Role of CYP2D6 Polymorphisms in the Outcome of Postoperative Pain Treatment.

OBJECTIVE: To investigate the role of CYP2D6 phenotype in the outcome of postoperative (PO) pain (POP) treatment. DESIGN: Longitudinal cohort study. Open-label trial with post hoc analysis. SETTING: General Hospital Surgery and Recovery Units. PATIENTS: Ninety unrelated Caucasians submitted to abdominal/thoracic surgery. INTERVENTIONS: Standard multimodal POP treatment including opioids (tramadol) and nonsteroidal anti-inflammatory drugs (ketoprofen) at different dosages and infusion rates according to the predicted mild, moderate, or severe POP. OUTCOME MEASURES: Pain (Numeric Rating Scale-NRS) and sedation (Ramsay Sedation Scale-RSS) up to 24 hours after surgery. By genotyping 16 CYP2D6 alleles, the four CYP2D6 phenotypes poor metabolizer (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM) were predicted. RESULTS: As compared with the CYP2D6-EM phenotype, in the early PO time (30 min) a higher RSS mean score in IM was observed (P = 0.035). A suggestion towards higher mean score in PM (P = 0.091) and a minor mean score in UM (P = 0.091) was also detected. No difference in the outcome of pain across the CYP2D6 phenotypes was observed. CONCLUSIONS: In respect to the normal CYP2D6 phenotype, our results suggested that slowly metabolizers (IMs and PMs) might have a major sedation, whereas more rapid metabolizers (UM) a minor sedation, in the early time after surgery. A minor role of CYP2D6 phenotype in PO analgesia may be suggested.

The Role of TOMM40 in Cardiovascular Mortality and Conduction Disorders: An Observational Study.

Aims: TOMM40 single nucleotide polymorphism (SNP) rs2075650 consists of allelic variation c.275-31A > G and it has been linked to Alzheimer disease, apolipoprotein and cholesterol levels and other risk factors. However, data on its role in cardiovascular disorders are lacking. The first aim of the study is to evaluate mortality according to TOMM40 genotype in a cohort of selected patients affected by advanced atherosclerosis. Second aim was to investigate the relationship between Xg and AA alleles and the presence of conduction disorders and implantation of defibrillator (ICD) or pacemaker (PM) in our cohort. Materials and Methods: We enrolled 276 patients (mean age 70.16 ± 7.96 years) affected by hemodynamic significant carotid stenosis and/or ischemia of the lower limbs of II or III stadium Fontaine. We divided the population into two groups according to the genotype (Xg and AA carriers). We evaluated several electrocardiographic and echocardiographic parameters, including heart rate, rhythm, presence of right and left bundle branch block (LBBB and RBBB), PR interval, QRS duration and morphology, QTc interval, and left ventricular ejection fraction (LVEF). We clinically followed these patients for 82.53 ± 30.02 months and we evaluated the incidence of cardiovascular events, number of deaths and PM/ICD implantations. Results: We did not find a difference in total mortality between Xg and AA carriers (16.3 % vs. 19.4%; p = 0.62). However, we found a higher mortality for fatal cardiovascular events in Xg carriers (8.2% vs. 4.4%; HR = 4.53, 95% CI 1.179-17.367; p = 0.04) with respect to AA carriers. We noted a higher percentage of LBBB in Xg carriers (10.2% vs. 3.1%, p = 0.027), which was statistically significant. Presence of right bundle branch block (RBBB) was also higher in Xg (10.2% vs. 4.4%, p = 0.10), but without reaching statistically significant difference compared to AA patients. We did not observe significant differences in heart rate, presence of sinus rhythm, number of device implantations, PR and QTc intervals, QRS duration and LVEF between the two groups. At the time of enrolment, we observed a tendency for device implant in Xg carriers at a younger age compared to AA carriers (58.50 ± 0.71 y vs. 72.14 ± 11.11 y, p = 0.10). During the follow-up, we noted no statistical difference for new device implantations in Xg respect to AA carriers (8.2% vs. 3.5%; HR = 2.384, 95% CI 0.718-7.922; p = 0.156). The tendency to implant Xg at a younger age compared to AA patients was confirmed during follow-up, but without reaching a significant difference(69.50 ± 2.89 y vs. 75.63 ± 8.35 y, p = 0.074). Finally, we pointed out that Xg carriers underwent device implantation 7.27 ± 4.43 years before AA (65.83 ± 6.11 years vs. 73.10 ± 10.39 years) and that difference reached a statistically significant difference (p = 0.049) when we considered all patients, from enrollment to follow-up. Conclusions: In our study we observed that TOMM40 Xg patients affected by advanced atherosclerosis have a higher incidence of developing fatal cardiovascular events, higher incidence of LBBB and an earlier age of PM or ICD implantations, as compared to AA carriers. Further studies will be needed to evaluate the genomic contribution of TOMM40 SNPs to cardiovascular deaths and cardiac conduction diseases.

Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.

INTRODUCTION: Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. OBJECTIVES: The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. MATERIALS AND METHODS: Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). RESULTS: As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. CONCLUSIONS: In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.

Italian Case Report with a Double Mutation in PSEN1 (K311R and E318G).

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The clinical spectrum of suspected AD has been extended from mild cognitive impairment (MCI) to preclinical AD which includes people who have typical cognitive function but harbor the underlying biological features of AD. We report the first case of an Italian patient affected by MCI (MMSE 24\30), characterized by a double mutation p.Lys311Arg (K311R) and p.Glu318Gly (E318G) in Presenilin-1 but with the absence of abnormal accumulation of amyloid beta.

The APOE polymorphism in Alzheimer's disease patients with neuropsychiatric symptoms and syndromes.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a common feature of Alzheimer's disease (AD), resulting in particular AD endophenotypes. The common AD genetic risk factor apolipoprotein E (APOE) has been suggested underlying these AD endophenotypes. METHODS: APOE genotyping, a comprehensive geriatric assessment (CGA), and Neuropsychiatric Inventory were performed on 322 consecutive older patients. Patients were divided into three groups: AD with NPS (N = 93), AD without NPS (N = 108), and, as a control group, patients with no cognitive impairment (NoCI: N = 121). Patients with NPS were further sub-divided in four groups according to the European Alzheimer's Disease Consortium (EADC) classification of neuropsychiatric syndromes in AD: hyperactive, psychotic, affective, and apathetic. RESULTS: AD patients with NPS showed a significantly higher grade of cognitive impairment, more severity stage of dementia, more disability in the activities of daily living (ADL), and the instrumental ADL than AD patients without NPS. As expected, an higher frequency of APOE ε3/ε4 genotype was observed in patients with AD, both with and without NPS, than patients with NoCI. No difference in the distribution of APOE genotypes was found between AD patients with vs. without NPS. However, in AD patients APOE ε4-carriers, there was an increased risk of affective [odds ratio (OR): 2.34, 95% confidence interval (CI): 1.19-4.58) and apathetic (OR: 2.24,95%CI: 1.19-4.22) syndromes. CONCLUSIONS: These findings did not suggest a significant association between APOE polymorphism and presence of NPS in AD patients. In AD patients with NPS, however, APOE ε4-carrier status was associated with an increased risk of affective and apathetic syndromes.

Polymorphism C in the serotonin transporter gene in depression-free elderly patients with vascular dementia.

BACKGROUND: Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD). AIMS: To evaluate the possible involvement of different SLC6A4 genotypes/haplotypes in VaD. METHODS: The analysis of the 3 markers rs3813034, rs140701 and rs4795541 spanning the SLC6A4 locus was made in 541 consecutive patients clinically diagnosed as having VaD (n = 372) or no cognitive impairment (n = 169) attending a geriatric ward. A community-dwelling sample of 353 healthy subjects, as a reference for the genetic frequencies in the recruitment area, was also included in the study. All patients and subjects were free from any symptoms of depression, obsessive-compulsive disorder and anxiety. A complete neuroimaging documentation was available for all patients. RESULTS: No important differences were observed in genotype distribution across the study groups. Similarly, no important differences were observed in haplotype distribution when a 3-point analysis was made. CONCLUSION: Our findings suggest that polymorphism C in the promoter region of the SLC6A4 gene plays a minor role, if any, in the pathogenesis of VaD.

Pharmacogenetics in the clinical analysis laboratory: clinical practice, research, and drug development pipeline.

Introduction: Over the last decade, the spread of next-generation sequencing technology along with the rising cost in health management in national health systems has led to widespread use/abuse of pharmacogenetic tests (PGx) in the practice of many clinical disciplines. However, given their clinical significance, it is important to standardize these tests for having an interaction with the clinical analysis laboratory (CAL), in which a PGx service can meet these requirements. Areas covered: A diagnostic test must meet the criteria of reproducibility and validity for its utility in the clinical routine. This present review mainly describes the utility of introducing PGx tests in the CAL routine to produce correct results useful for setting up personalized drug treatments. Expert opinion: With a PGx service, CALs can provide the right tool to help clinicians to make better choices about different categories of drugs and their dosage and to manage the economic impact both in hospital-based settings and in National Health Services, throughout electronic health records. Advances in PGx also allow a new approach for pharmaceutical companies in order to improve drug development and clinical trials. As a result, CALs can achieve a powerful source of epidemiological, clinical, and research findings from PGx tests.

Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer's disease.

BACKGROUND: Serotoninergic pathways underlying delusion symptoms in Alzheimer's disease (AD) have not been fully clarified. 5-Hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats in the promoter region of serotonin transporter encoding-gene affecting transcription. METHODS: We investigated the association of 5-HTTLPR with delusions in a total of 257 consecutive patients clinically diagnosed as AD according to the National Institute on Aging-Alzheimer's Association criteria. All participants underwent a comprehensive evaluation with a standardized comprehensive geriatric assessment and Neuropsychiatric Inventory. RESULTS: Delusion symptoms were observed in 171 patients (66.54%). In respect to AD patients without delusions, AD patients with delusions showed a low prevalence of S-plus carriers (5-HTTLPR-L/S + 5-HTTLPR-S/S genotypes) [p < 0.001; odds ratio (OR) = 0.240, 95% confidence interval (CI) = 0.121-0.471]. Logistic regression analysis adjusted for the apolipoprotein E polymorphism showed that in AD patients with delusions the presence of an 5-HTTLPR-S allele may reduce disease duration (p = 0.005; OR = 0.680, 95% CI = 0.522-0.886) and increase aberrant motor activity (p = 0.013; OR = 2.257, 95% CI = 1.195-4.260). The present findings suggested that 5-HTTLPR might be associated with delusions in AD. S-plus carriers might be associated with protective effect against delusions in AD. CONCLUSIONS: More studies on wider samples of high selected demented patients are needed to confirm our results. However, the present findings suggested that a genetic factor related to serotonin metabolism might exert a protective role on the clinical expression of neuropsychiatric clusters in AD with important implications regarding mechanisms underlying delusions and their possible treatment across the AD and dementia spectrum.

The RELN locus in Alzheimer's disease.

Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in 223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females.

CYP2D6 genotypes in revolving door patients with bipolar disorders: A case series.

RATIONALE: In psychiatric disorders, interindividual differences in cytochrome P450 (CYP)2D6 (CYP2D6) enzymatic activity could be responsible of adverse drug reactions (ADRs) and therapeutic failures (TFs) for CYP2D6-metabolized drugs, contributing to the periodical hospital readmissions of the revolving door (RD) condition. PATIENT CONCERNS: We investigated CYP2D6 genotypes in a controlled series of 5 consecutive RD patients with Bipolar Disorder (BD). DIAGNOSES: Psychiatric patients affected by Bipolar Disorder. INTERVENTIONS: We defined TFs as a difference at the Brief Psychiatric Rating Scale score ΔBPRS < 25% at each 1-week of stable treatment, and ADRs as the onset of extrapyramidal symptoms and/or metabolic impairment with weight gain. OUTCOMES: At 3 months, a mean number of 2.75 ±â€Š1.26 ADR and a mean ΔBPRS score of 16.07 ±â€Š0.05% were observed. At 6 months of follow-up, compared to the only patient without BD (ΔBPRS < 32.10%), BD patients (n = 4) showed TFs (ΔBPRS < 25%). CYP2D6 genotyping revealed intermediate metabolizer phenotypes for BD patients and an extensive metabolizer phenotype for the patient without BD. In BD patients, the ratio of drugs maintained/discontinued for TFs or ADRs was 1.75 for non-CYP2D6 versus 0.33 for CYP2D6 interacting drugs, while the proportion of ADR:TF was 0:4 versus 6:3. LESSONS: Our findings may suggest that CYP2D6 clinically relevant genotypes may be involved in the unwanted outcomes observed in RD patients with BD.

Erythrocyte Associated Amyloid-ß as Potential Biomarker to Diagnose Dementia.

BACKGROUND: Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid ß-peptide (Aß) in the human brain, its pathogenic role has to be completely clarified. Aß moves from the bloodbrain barrier to the plasma and an increased Aß production in brain could be associated with higher Aß concentrations in blood. A recent study has evaluated Aß40 and Aß42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aß concentration in RBCs. OBJECTIVE: The aim of the study was to investigate if erythrocyte associated Aß (iAß) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes. METHOD: To answer these questions we assessed iAß40 and iAß42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD. RESULTS: In this population we found significant differences in iAß42 between controls and cognitive impaired patients. Moreover, iAß42 significantly differed between dementia vs MCI. AD also showed different iAß42 levels as compared to VaD. Conversely, no differences were found for iAß40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAß42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found. CONCLUSION: Our findings support the evidence that iAß42 could be an instrument to early recognize dementia and predict cognitive impairment.

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder.

Klotho protein, encoded by the Klotho gene (KL) at locus 13q12, is an antiaging hormone-like protein playing a pivotal role in cell metabolism homeostasis and associated to longevity and age-related diseases. In particular, altered cell metabolism in central nervous system may influence the behavior of serotoninergic neurons. The role of KL in the response to treatment with selective serotonin reuptake inhibitors (SSRIs) in late-life depressive syndromes and late-life major depressive disorder (MDD) is unclear. We genotyped three single-nucleotide polymorphisms (SNPs) of KL in 329 older patients with diagnosis of late-life MDD, treated with SSRIs and evaluated with the Hamilton Rating Scale for Depression 21-items (HRSD-21) at baseline and after 6 months. A reduction ≥50 and <10 % in HDRS-21 score was considered as response or nonresponse to therapy, respectively, and the values of reduction between 10 and 49 % as poor responders. After 6 months of SSRI treatment, 176 patients responded, 54 patients did not respond and 99 patients showed a poor response. Ordinal logistic models showed a significant association between mutation of SNP rs1207568 and responders and, similarly, for each unitary risk allele increase overlapping results were found. Conversely, a significantly higher frequency of the minor genotype of SNP rs9536314 was found in nonresponders. Considering the pre-post differences of HRSD-21 scores as a continue variable, we confirmed a significant improvement of depressive symptoms after treatment in patients carrying at least one minor allele at rs1207568 and a worse response in patients homozygous for the minor allele at rs9536314. Our results were the first that suggested a possible role of KL in the complex pathway of SSRI response in late-life MDD.

Role of the APOE polymorphism in carotid and lower limb revascularization: A prospective study from Southern Italy.

BACKGROUND: Atherosclerosis is a complex multifactorial disease and the apolipoprotein E (APOE) polymorphism has been associated to vascular complications of atherosclerosis. OBJECTIVES: To investigate the relationship between the APOE genotypes and advanced peripheral vascular disease. MATERIALS AND METHODS: 258 consecutive patients (201 males and 57 females, mean age 70.83 ± 7.89 years) with severe PVD were enrolled in a 42-months longitudinal study (mean 31.65 ± 21.11 months) for major adverse cardiovascular events. At follow-up genotypes of the APOE polymorphism were investigated in blinded fashion. RESULTS: As compared with ε3/ε3, in ε4-carriers a significant higher incidence of major adverse cardiovascular events (35.58% vs. 20.79%; p = 0.025) and total peripheral revascularization (22.64% vs. 5.06%; p < 0.001) was observed. Prospective analysis, showed that ε4-carriers have an increased hazard ratio for major adverse cardiovascular events (adjusted HR 1.829, 95% CI 1.017-3.287; p = 0.044) and total peripheral revascularization (adjusted HR = 5.916, 95% CI 2.405-14.554, p <0.001). CONCLUSIONS: The ε4 allele seems to be risk factor for major adverse cardiovascular events, and in particular for total peripheral revascularization in patients with advanced atherosclerotic vascular disease.

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy.

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.

Simple and effective determination of apolipoprotein E genotypes by positive/negative polymerase chain reaction products.

Several protein and DNA-based methods have been previously described for the identification of apolipoprotein E isoforms or genotypes. However, all of them generate frequently false-positive results. The purpose of this study was to set up a new, simple, and effective method for the analysis of the apoE polymorphism. A total of 1,253 subjects previously examined for the apolipoprotein E polymorphism by restriction fragment length polymorphism were reanalyzed by our new method based on Taq DNA polymerase's inability to correctly initiate the replication in the presence of a mismatch at the 3' end of the primer. We conceived a combination of 4 specific primers in 3 different pairs sharing the same stringent polymerase chain reaction conditions to directly detect the presence/absence of polymerase chain reaction products, and thus reveal the 6 apolipoprotein E genotypes. We confirm our previous results in 1,171 subjects, whereas in 82 subjects out of 1,253 (about 6%), the results have been reinterpreted. The final analysis revealed a total of 12 homozygotic subjects for the e2 allele (1.0%), 874 homozygotes for the e3 allele (69.8 %), and 8 homozygotes for the e4 allele (0.6 %). The frequence of heterozygotes was 8.7% for the e2/e3 genotype (n=109), 1.4% for the e2/e4 genotype (n=17), and 0.6% for the e3/e4 genotype (n=8). Relative allele frequencies were e2=0.060, e3=0.834, and e4=0.106. We describe a new, simple, unequivocal, and nonexpensive method for the identification of the 6 apoE genotypes.

Psychiatry meets pharmacogenetics for the treatment of revolving door patients with psychiatric disorders.

INTRODUCTION: Therapeutic failures (TFs) and adverse drug reactions (ADRs), together with the recurring nature of the clinical course of psychiatric disorders, mainly bipolar disorders (BDs), strongly contributed to the prevalence and frequency of hospital readmissions observed in these patients. This is the revolving door (RD) condition, dramatically rising costs for the management of these patients in psychiatric settings. Areas covered: We searched in the medical literature until May 2016 to review the role of functional variants in the cytochrome P450 (CYP) 2D6 gene on observed ADRs and TFs in RD patients with BDs, conferring a different capacity to metabolize psychotropic drugs. Expert commentary: CYP2D6 functional polymorphisms might directly contributed to the prevalence and frequency of the RD condition, commonly observed in BD patients. Although several environmental and socio-demographic/diagnostic variables such as alcohol/drug abuse, and medication non-compliance accounted for a significant proportion of the ability to predict RD prevalence and frequency, the pharmacogenetics of CYP, particularly CYP2D6, may help to identify BD patients at risk for ADRs and TFs. These patients may be addressed towards alternative treatments, thus improving their quality of life, and reducing RD prevalence and frequency and the overall costs for their management.

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.

Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors.

PURPOSE: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions. EXPERIMENTAL DESIGN: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTP1, TRbeta1, RARbeta2, HIC1, APC, CCND2, and CDH1 genes. RESULTS: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRbeta1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RARbeta2 locus (P < 0.03). CONCLUSIONS: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.