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Background In the substantia nigra of Parkinson's disease (PD) patients, increased lipid peroxidation, decreased activities of the mitochondrial complex I of the respiratory chain, catalase and glutathione-peroxidase, and decreased levels of reduced glutathione have been reported. These observations suggest that oxidative stress and mitochondrial dysfunction play a role in the neurodegeneration in PD. We assessed enzymatic activities of respiratory chain and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with PD. Methods We studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, and coenzyme Q10 levels in skin fibroblasts cultures from 20 Parkinson's disease (PD) patients and 19 age- and sex- matched healthy controls. Results When compared with controls, PD patients showed significantly lower specific activities for complex V (both corrected by citrate synthase activity and protein concentrations). Oxidized, reduced and total coenzyme Q10 levels (both corrected by citrate synthase and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, did not differ significantly between PD-patients and control groups. Values for enzyme activities in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinson's Disease Rating scales and Hoehn-Yahr staging. Conclusions The main result of this study was the decreased activity of complex V in PD patients. This complex synthesizes ATP from ADP using an electrochemical gradient generated by complexes I-IV. These results suggest decreased energetic metabolism in fibroblasts of patients with PD.

Epidermal growth factor receptor (EGFR) and its downstream factors KRAS and BRAF are mutated in several types of cancer, affecting the clinical response to EGFR inhibitors. Mutations in the EGFR kinase domain predict sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in lung adenocarcinoma, while activating point mutations in KRAS and BRAF confer resistance to the anti-EGFR monoclonal antibody cetuximab in colorectal cancer. The development of new generation methods for systematic mutation screening of these genes will allow more appropriate therapeutic choices. We describe a high resolution melting (HRM) assay for mutation detection in EGFR exons 19-21, KRAS codon 12/13 and BRAF V600 using formalin-fixed paraffin-embedded samples. Somatic variation of KRAS exon 2 was also analysed by massively parallel pyrosequencing of amplicons with the GS Junior 454 platform. We tested 120 routine diagnostic specimens from patients with colorectal or lung cancer. Mutations in KRAS, BRAF and EGFR were observed in 41.9%, 13.0% and 11.1% of the overall samples, respectively, being mutually exclusive. For KRAS, six types of substitutions were detected (17 G12D, 9 G13D, 7 G12C, 2 G12A, 2 G12V, 2 G12S), while V600E accounted for all the BRAF activating mutations. Regarding EGFR, two cases showed exon 19 deletions (delE746-A750 and delE746-T751insA) and another two substitutions in exon 21 (one showed L858R with the resistance mutation T590M in exon 20, and the other had P848L mutation). Consistent with earlier reports, our results show that KRAS and BRAF mutation frequencies in colorectal cancer were 44.3% and 13.0%, respectively, while EGFR mutations were detected in 11.1% of the lung cancer specimens. Ultra-deep amplicon pyrosequencing successfully validated the HRM results and allowed detection and quantitation of KRAS somatic mutations. HRM is a rapid and sensitive method for moderate-throughput cost-effective screening of oncogene mutations in clinical samples. Rather than Sanger sequence validation, next-generation sequencing technology results in more accurate quantitative results in somatic variation and can be achieved at a higher throughput scale.

Cyclooxygenases (COX-1 and COX-2) are key enzymes in several physiopathological processes. Many adverse drugs reactions to NSAIDs are attributable to COX-inhibition. The genes coding for these enzymes ( and ) are highly variable, and variations in these genes may underlie the risk of developing, or the clinical evolution of, several diseases and adverse drug reactions. We analyze major variations in the and genes, allele frequencies, functional consequences and population genetics. The most salient clinical associations of gene variations are related to colorectal cancer and stroke. In many studies, the SNPs interact with NSAIDs use, dietary or environmental factors. We provide an up-to-date catalog of clinical associations based on case-control studies and genome-wide association studies, and future research suggestions.

To detect differences in the frequency of the known nonsynonymous CYP2W1 polymorphisms between colorectal cancer patients and healthy subjects. The study group consisted of 150 colorectal patients and 263 controls. The presence of five nonsynonymous CYP2W1 polymorphisms was analyzed by novel amplification-restriction methods. Two nonsynonymous SNPs causing the amino acid substitutions Val432Ile and Gln482His were monomorphic in the population study. Two nonsynonymous SNPs previously unknown in Caucasians, 1463T (rs3808348) and 173C (no rs number assigned), were detected in the population study, although these were not associated with colorectal cancer risk. Regarding the 541G/A polymorphism (rs3735684), the 541G allele (odds ratio: 2.2; 95% CI: 1.2-4.1) and the 541GG genotype (odds ratio: 2.06; 95% CI: 1.1-3.9) were associated with increased colorectal cancer risk in the population studied. Conversely, the 173C-541A-1463C haplotype (odds ratio: 0.46; 95% CI: 0.2-0.9) showed a protective odds ratio value. CYP2W1 variant alleles are common among Caucasian individuals and, of these, the CYP2W1 G541A (Ala181Thr) polymorphism is associated with increased colorectal cancer risk.

We analyzed the allelic and genotypic frequencies of the glutathione-S-transferase P1 （GSTPI） rs1695 single nucleotide polymorphism （SNP） in 290 patients with multiple sclerosis （MS） and in 310 healthy controls. We found no significant association between the rs1695 variant and MS. Among MS patients, there was no relationship between the rs1695 variant and either gender, clinical type of MS or the age of onset of MS.

José AG Agúndez speaks to Emma Sinclair, Assistant Commissioning Editor José AG Agúndez is a Doctor of Medicine and Professor in the Department of Pharmacology at the University of Extremadura (Extremadura, Spain) He is involved in pharmacogenomics research and he has taught pharmacology and pharmacogenomics to medical and veterinary students since 1986. Presently he coordinates the genomics node of the Spanish Network of Adverse Reactions to Allergens and Drugs (RIRAAF) and he serves as a consultant for several international research organizations.

Genetic polymorphisms for histamine-metabolizing enzymes are responsible for interindividual variation in histamine metabolism and are associated with diverse diseases. Initial reports on polymorphisms of histamine-related genes including those coding for the enzymes histidine decarboxylase (HDC), diamine oxidase (ABP1) and histamine -methyltransferase (HNMT), as well as histamine receptor genes, often have pointed to polymorphisms that occur with extremely low frequencies or that could not be verified by later studies. In contrast, common and functionally significant polymorphisms recently described have been omitted in many association studies. In this review we analyze allele frequencies, functional and clinical impact and interethnic variability on histamine-related polymorphisms. The most relevant nonsynonymous polymorphisms for the gene are rs17740607 Met31Thr, rs16963486 Leu553Phe and rs2073440 Asp644Glu. For the most relevant polymorphisms are rs10156191 Thr16Met, rs1049742 Ser332Phe, and particularly because of its functional effect, rs1049793 His645Asp. In addition the polymorphisms rs45558339 Ile479Met and rs35070995 His659Asn are relevant to Asian and African subjects, respectively. For the only nonsynonymous polymorphism present with a relevant frequency is rs1801105 Thr105Ile. For the polymorphism rs7651620 Glu270Gly is relevant to African subjects only. The rs2067474 polymorphism, located in an enhancer element of the gene promoter, is common in all populations. No common nonsynonymous SNPs were observed in the gene and two SNPs were observed with a significant frequency in the gene: rs11665084 Ala138Val and rs11662595 His206Arg. This review summarizes relevant polymorphisms, discusses controversial findings on association of histamine-related polymorphisms and allergies and other diseases, and identifies topics requiring further investigation.

Allergic rhinitis is associated with elevated serum IgE levels. IgE response is mediated by the high-affinity IgE receptor (FcεRI), which is polymorphic. Studies analyzing the association between allergic rhinitis and FcεRI variants have been conducted with controversial results. The objective of this study is to analyze, in 1,041 individuals, the putative clinical association of allergic rhinitis with common polymorphisms in FcεRI subunits genes. These SNPs included FECR1A rs2494262, rs2427837 and rs2251746; FECR1B rs1441586, rs569108 and rs512555; FCER1G rs11587213, rs2070901 and rs11421. Statistically significant differences were observed for the FCER1B rs569108 and rs512555 polymorphisms frequencies when comparing patients with allergic rhinitis without asthma and controls. The OR (95% CI) value for the 237Gly allele (rs569108) is equal to 0.26 (0.08–0.86, P = 0.017) and for the G allele (rs512555) it is equal to 0.27 (0.08–0.88, P = 0.020). These two SNPs are linked (D’ = 1.0, LOD = 56.05). Also observed was a statistically significant trend towards lower IgE values among allergic rhinitis patients with variant alleles for both SNPs. In conclusion, in patients with allergic rhinitis without asthma, the FCER1B rs569108 and rs512555 polymorphisms are associated with increased risk of developing allergic rhinitis and with lower IgE levels.

Histamine plays an important role in the pathogenesis of allergic diseases. Genetic variations in histamine receptors (HRH) may influence the expression of allergic diseases. This study analyzes the association between HRH variants and NSAID hypersensitivity reactions. The authors analyzed copy number variations (CNVs) and common functional SNPs in genes HRH1, HRH2 and HRH4 in 442 unrelated patients with hypersensitivity to NSAIDs and in 414 healthy unrelated controls. The authors identified, both in patients and control subjects, individuals carrying CNVs in HRH genes. The most common genotype corresponded to two copies of each gene, but carriers of one or three copies of HRH1 (5% of individuals), HRH2 (1.1%) and HRH4 genes (0.9%) were also identified. For the first time, we describe CNVs in human HRH genes. Neither common functional SNPs in HRH genes nor CNVs influenced the risk of developing hypersensitivity to NSAIDs.

Background Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene PON1 , located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous PON1 polymorphisms and the risk of developing astrocytoma and meningioma. Methods Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous PON1 genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain. Results The frequencies of the PON1 genotypes and allelic variants of the polymorphisms PON1 L55M and PON1 Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: PON1 55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; PON1 192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the p values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma. Conclusions Common nonsynonymous PON1 polymorphisms are not related with the risk of developing astrocytoma and meningioma.