Candidate genes of the development of antipsychotic-induced parkinsonism in patients with schizophrenia

Antipsychotic-induced parkinsonism is an undesirable reaction from the extrapyramidal system that occurs against the background of taking antipsychotics (AP), more often in patients with schizophrenia. Antipsychotic-induced parkinsonism belongs to the group of secondary parkinsonism. Its prevalence in the world is about 36%. It is assumed that this undesirable AP reaction is genetically determined. In recent years, numerous associative genetic studies of predisposition to the development of antipsychotic-induced parkinsonism have been conducted. However, the research results are contradictory.Purpose. Review of the results of studies of genetic predictors of antipsychotic-induced parkinsonism in patients with schizophrenia.Materials and methods. We searched for full-text publications in Russian and English in the RSCI, PubMed, Web of Science, Springer databases using keywords and combined searches for words over the past decade.Results. The review considers candidate genes encoding proteins/enzymes involved in the pharmacodynamics and pharmacokinetics of AP. We analyzed 23 genome-wide studies examining 108 genetic variations, including SNV/polymorphisms of 26 candidate genes involved in the development of AIP in schizophrenic patients. Among such a set of obtained results, only 22 positive associations were revealed: rs1799732 (141CIns/Del), rs1800497 (C/T), rs6275 (C/T) DRD2; rs167771 (G/A) DRD3; VNTR*9R DAT1; rs4680 (G/A) СOMT; rs6311 (C/T) 5HTR2A; rs6318 (C/G), rs3813929 (С/Т), haplotype-997G, -759C, -697C и 68G HTR2C; rs2179652 (C/T), rs2746073 (T/A), rs4606 (C/G), rs1152746 (A/G), rs1819741 (С/Т), rs1933695 (G/A), haplotype rs1933695-G, rs2179652-C, rs4606-C, rs1819741-T и rs1152746-G, haplotype rs1933695-G, rs2179652-T, rs4606-G, rs1819741-C и rs1152746-A RGS2; haplotype TCCTC ADORA2A; rs4795390 (C/G) PPP1R1B; rs6265 (G/A) BDNF; rs12678719 (C/G) ZFPM2; rs938112 (C/A) LSMAP; rs2987902 (A/T) ABL1; HLA-B44; rs16947 (A/G), rs1135824 (A/G), rs3892097 (A/G), rs28371733 (A/G), rs5030867 (A/C), rs5030865 (A/C), rs1065852 (C/T), rs5030863 (C/G), rs5030862 (A/G), rs28371706 (C/T), rs28371725 (A/G), rs1080983 (A/G) CYP2D6. However, at the present time it should be recognized that there is no final or unique decision about the leading role of any particular SNV/polymorphism in the development of AIP.Conclusion. Disclosure of genetic predictors of AP-induced parkinsonism development may provide a key to the development of a strategy for personalized prevention and treatment of the neurological complication of AP-therapy of schizophrenia in real clinical practice.

Pharmacogenomics of Antihypertensive Drugs in Brazil: recent progress and clinical implications

Background: The available antihypertensive drugs are effective and well tolerated agents. However, only about half of patients with treated hypertension achieve appropriate blood pressure control. Genetic and non-genetic factors contribute to the interindividual variability of the therapeutic response Objective: This review constitutes a comprehensive update of the pharmacogenomics of antihypertensive drugs and their clinical implications in Brazil. Results: Twenty-five studies explored the influence of gene variants on drug response in patients with primary, resistant, or gestational hypertension. Variants in BDKRB2, NOS3, PRKCA, and VEGFA influenced the response to enalapril in patients with primary hypertension. AGT and MMP2 variants were associated with high risk of resistance to antihypertensive treatment, whereas NOS2 variants were related to low risk. Moreover, NAT2 slow acetylators showed an increased response to hydralazine in patients with resistant hypertension. HMOX1, NAMPT, MMP9, NOS3 and TIMP1 variants might be markers of drug responsiveness in hypertensive or preeclamptic pregnant women. Power and replication of studies, polygenic nature of response to therapy, and treatment with multiple drugs were important challenges to be overcome for identifying genetic predictors of antihypertensive response in Brazil. Conclusion: Pharmacogenomic studies in Brazilian cohorts provide some evidences of variants, mainly in pharmacodynamics genes, which influence the response to antihypertensive drugs. However, some findings are limited by cohort size or therapeutic scheme and may be influenced by interactions with other genetic and non-genetic factors. Therefore, further investigations are needed to elucidate the contribution of pharmacogenomics to the efficacy and safety of antihypertensive therapy.

FASN, SCD1 and ANXA9 gene polymorphism as genetic predictors of the fatty acid profile of sheep milk

In this study, single nucleotide polymorphisms (SNPs) in the ANXA9 (annexin 9), FASN (fatty acid synthase) and SCD1 (stearoyl-CoA desaturase 1) genes were analyzed as factors influencing fatty acid profiles in milk from Zošľachtená valaška sheep. SNP in selected genes was identified using polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR–RFLP). The long-chain fatty acids profile in sheep milk was identified by gas chromatography. Statistical analysis of the SCD1/Cfr13I polymorphism showed that the milk of the homozygous AA animals was characterized by a lower (P < 0.05) share of C4:0, C6:0, C8:0, C10:0, C12:0, C14:0 in comparison to the homozygous CC sheep. The milk of heterozygous sheep was characterized by a higher (P < 0.05) proportion of C13:0 acid compared to the milk of sheep with the homozygous AA type. A higher (P < 0.05) level of saturated fatty acids (SFA) was found in the milk of CC genotype sheep compared to the AA genotype. Our results lead to the conclusion that the greatest changes were observed for the SCD1/Cfr13I polymorphism and the least significant ones for FASN/AciI. Moreover, it is the first evidence that milk from sheep with SCD1/Cfr13I polymorphism and the homozygous AA genotype showed the most desirable fatty acids profile.

Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype—a risk allele associated with increased aldosterone secretion (either β2AR or ESR2 ) and a risk allele associated with amplification of aldosterone’s effects ( SGK1 ) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/SGK, ESR2/SGK , and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the β2AR/SGK (β=5.46; P <0.001) and ESR2/SGK ( β =4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/SGK and ESR2/SGK . On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of β2AR/SGK1 and ESR2 / SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy—gene-driven, personalized medicine.

Constitutional markers of urticaria and their prognostic significance (analysis of scientific literature)

Annotation. The purpose of the work is to analyze the scientific literature regarding the constitutional markers of urticaria and their prognostic significance. The analysis of modern scientific literature in the scientometric databases PubMed and MEDLINE is carried out. A review of the literature indicates that significant progress has been made in understanding the etiopathogenesis of urticaria in recent decades, with some clinical and anamnestic signs suggestive of adverse outcomes. However, identifying patients with the highest risk of complications remains an unresolved issue. In connection with the development and implementation in clinical practice of methods of genetic typing, much attention is paid to the search for genetic predictors of adverse course of this dermatosis. To date, phenotypic marker profiles that have been little modified over a lifetime and available for visualization in everyday clinical practice have not been properly considered in assessing the risk of urticaria. Modern anthropocentric approach to solving the problem of risk prediction in urticaria opens up the prospect of taking into account constitutional (personality-typological, somato-typological) and genetic factors that are the basis of psychobiological reactivity of the individual, determining individual variability of pathogenesis and clinical manifestations, patterns severity and frequency of complications.