N-acetyltransferase 2 (NAT2) and Cytochrome 2C9 (CYP2C9) Genes Polymorphisms in Type 2 Diabetes Mellitus Patients in Yaoundé, Cameroon

Although several environmental factors influence the onset of type 2 Diabetes Mellitus (T2DM), genetic factors contribute to an individual vulnerability to this disease. This study was aimed at studying CYP2C9*3 single nucleotide polymorphism (SNP) and NAT2 gene polymorphisms, and their correlation, if any, in the susceptibility to type 2 diabetes in Yaoundé, Cameroon. This was a case-control study involving 70 participants living in Yaoundé, Cameroon. DNA was extracted by Chelex 100 method. Polymorphisms of NAT2 gene and CYP2C9*3 SNP were assessed using Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP). NAT2 gene characterization revealed the predominance of NAT2*5 alleles (35%) and slow metabolizing phenotype (72.9%). CYP2C9 gene characterization revealed the predominance of the wild-type allele (54%) and intermediate metabolizing phenotype (91%). Individuals with the “NAT2 slow metabolizer” phenotype were more likely to have T2DM while those with “intermediate metabolizer” phenotype were less likely to develop this disease (OR = 3.9740, P = 0.0009 and OR = 0.1406, P = 0.0044, respectively). CYP2C9*3 had no discernable predisposition to T2DM (OR= 0.1765, P= 0.1981). This study demonstrates that the NAT2 slow metabolizer phenotype could be associated with the development of T2DM in Yaoundé, Cameroon.

DO VKORC1 AND CYP2C9 MUTATIONS LEAD TO WARFARIN RESISTANCE?

The objective of this study was to determine the influence of VKORC1 and CYP2C9 polymorphisms on warfarin resistant patients. Warfarin resistance is described as the inability to prolong the prothrombin time or raise the INR up to the 2 therapeutic range when the drug is given at typically doses. Polymorphisms may play a role as some VKORC1 and CYP2C9 variant alleles are known to be associated with these circumstances. 28 patients who were taking warfarin more than 15 mg/day and had INR values below 2.1 and had thromboembolic events while using warfarin were enrolled in this study. Heterozygote mutation in the VKORC1 gene was identified in 15 of 28 patients. Seven patients had heterozygote mutation of the CYP2C9 gene, and that may correspond to the ultrarapid metabolism of warfarin. VKORC1 and CYP2C9 polymorphism contribute to the difference in dose requirement amongst the patients, but other additional possible factors may play a role in different races. We suggest that medicians may use this tests before starting warfarin therapy and shape the treatment course according to this results.

Influence of Pathogenic and Metabolic Genes on the Pharmacogenetics of Mood Disorders in Alzheimer’s Disease

Background: Mood disorders represent a risk factor for dementia and are present in over 60% of cases with Alzheimer’s disease (AD). More than 80% variability in drug pharmacokinetics and pharmacodynamics is associated with pharmacogenetics. Methods: Anxiety and depression symptoms were assessed in 1006 patients with dementia (591 females, 415 males) and the influence of pathogenic (APOE) and metabolic (CYP2D6, CYP2C19, and CYP2C9) gene variants on the therapeutic outcome were analyzed after treatment with a multifactorial regime in a natural setting. Results and Conclusions: (i) Biochemical, hematological, and metabolic differences may contribute to changes in drug efficacy and safety; (ii) anxiety and depression are more frequent and severe in females than males; (iii) both females and males respond similarly to treatment, showing significant improvements in anxiety and depression; (iv) APOE-3 carriers are the best responders and APOE-4 carriers tend to be the worst responders to conventional treatments; and (v) among CYP2D6, CYP2C19, and CYP2C9 genophenotypes, normal metabolizers (NMs) and intermediate metabolizers (IMs) are significantly better responders than poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) to therapeutic interventions that modify anxiety and depression phenotypes in dementia. APOE-4 carriers and CYP-related PMs and UMs deserve special attention for their vulnerability and poor response to current treatments.

PHARMACOGENETIC PROFILE AND PERSONALIZATION POSSIBILITIESIN TREATMENT OF PATIENTS WITH CHRONIC PELVIC PAIN SYNDROME

Chronic pelvic pain syndrome (CPPS) is equally common in both men and women, causes worsening quality of life, social isolation and disability. The treatment of CPPS requires long-term pharmacotherapy associated with the development of class-specific side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Genetic study of the carriage of polymorphic alleles of the CYP2C9 gene involved in the metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to patients with CPPS is an urgent and in-demand task of modern healthcare. This study allows us not only to determine the genotypes of patients with CPPS but also to identify ways of personalized approach to therapy.

Variations in the frequencies of polymorphisms in the CYP2C9 gene in six major ethnicities of Pakistan

Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Baloch population possesses low activity genotypes. The frequencies found in various ethnic groups in Pakistan were comparable with ethnicities in the South Asian region except for the Baloch population. These results suggest that pharmacogenetics screening for low activity genotypes may be a helpful tool for clinicians while prescribing medications metabolized by CYP2C9.