from combinatorial PGx testing were poorly documented. Medications affected by these results were often prescribed after testing, highlighting the need for discrete results and clinical decision support.

The first approaches in recent years for the integration of pharmacogenomic plausibility checks into clinical practice show both a promising improvement in the drug therapy safety, but also difficulties in application. One of the difficulties is the meaningful interpretation of the text-based results by the medical practitioner. We propose here as an appropriate and sensible solution to avoid misunderstandings and to include evidence-based, pharmacogenomic recommendations in prescriptions, which should be the graph-based visualization of the reports. This allows for a plausible interpretation and relate complex, even contradictory guidelines. The improved overview over the pharmacogenomics (PGx) guidelines using the graphical visualization makes the medical practitioner\'s choice of dose and medication more patient-specific, improves the treatment outcome and thus, increases the drug therapy safety.

UNASSIGNED: Once thought to be primarily a result of lifestyle, it is now known that obesity has significant genetic components. Dozens of genes have been linked to obesity, and office-based genetic testing for obesity-associated genes is now readily available. As both pharmacotherapy and genetic testing for obesity become more accessible, pharmacogenetic personalization is becoming a reality. In this case report, a patient with a PLXNA4 polymorphism had a superior weight loss response to phentermine/topiramate therapy than has previously been reported in the literature. Thus, variants in PLXNA4 may provide a genetic basis for this patient\'s superior response to weight loss pharmacotherapy and cardiovascular risk factor reduction.
UNASSIGNED: In this case study, office-based genetic testing was utilized to identify the presence of variants in nearly 80 genes that have been linked to obesity in a patient who had hyper-responsive weight loss results on phentermine/topiramate pharmacotherapy.
UNASSIGNED: A variant of the PLXNA4 gene, which has known pathogenic variants linked to genetic obesity syndromes, was identified in this patient who had a superior weight loss response to phentermine/topiramate pharmacotherapy.
UNASSIGNED: Due to overlapping molecular pathways, it is possible that PLXNA4 variants convey a superior weight-loss response and therefore superior cardiovascular risk factor reduction phentermine/topiramate therapy. Further studies are needed to examine the relationship between PLXNA4 variants and weight loss with phentermine/topiramate pharmacotherapy.