The aim: To establish possible associations of the insulin receptor substrate-1 (IRS-1) gene polymorphism with the severity of the metabolic syndrome components in patients with arterial hypertension (AH).
Material and methods: 187 patients with AH aged 45-55 years and 30 healthy individuals. Methods: anthropometry, reactive hyperemia, color Doppler mapping, biochemical blood analysis, HOMA-insulin resistance (IR), glucose tolerance test, enzyme immunoassay, molecular genetic method.
Results: Among hypertensive patients, 103 had abdominal obesity, 43 - type 2 diabetes, 131 - increased blood triglycerides, 19 - decreased high density lipoproteins, 59 - prediabetes (33 - fasting hyperglycemia and 26 - impaired glucose tolerance), 126 had IR. At the same time, hypertensive patients had the following distribution of IRS-1 genotypes: Gly/Gly - 47.9%, Gly/Arg - 42.2% and Arg/Arg - 10.7%, whereas in healthy individuals the distribution of genotypes was significantly different: Gly/Gly - 86.8% (p <0.01), Gly/ Arg - 9.9% (p <0.01) and Arg/Arg - 3.3% (p <0.05). Hypertensive patients with Arg/Arg and Gly/Arg genotypes had significantly higher HOMA-IR (p <0.01), glucose, insulin and triglycerides levels (p <0.05), than in Gly/Gly genotype. At the same time, body mass index, waist circumference, blood pressure, adiponectin, HDL, interleukin-6, C-reactive protein, degree of endothelium-dependent vasodilation, as well as the frequency of occurrence of impaired glucose tolerance did not significantly differ in IRS-1 genotypes.
Conclusions: In hypertensive patients, the genetic polymorphism of IRS-1 gene is associated with such components of the metabolic syndrome as hypertriglyceridemia and fasting hyperglycemia; it is not associated with proinflammatory state, endothelial dysfunction, dysglycemia, an increase in waist circumference and decrease in HDL.
METHODS: Articles that report genetic polymorphisms, genotype frequencies and allele frequencies in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 were retrieved from the PubMed database.
RESULTS AND DISCUSSIONS: A total of 86 studies that fulfilled the eligibility criteria representing different ethnic populations of SEEA, ie, Burmese, Chinese, Japanese, Karen ethnic minority, Korean, Malaysian, Philippino, Singaporean, Taiwanese, Thai, Indonesian, and Vietnamese, were included in the analysis. In general, the genotype frequencies across SEEA populations are comparable. The CYP2C9*1/*1 (69.3%-99.1%), *1/*3 (2.3%-20.1%) and *3/*3 (0%-2.2%) genotypes are reported in most SEEA populations. Six major CYP2C19 genotypes, ie, *1/*1 (6.25%-88.07%), *1/*2 (21.5%-86.46%), *1/*3 (0.8%-15.8%), *2/*2 (3.4%-14.5%), *2/*3 (0%-7.3%) and *3/*3 (0%-10.2%), are reported in most SEEA populations. Major CYP2D6 genotypes include *10/*10 (0%-69.6%), *1/*1 (0%-61.21%) and *1/*10 (0%-62.0%). Major CYP3A5 genotypes are *3/*3 (2.0%-71.4%), *1/*3 (16.0%-57.1%) and *1/*1 (0%-82.0%). Genotyping of abnormal genotypes of CYP2C9 (*1/*3), CYP2C19 (*1/*2, *1/*3), CYP3A5 (*1/*3) and CYP2D6 (*5/*10) associated with IM (Intermediate metabolizer) status, may be clinically beneficial in SEEA populations. Similarly, with CYP2C19 (*2/*2, *2/*3), CYP2D6 (*5/*5 ) linked to PM (Poor metabolizer), CYP2D6 (*10/*10, *1/*5 and to lesser extent *1/*4, *2/*5, *10/*41, *10/*49, *10/*14) and CYP3A5 (*1/*1) associated with EM (extensive metabolizer).
WHAT IS NEW AND CONCLUSION: Sufficient number of studies has provided comparable results in general. This review suggests that comparable genotype frequencies of CYP2C9, CYP2C19, CYP2D6 and CYP3A5 exist among the SEEA populations. It is noted that more research data are reported from East Asians compared with South-East Asians. Concerned efforts are required to establish partnerships among SEEA countries that will ensure sufficient data from South-East Asian countries which will assist in establishing the databases for SEEA populations.
METHODS: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles.
RESULTS: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide.
CONCLUSION: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide's pharmacokinetics.
METHODOLOGY: This is a prospective study where patients (n=119) blood was tested for anti-HAVIgG and CYP3A4*18 polymorphism.
RESULTS: The overall anti-HAV seroprevalence was 88.2%. The etiology of CLD was hepatitis B in 96 patients (80.7%) and hepatitis C in 23 patients (19.3%). There was a significant increase in the age of the prevalence of this disease after 30 years of age (p=0.008). CYP3A4*18 polymorphism was detected in 3 (2.5%) of the patients with chronic liver disease. However, there was no significant association between CP3A4*18 mutation and anti-HAV serology.
CONCLUSIONS: Age was the most important factor in determining anti-HAV positivity. It is concluded that CYP3A4*18 genetic polymorphism does not play a main role in influencing the seroprevalence of anti-hepatitis A among chronic viral hepatitis B and C liver disease patients.