Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro.

Prostate (PC) and breast cancer (BC) are heterogeneous hormonal cancers. Treatment resistance and adverse effects are the main limitations of conventional chemotherapy treatment. The use of sensitizing agents could improve the effectiveness of chemotherapeutic drugs as well as obviate these limitations. This study analyzes the effect of single catechin (CAT), procyanidin B2 (ProB2) treatment as well as the co-adjuvant treatment of each of these compounds with docetaxel (DOCE). We used PC- and BC-derived cell lines (PC3, DU-145, T47D, MCF-7 and MDA-MB-231). The short and long-term pro-apoptotic, anti-proliferative and anti-migratory effects were analyzed. RT-qPCR was used to discover molecular bases of the therapeutic efficacy of these compounds. ProB2 treatment induced a two- to five-fold increase in anti-proliferative and pro-apoptotic effects compared to single DOCE treatment, and also had a more sensitizing effect than DOCE on DU145 cells. Regarding BC cells, ProB2- and CAT-mediated sensitization to DOCE anti-proliferative and pro-apoptotic effects was cell-independent and cell-dependent, respectively. Combined treatment led to high-efficacy effects on MCF-7 cells, which were associated to the up-regulation of CDKN1A, BAX, caspase 9 and E-cadherin mRNA under combined treatment compared to single DOCE treatment. CAT and ProB2 can enhance the efficacy of DOCE therapy on PC and BC cells by the sensitizing mechanism.

Hypercytokinemia in COVID-19: Tear cytokine profile in hospitalized COVID-19 patients.

The aim of this study is to analyze the concentrations of cytokines in tear of hospitalized COVID-19 patients compared to healthy controls. Tear samples were obtained from 41 healthy controls and 62 COVID-19 patients. Twenty-seven cytokines were assessed: interleukin (IL)-1b, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL9, IL-10, IL-12, IL-13, IL-15, IL-17, eotaxin, fibroblast growth factor basic, granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interferon gamma-induced protein, monocyte chemo-attractant protein-1, macrophage inflammatory protein (MIP)-1a, MIP-1b, platelet-derived growth factor (PDGF), regulated on activation normal T cell expressed and secreted, tumor necrosis factor-α and vascular endothelial growth factor (VEGF).In tear samples of COVID-19 patients, an increase in IL-9, IL-15, G-CSF, GM-CSF, IFN-γ, PDGF and VEGF was observed, along with a decrease in eotaxin compared to the control group (p < 0.05). A poor correlation between IL-6 levels in tear and blood was found. IL-1RA and GM-CSF were significantly lower in severe patients and those who needed treatment targeting the immune system (p < 0.05). Tear cytokine levels corroborate the inflammatory nature of SARS-CoV-2.

Genome-wide association study biomarkers in T-cell mediated rejection: selective effect according to the Banff classification.

BACKGROUND: A genome-wide association study (GWAS) in kidney transplant recipients reported the association of two polymorphisms located in the PTPRO gene and upstream of the CCDC67 (DEUP1) gene with increased risk of acute T cell-mediated rejection (TCMR). We aimed at replicating the assessment of mentioned associations and additionally ascertaining the influence of treatment and clinical features of the patients. METHODS: The polymorphisms, PTPRO-rs7976329 and CCDC67-rs10765602 were genotyped by TaqMan chemistry in 641 consecutive kidney transplant recipients. The diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. Associations were evaluated by Chi-square test or Fisher's exact test when necessary and multivariate logistic regression. RESULTS: Considering the GWAS study we only replicated the association of the PTPRO-rs7976329*C allele in the Banff grade < II subjects. However, the homozygous mutant genotypes of both polymorphism seemed to increase the risk of TCMR Banff grade < II in the overall cohort and after stratification by Thymoglobulin induction therapy. In the multivariate analysis, we confirmed the association of PTPRO-rs7976329 with TCMR Banff grade < II, independently of the Thymoglobulin induction therapy and of CCDC67-rs10765602 only in the group of patients not receiving Thymoglobulin induction therapy. No association of these polymorphisms with TCMR Banff grade ≥ II was observed in either the overall cohort or in the subgroups stratified by Thymoglobulin therapy. CONCLUSIONS: Our study shows that the increased risk of TCMR related to polymorphisms PTPRO-rs7976329 and CCDC67-rs10765602 previously reported in a GWAS was replicated only in homozygous patients who presented TCMR Banff grade < II and for the minor allele of either polymorphism.

Variation in Susceptibility to Downy Mildew Infection in Spanish Minority Vine Varieties.

Downy mildew is one of the most destructive diseases affecting grapevines (Vitis vinifera L.). Caused by the oomycete Plasmopara viticola (Berk. and Curt.) Berl. and de Toni, it can appear anywhere where vines are cultivated. It is habitually controlled by the application of phytosanitary agents (copper-based or systemic) at different stages of the vine growth cycle. This, however, is costly, can lead to reduced yields, has a considerable environmental impact, and its overuse close to harvest can cause fermentation problems. All grapevines are susceptible to this disease, although the degree of susceptibility differs between varieties. Market demands and European legislation on viticulture and the use of phytosanitary agents (art. 14 of Directive 128/2009/EC) now make it important to know the sensitivity of all available varieties, including minority varieties. Such knowledge allows for a more appropriate use of phytosanitary agents, fosters the commercial use of these varieties and thus increases the offer of wines associated with different terroirs, and helps identify material for use in crop improvement programmes via crossing or genetic transformation, etc. Over 2020-2021, the susceptibility to P. viticola of 63 minority vine varieties from different regions of Spain was examined in the laboratory using the leaf disc technique. Some 87% of these varieties were highly susceptible and 11% moderately susceptible; just 2% showed low susceptibility. The least susceptible of all was the variety Morate (Madrid, IMIDRA). Those showing intermediate susceptibility included the varieties Sanguina (Castilla la Mancha, IVICAM), Planta Mula (Comunidad Valenciana, ITVE), Rayada Melonera (Madrid, IMIDRA), Zamarrica (Galicia, EVEGA), Cariñena Roja (Cataluña, INCAVI), Mandrègue (Aragón, DGA) and Bastardo Blanco (Extremadura, CICYTEX). The highly susceptible varieties could be differentiated into three subgroups depending on sporulation severity and density.

A polymorphism in PTPN2 gene is associated with an earlier onset of type 1 diabetes.

The Wellcome Trust Case Control Consortium (WTCCC) genome-wide study found association of PTPN2 with three autoimmune diseases, among them is type 1 diabetes (T1D). This result was confirmed by a follow-up study that pointed to new independent signals within the region. However, both studies were performed in patients with an early-onset T1D. We aimed at replicating the previous results and studying the influence of these polymorphisms in the age at T1D debut. We genotyped 439 T1D Spanish subjects (age at onset, 1 to 65 years) and 861 controls for two PTPN2 single nucleotide polymorphisms (SNPs), rs2542151 and rs478582, and studied the effect of both polymorphisms in age at onset through stratified and continuous analyses. The frequency of rs2542151*G carriers was significantly higher in the early-onset group compared with late-onset patients (p = 0.023) and with controls (OR = 1.61 [1.14-2.26]; p = 0.005). No significant differences were found between controls and late-onset patients. The log-rank chi-square test for the Kaplan-Meier plots (carriers of susceptibility allele vs non carriers) was statistically significant (χ (1df) (2) = 4.485; p = 0.034), yielding an earlier disease debut for G carriers. The analysis of the SNP rs478582 did not reach statistical significance. In summary, we replicate the association detected by the WTCCC and propose that the rs2542151*G allele confers risk to an earlier onset of T1D.

Evaluation and Pre-selection of New Grapevine Genotypes Resistant to Downy and Powdery Mildew, Obtained by Cross-Breeding Programs in Spain.

The need to develop an environmentally friendly, sustainable viticulture model has led to numerous grapevine improvement programmes aiming to increase resistance to downy and powdery mildew. The success of such programmes relies on the availability of protocols that can quantify the resistance/susceptibility of new genotypes, and on the existence of molecular markers of resistance loci that can aid in the selection process. The present work assesses the degree of phenotypic resistance/susceptibility to downy and powdery mildew of 28 new genotypes obtained from crosses between "Monastrell" and "Regent." Three genotypes showed strong combined resistance, making them good candidates for future crosses with other sources of resistance to these diseases (pyramiding). In general, laboratory and glasshouse assessments of resistance at the phenotype level agreed with the resistance expected from the presence of resistance-associated alleles of simple sequence repeat (SSR) markers for the loci Rpv3 and Ren3 (inherited from "Regent"), confirming their usefulness as indicators of likely resistance to downy and powdery mildew, respectively, particularly so for downy mildew.

Association of Polymorphisms in T-Cell Activation Costimulatory/Inhibitory Signal Genes With Allograft Kidney Rejection Risk.

The genes CD28, CD86 and CTLA-4 conform the costimulatory (CD28-CD86) or inhibitory (CTLA-4-CD86) signal in T-cell activation. T-cell immune response has a critical role in allograft rejection, and single nucleotide polymorphisms (SNPs) located in these genes have been widely analyzed with controversial results. We analyzed a group of SNPs located in the three genes: CD28: rs3116496; CD86: rs1129055; and CTLA-4: rs231775 and rs3087243 in a cohort of 632 consecutively recruited kidney transplanted subjects. All polymorphisms were genotyped by TaqMan chemistry and the diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. The analyses showed a statistically significant protective effect to T cell-mediated rejection (TCMR) in carriers of the CTLA-4 rs3087243*G allele, especially in patients with TCMR Banff ≥2 in the overall cohort and in patients without thymoglobulin induction therapy. Both associations were corroborated as independent factors in the multivariate analysis. Interestingly, associations with rejection were not found for any SNP in patients with thymoglobulin induction therapy. As expected, considering the major role of these genes in T-cell activation, no effect was observed for antibody-mediated rejection (ABMR). In conclusion, the SNP rs3087243 located in the CTLA-4 gene may be considered a useful independent biomarker for TCMR risk especially for severe TCMR in patients who did no received thymoglobulin induction therapy.

Localization of Type 1 Diabetes susceptibility in the ancestral haplotype 18.2 by high density SNP mapping.

Previous studies have suggested that the ancestral haplotype 18.2 (AH18.2) carries additional susceptibility gene to Type 1 Diabetes (T1D) on the Major Histocompatibility Complex (MHC). We analyzed 10 DR3/TNFa1b5 homozygous subjects in order to establish the conservation of the AH18.2 and then compared this conserved region with other DR3 haplotype, the AH8.1. The Illumina's HumanHap550 Bead chip was used to perform an extensive genotyping of the MHC region. The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the second susceptibility gene is located within this region. We can exclude the region centromeric to HLA-DRA gene and telomeric to DDR1 gene. A comparison between the AH18.2 and AH8.1 haplotypes showed that 233 SNPs were different in the aforementioned conserved region. These data suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional susceptibility alleles for T1D on the AH18.2 haplotype.

Narcea-an unknown, ancient cultivated rose variety from northern Spain.

The present work reports the discovery and the complete characterisation of an ancient cultivated rose variety found growing in a private garden in the southwest of the Principality of Asturias (northern Spain). The variety is here given the name Narcea. The majority of roses currently cultivated belong to the so-called group of 'Modern Roses', all of which were obtained after 1867 via artificial crosses and improvement programmes. All are destined for ornamental use. Until the 19th century, the great majority of the many ancient cultivated roses in Europe were used in perfumery and cosmetics, or had medicinal uses. Rosa damascena and Rosa centifollia are still grown and used by the French and Bulgarian perfume industries. The Asturian Massif of the Cantabrian Mountain Range provides a natural habitat for some 75% of the wild members of the genus Rosa, but until now there was no evidence that this area was home to ancient cultivated roses. A complete botanical description is here provided for a discovered ancient rose. It is also characterised according to a series of sequence tagged microsatellite sites, and its agronomic features are reported. In addition, a histological description (optical and scanning electronic microscope studies) of the petals is offered, along with an analysis of the volatile compounds present in these organs as determined by solid phase microextraction and gas chromatography-mass spectroscopy. The results reveal the uniqueness of this ancient type of rose and suggest it may be of interest to the perfume industry.

Factors Affecting the Vineyard Populational Diversity of Plasmopara viticola.

Vitis vinifera is very susceptible to downy mildew (Plasmopara viticola). A number of authors have suggested different genetic populations of this fungus exist in Europe, each showing a different degree of virulence. Work performed to date indicates this diversity to be the result of different factors. In areas where gene flow is greater and recombination more frequent, the diversity of P. viticola appears to be wider. In vineyards isolated by geographic barriers, a race may become dominant and produce clonal epidemics driven by asexual reproduction. The aim of the present work was to identify the conditions that influence the genetic diversity of P. viticola populations in the vineyards of northwestern Spain, where the climatic conditions for the growth of this fungus are very good. Vineyards situated in a closed, narrow valley of the interior, in more open valleys, and on the coast were sampled and the populations of P. viticola detected were differentiated at the molecular level through the examination of microsatellite markers. The populations of P. viticola represented in primary and secondary infections were investigated in the same way. The concentration of airborne sporangia in the vegetative cycle was also examined, as was the virulence of the different P. viticola populations detected. The epidemiological characteristics of the fungus differed depending on the degree of isolation of the vineyard, the airborne spore concentration, and on whether the attack was primary or secondary. Strong isolation was associated with the appearance of dominant fungal races and, therefore, reduced populational diversity.

CFD modelling of air quality in Pamplona City (Spain): Assessment, stations spatial representativeness and health impacts valuation.

A methodology based on CFD-RANS simulations (WA CFD-RANS, Weighted Averaged Computational Fluid Dynamic-Reynolds-Averaged Navier-Stokes simulations) which includes appropriate modifications, has been applied to compute the annual, seasonal, and hourly average concentration of NO2 and NOX throughout the city of Pamplona (Spain) at pedestrian level during 2016. The results have been evaluated using measurements provided both by the city's network of air quality monitoring stations and by a network of mobile microsensors carried around by cyclists during their daily commutes, obtaining a maximum relative error lower than 30% when computing NO2 annual average concentrations. The model has taken into account the actual city layout in three dimensions, as well as the traffic emissions. The resulting air pollution maps provided information critical for studying the traffic-related health effects of NO2 and their associated external costs in the city of Pamplona and the spatial representativeness of the current network of air quality monitoring stations (it has not been carried out for an entire city to date). The developed methodology can be applied to similar cities, providing useful information for the decision-makers.

Impacts of Interleukin-18 Polymorphisms on the Incidence of Delayed-Onset Cytomegalovirus Infection in a Cohort of Kidney Transplant Recipients.

BACKGROUND: The incidence of cytomegalovirus (CMV) infection in solid organ transplant recipients may be reduced by antiviral prophylaxis, but this strategy may lead to delayed-onset CMV infection. The proinflammatory cytokine interleukin (IL)-18 plays a major role in viral host defense responses. This study examines the impacts of 2 single-nucleotide polymorphisms (SNPs) in the promoter region of the IL-18 gene, -607C/A (rs1946518) and -137G/C (rs187238), on the incidence of delayed-onset CMV infection in patients undergoing kidney transplant. METHODS: This retrospective study analyzed 2 IL-18 SNPs in consecutive adult kidney transplant recipients using real-time polymerase chain reaction with TaqMan probes. Participants were enrolled over the period 2005-2013 and stratified according to their IL-18 SNP genotype. The concordance index (Harrell's c-index) was used as a measure of the discriminatory power of the predictive models constructed with bootstrapping to correct for optimistic bias. RESULTS: Seven hundred nine patients received transplants in the study period, and 498 met selection criteria. Cytomegalovirus infection and disease incidence were 38% and 7.5%, respectively. In multivariate competing risk regression models, carriers of the -607C/-137G haplotype who received prophylaxis showed a higher incidence of CMV replication after antiviral agent discontinuation (hazard ratio = 2.42 [95% confidence interval, 1.11-5.26]; P = .026), whereas CMV disease was not observed in those given prophylaxis who were noncarriers of this polymorphism (P = .009). CONCLUSIONS: Our findings suggest that the -607C/-137G IL-18 haplotype is associated with a higher incidence of postprophylaxis CMV replication. The prior identification of this polymorphism could help select alternative measures to prevent delayed-onset CMV infection in these patients.

The Interferon-Gamma +874 A/T Polymorphism Is Not Associated With CMV Infection After Kidney Transplantation.

The +874 A/T polymorphism in the interferon gamma (IFNG) gene has been associated with Cytomegalovirus (CMV) infection risk in lung and kidney transplant recipients. To replicate this association, we performed a retrospective observational study of this polymorphism and immunosuppressive therapies considering the prophylactic treatment in 600 consecutive kidney transplanted recipients. We found no association of the aforementioned polymorphism with CMV infection in univariate and multivariate analyses regardless of the prophylactic treatment. In addition, the immunosuppressive treatment with mammalian target of rapamycin inhibitors (imTOR) showed a protective effect in all patients independently of prophylaxis. Moreover, in the adjusted model, we found interactions between prophylaxis with high-risk (Donor+/Recipient-, D+/R-) status (p-interaction = 0.01), with thymoglobulin induction therapy (p-interaction = 0.03) and with thymoglobulin anti-rejection therapy (p-interaction = 0.002). Data also revealed that prophylaxis was not an advantage in the not D+/R- and without thymoglobulin therapy group (HR = 0.98, p = 0.95). The benefit of prophylaxis was observed in all groups with thymoglobulin therapy, but it was maximal in the high-risk CMV infection group with both thymoglobulin induction therapy and thymoglobulin anti-rejection therapy (HR = 0.01, p < 0.001). In conclusion, the IFNG +874 polymorphism is not a predictive marker of CMV infection. The protective effect of imTOR is not improved with prophylaxis. Interestingly, the thymoglobulin therapy associated with prophylaxis is not a risk factor for CMV infection, and prophylaxis is not effective in recipients with no high-risk CMV status and without thymoglobulin therapy.

Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases.

BACKGROUND: Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. RESULTS: Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. CONCLUSION: Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk.

A recent genome-wide scan of nonsynonymous SNPs and ulterior validation in case-control and family analyses evidenced a susceptibility locus for type 1 diabetes (T1D) on chromosome 2q24.3. We aimed at testing the effect of this locus in other autoimmune diseases with complex genetic background, such as multiple sclerosis (MS). Four SNPs along the locus, rs13422767, rs2111485, rs1990760 and rs2068330, were genotyped using TaqMan MGB chemistry in 311 T1D and 412 MS patients and 535 ethnically matched healthy controls. The previously reported association of this locus was found for the first time in MS (rs2068330, G vs C: P=0.001; OR (95% CI)=0.73 (0.6-0.88)) and a trend for replication was observed in our Spanish diabetic cohort. Therefore, genes included in this locus - IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of these autoimmune diseases, although strong linkage disequilibrium in the region hampered further localization of the etiologic gene.

Association of MYO9B haplotype with type 1 diabetes.

MYO9B (myosin IXB) polymorphisms were associated with celiac disease and ulcerative colitis susceptibility, presumably through alteration of the intestinal permeability. Recently this gene was also associated with several diseases with an autoimmune component, such as rheumatoid arthritis and systemic lupus erythematosus. We aimed to test, for the first time, the potential role of MYO9B polymorphisms in type 1 diabetes (T1D), an autoimmune condition preceded by changes in intestinal barrier integrity. Three previously associated MYO9B polymorphisms (rs962917, rs2279003, and rs2305764) were studied in 316 T1D patients and 706 ethnically matched controls. Minor alleles of those polymorphisms were more frequent in diabetic patients than in controls and the haplotype carrying major alleles in those positions, rs962917*G/rs2279003*C/rs2305764*G, significantly reduced the risk of T1D in the Spanish population (p = 0.004; OR [95% confidence interval] = 0.68 [0.52-0.90]). Our data suggest an involvement of this MYO9B chromosomal region in T1D predisposition, indicating extensive influence on autoimmune diseases.

Application of a short term air quality action plan in Madrid (Spain) under a high-pollution episode - Part II: Assessment from multi-scale modelling.

Air pollution continues to be one of the main issues in urban areas. In addition to air quality plans and emission abatement policies, additional measures for high pollution episodes are needed to avoid exceedances of hourly limit values under unfavourable meteorological conditions such as the Madrid's short-term action NO2 protocol. In December 2016 there was a strong atmospheric stability episode that turned out in generalized high NO2 levels, causing the stage 3 of the NO2 protocol to be triggered for the first time in Madrid (29th December). In addition to other traffic-related measures, this involves access restrictions to the city centre (50% to private cars). We simulated the episode with and without measures under a multi-scale modelling approach. A 1 km2 resolution modelling system based on WRF-SMOKE-CMAQ was applied to assess city-wide effects while the Star-CCM+ (RANS CFD model) was used to investigate the effect at street level in a microscale domain in the city centre, focusing on Gran Vía Avenue. Changes in road traffic were simulated with the mesoscale VISUM model, incorporating real flux measurements during those days. The corresponding simulations suggest that the application of the protocol during this particular episode may have prevented concentrations to increase by 24 µg·m-3 (14% respect to the hypothetical no action scenario) downtown although it may have cause NO2 to slightly increase in the city outskirts due to traffic redistribution. Speed limitation and parking restrictions alone (stages 1 and 2 respectively) have a very limited effect. The microscale simulation provides consistent results but shows an important variability at street level, with reduction above 100 µg·m-3 in some spots inside Gran Vía. Although further research is needed, these results point out the need to implement short-term action plans and to apply a consistent multi-scale modelling assessment to optimize urban air quality abatement strategies.

Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population.

BACKGROUND: The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population. METHODS: A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System. RESULTS: We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17-2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45-6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed. CONCLUSION: Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia.

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.

Evidence for the association of the SLC22A4 and SLC22A5 genes with type 1 diabetes: a case control study.

BACKGROUND: Type 1 diabetes (T1D) is a chronic, autoimmune and multifactorial disease characterized by abnormal metabolism of carbohydrate and fat. Diminished carnitine plasma levels have been previously reported in T1D patients and carnitine increases the sensitivity of the cells to insulin. Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease. For these reasons, we investigated for the first time the association with T1D of six single nucleotide polymorphisms (SNPs) mapping to these candidate genes: slc2F2, slc2F11, T306I, L503F, OCTN2-promoter and OCTN2-intron. METHODS: A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software. RESULTS: When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (chi2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41-0.93); p = 0.02). CONCLUSION: The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk.