About 80% of CKD (chronic kidney disease) patients are hypertensive, and kidney function and blood pressure are clearly related to both physiologic and pathologic conditions in a “vicious cycle”. In ...this pathologic scenario, there is a renin–angiotensin system (RAS) hyperactivity associated to progression of renal damage. Current guidelines indicate as the first choice of antihypertensive intervention, the pharmacologic blockade of the RAS. Nonetheless, both response to treatment and renal protection have considerable inter-individual variability. The main aims of this review are to describe the genetic characteristics of RAS components and to identify the possible pharmacogenetic implications for RAS-blocker drugs in the hypertension–CKD scenario. To date, RAS polymorphisms have not been consistently associated to antihypertensive response and studies focusing on CKD are scarce. Nonetheless, pharmacogenetic studies for the RAS-blocker drugs could still be further explored, especially with new generation tools and focusing not only on the antihypertensive response, but also on renal protection as well.
Pharmacogenetic testing is available to healthcare professionals to guide drug selection and prevent adverse events. However, its implementation in the clinical practice of psychiatry/neurology still ...has barriers, mainly due to a lack of evidence. We conducted a literature search on Cochrane Library, Embase and Pubmed, from their inception to 18 June 2020. We included 16 published systematic reviews. The most studied drug categories were anticonvulsants and selective serotonin reuptake inhibitors associated with human leukocyte antigen and cytochrome P450 genes (
,
,
,
,
), classified as critically low quality/low quality. There is a need for more robust studies with adequate design to assess the potential benefits of adopting pharmacogenetics in health systems and services.
The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine ...dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment.
This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis.
Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied.
CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Familial hypercholesterolemia (FH) is an autosomal dominant disease mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. FH patients present a wide variability regarding ...response to drugs and they are usually undertreated. Here, we review studies that evaluated the association between the type of LDLR mutation and the response to lipid-lowering therapy. The main findings were that patients with a null LDLR mutation had: higher baseline LDL-C, higher LDL-C after drug therapy, lower proportion of patients within the LDL-C target value and higher frequencies of CVD. Thus, we conclude that FH patients harboring a null mutation have a trend to an increased risk, even if diagnosis is early established and lipid-lowering treatment instituted. It is suggested that these individuals may benefit from the use of newly approved lipid-lowering agents.
Background
Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual ...variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in
ERCC1
,
ABCB1
,
CYP2C8
, and
CYP3A5
genes on the incidence of severe toxicities, including nephro- and hepatotoxicity.
Methods
A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin was recruited at the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consultations or from electronic medical records. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR.
Results
ABCB1
c.1236C>T was associated with moderate-to-severe (grades 2–4) nephrotoxicity (OR
adjusted
2.40; 95% CI 1.39–4.15), even after adjustment for age (≥ 65) and diabetes. The risk association between
ABCB1
c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (OR
adjusted
2.16; 95% CI 1.22–3.82).
ERCC1
c.118C>T was the only individual variable associated with an increased risk for moderate-to-severe (grades 2–4) hepatotoxicity (OR 3.71; 95% CI 1.08–12.77), severe nausea (OR 4.18; 95% CI 1.59–10.95), and severe myalgia (OR 1.95; 95% CI 1.12–3.40).
Conclusions
ABCB1
c.1236C>T and
ERCC1
c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers.
Purpose
Recent studies reported the association of
SLCO1B1
haplotypes with the development of musculoskeletal side effects during simvastatin use. The aim was to evaluate the pharmacogenetic ...association of
SLCO1B1
haplotypes with atorvastatin-induced myalgia in a sample of individuals on high-dose atorvastatin regimens.
Methods
One hundred and forty-three patients with familial hypercholesterolemia were followed for at least 12 months while receiving atorvastatin. Genotypes for the rs2306283 (c.A388G) and rs4149056 (c.T521C) polymorphisms were detected by high-resolution melting analysis. These markers form four distinct haplotypes (*1A, *1B, *5 and *15).
Results
During the follow-up period, 14 (9.8%) patients developed myalgia and 16 (11.2%) presented CK levels more than 3 times the upper limit of the normal range. No association of the
SLCO1B1
rs2306283 and rs4149056 genotypes or haplotypes with the presence of myalgia or creatine kinase (CK) values was found. Presence of rs2306283 AG + GG genotypes was not associated with increased risks of myalgia or abnormal CK values (OR 2.08, 95% CI 0.62–7.00,
p
= 0.24 and OR 0.51, 95% CI 0.21–1.26,
p
= 0.15 respectively). The presence of rs4149056 TC + CC genotypes was also not associated with increased risk of myalgia or abnormal CK values (OR 2.24, 95% CI 0.47–10.72,
p
= 0.31 and OR 1.51, 95% CI 0.57–3.96,
p
= 0.41 respectively).
Conclusions
Our findings reaffirm that the
SLCO1B1
genetic risk appears to be greater in those patients receiving simvastatin compared with those receiving atorvastatin. This suggests that the importance of
SLCO1B1
haplotypes depends on the specific statin that has been used.
Abstract Objectives Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on ...lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods For 14 ± 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results The frequencies of the types of LDLR mutations were: null-mutation ( n = 40, 25.6%), defective-mutation ( n = 59, 37.8%), and without an identified mutation ( n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 ± 1.9 mmol/L, 7.9 ± 1.7 mmol/L), compared to those with a defective (8.9 ± 2.2 mmol/L, 7.0 ± 2.0 mmol/L), or no mutation (7.9 ± 1.9 mmol/L, 5.8 ± 1.9 mmol/L) ( p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) ( p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41–58.16, p = 0.02). Conclusions Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation.
Resistant hypertension (RH) is defined as uncontrolled blood pressure despite treatment with three or more antihypertensive medications, including, if tolerated, a diuretic in adequate doses. It has ...been widely known that race is associated with blood pressure control. However, intense debate persists as to whether this is solely explained by unadjusted socioeconomical variables or genetic variation. In this scenario, the main aim was to evaluate the association between genetic ancestry and resistant hypertension in a large sample from a multicenter trial of stage II hypertension, the ReHOT study. Samples from 1,358 patients were analyzed, of which 167 were defined as resistant hypertensive. Genetic ancestry was defined using a panel of 192 polymorphic markers. The genetic ancestry was similar in resistant (52.0% European, 36.7% African and 11.3% Amerindian) and nonresistant hypertensive patients (54.0% European, 34.4% African and 11.6% Amerindian) (p > 0.05). However, we observed a statistically suggestive association of African ancestry with resistant hypertension in brown patient group. In conclusion, increased African genetic ancestry was not associated with RH in Brazilian patients from a prospective randomized hypertension clinical trial.
Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these ...events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist's warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient's INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2-3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 ± 0.010 vs. 0.382 ± 0.016; and 0.144 ± 0.010 vs. 0.543 ± 0.014,
< 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 ± 0.015; 0.540 ± 0.015,
< 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin.
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