Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin–angiotensin–aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41–0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47–1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40–0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12–1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039) supported by co-funding grants from the Biobank of the Hospital Universitario Virgen de las Nieves

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2–4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2–4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRCERDF funds (EU)Instituto de Salud Carlos III (PT13/0010/0039)Biobank of the University Hospital Virgen de las Nieve

Influencia genética en la variabilidad de la respuesta al tratamiento con Abatacept en pacientes con artritis reumatoide

La Artritis reumatoide (AR) es una enfermedad autoinmune crónica de etiología compleja en la que interviene factores sociodemográficos, ambientales y genéticos, cuya prevalencia en España es del 0.3-1.6%. El diagnóstico y tratamiento precoz de la AR son fundamentales para evitar el deterioro físico del paciente, que conlleva a un decremento de su calidad y esperanza de vida. El arsenal terapéutico disponible para el tratamiento de la AR es muy amplio, y está enfocado en la modificación del curso de la enfermedad. El metotrexato y las terapias biológicas son los fármacos más utilizados. Abatacept (ABA), es una proteína de fusión humana formada por el dominio extracelular de CTLA4 y la Fc de IgG1. Actúa bloqueando la señal coestimuladora de linfocitos T debido a su unión al complejo CD80/CD86, presente en células dendríticas, monocitos y linfocitos B, e impide la interacción de éste con el receptor CD28. De esta forma, se produce la inhibición de la activación y proliferación de linfocitos T, así como, la producción de citoquinas proinflamatorias. Como consecuencia clínica, disminuye el infiltrado celular en la membrana sinovial, y, por tanto, el daño articular. Existe una gran variabilidad interindividual en la respuesta al tratamiento con ABA, ya que, entre el 20-30% de los pacientes no alcanzan el objetivo terapéutico, produciéndose un agravamiento irrecuperable de la patología. La búsqueda de biomarcadores de respuesta a la terapia con ABA es uno de los grandes objetivos a conseguir por numerosos investigadores. Algunos estudios previos han manifestado la asociación de variables clínicas y bioquímicas que parecen estar implicadas en dicha variabilidad (FAMEb previos, FR, ACPA). Sin embargo, hasta el momento no se han evaluado marcadores genéticos implicados en el mecanismo de acción de ABA, como son los genes CTLA4, CD80, CD86, CD28, FCGR2A y FCGR3A, que se encuentran directamente implicados en la cascada de actuación de ABA y, cuyos polimorfismos podrían producir un cambio conformacional en los receptores que codifican, aumentando o disminuyendo la afinidad por ABA y modificando su función en el organismo. HIPÓTESIS “Marcadores clínicos, bioquímicos y genéticos podrían actuar como predictores de respuesta al tratamiento con Abatacept en pacientes diagnosticados de Artritis reumatoide”. OBJETIVOS Objetivo principal Evaluar la influencia de SNPs en los genes CTLA4, CD80, CD86, CD28, FcGR2A y FcGR3A, factores clínicos y bioquímicos, como marcadores predictores de la respuesta al tratamiento con ABA (respuesta EULAR, LDA y remisión), tras 6 y 12 meses, en pacientes diagnosticados de AR. Objetivos específicos Determinar los SNPs rs3087243 (CTLA4), rs231775 (CTLA4), rs5742909 (CTLA4), rs57271503 (CD80), rs1599795 (CD80), rs9289131 (CD80), rs1129055 (CD86), rs2715267 (CD86), rs9831894 (CD86), rs9872483 (CD86), rs3116496 (CD28), rs1801274 (FcGR2A) y rs396991 (FcGR3A) en pacientes tratados con ABA. Medir la efectividad de ABA según la respuesta EULAR, LDA y remisión, en función del DAS28, a los 6 y 12 meses desde el inicio del tratamiento, a través de parámetros bioquímicos (PCR, VSG) y físicos (NAD, NAT, EVAP, HAQ) en los pacientes tratados con ABA. Evaluar la influencia de las variables independientes: sexo, tabaquismo, edad de diagnóstico de AR, edad de inicio de tratamiento con ABA, años con AR sin ABA, edad de inicio de ABA, duración del tratamiento con ABA, vía de administración del fármaco, número de FAMEb previos, FAMEb previos, duración del tratamiento con FAMEb previos (meses), FAMEsc (MTX y LFN) y GC concomitantes, monoterapia con ABA, positividad de FR y ACPA, y, niveles basales de DAS28, NAT, NAD, EVAP, PCR, VSG y HAQ; con la efectividad del tratamiento, es decir, respuesta EULAR, LDA y remisión, en función del DAS28, tras 6 y 12 meses desde el inicio de ABA. Evaluar la asociación existente entre los genotipos obtenidos de los SNPs analizados y los parámetros determinantes de la efectividad del ABA.Tesis Univ. Granada

Role of Single-Nucleotide Polymorphisms in Genes Implicated in Capecitabine Pharmacodynamics on the Effectiveness of Adjuvant Therapy in Colorectal Cancer

Colorectal cancer (CRC) is a highly prevalent form of neoplasm worldwide. Capecitabine, an oral antimetabolite, is widely used for CRC treatment; however, there exists substantial variation in individual therapy response. This may be due to genetic variations in genes involved in capecitabine pharmacodynamics (PD). In this study, we investigated the role of single-nucleotide polymorphisms (SNPs) related to capecitabine’s PD on disease-free survival (DFS) in CRC patients under adjuvant treatment. Thirteen SNPs in the TYMS, ENOSF1, MTHFR, ERCC1/2, and XRCC1/3 genes were genotyped in 142 CRC patients using real-time PCR with predesigned TaqMan® probes. A significant association was found between favorable DFS and the ENOSF1 rs2612091-T allele (p = 0.010; HR = 0.34; 95% CI = 0.14–0.83), as well as with the TYMS/ENOSF1 region ACT haplotype (p = 0.012; HR = 0.37; 95% CI = 0.17–0.80). Other factors such as low histological grade (p = 0.009; HR = 0.34; 95% CI = 0.14–0.79) and a family history of cancer (p = 0.040; HR = 0.48; 95% CI = 0.23–0.99) were also linked to improved DFS. Therefore, the SNP ENOSF1 rs2612091 could be considered as a predictive genetic biomarker for survival in CRC patients receiving capecitabine-based adjuvant regimens.Grants co-funded by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039

Influence of the FCGR2A rs1801274 and FCGR3A rs396991 Polymorphisms on Response to Abatacept in Patients with Rheumatoid Arthritis

Abatacept (ABA) is an immunosuppressant indicated for treatment of rheumatoid arthritis (RA). Effectiveness might be influenced by clinical RA variants and single-nucleotide polymorphisms (SNPs) in genes encoding protein FCGR2A (His131Arg) and FCGR3A (Phe158Val) involved in pharmacokinetics of ABA. An observational cohort study was conducted in 120 RA Caucasian patients treated with ABA for 6 and 12 months. Patients with the FCGR2A rs1801274-AA genotype (FCGR2A-p.131His) showed a better EULAR response (OR = 2.43; 95% CI = 1.01–5.92) at 12 months and low disease activity (LDA) at 6 months (OR = 3.16; 95% CI = 1.19–8.66) and 12 months (OR = 6.62; 95% CI = 1.25–46.89) of treatment with ABA. A tendency was observed towards an association between the FCGR3A rs396991-A allele (FCGR3A-p.158Phe) and better therapeutic response to ABA after 12 months of treatment (p = 0.078). Moreover, we found a significant association between the lowaffinity FCGR2A/FCGR3A haplotypes variable and LDA after 12 months of ABA treatment (OR = 1.59; 95% CI = 1.01–2.58). The clinical variables associated with better response to ABA were lower age at starting ABA (OR = 1.06; 95% CI = 1.02–1.11) and greater duration of ABA treatment (OR = 1.02; 95% CI = 1.01–1.04), lower duration of previous biological therapies (OR = 0.99; 95% CI = 0.98–0.99), non-administration of concomitant disease-modifying antirheumatic drugs (DMARDs) (OR = 24.53; 95% CI = 3.46–523.80), non-use of concomitant glucocorticoids (OR = 0.12; 95% CI = 0.02–0.47), monotherapy (OR = 19.22; 95% CI = 2.05–343.00), lower initial patient’s visual analogue scale (PVAS) value (OR = 0.95; 95% CI = 0.92–0.97), and lower baseline ESR (OR = 0.92; 95% CI = 0.87–0.97). This study showed that high-affinity FCGR2A-p.131His variant, low-affinity FCGR3A-p.158Phe variant, and combined use of FCGR2A/FCGR3A genetic variations could affect ABA effectiveness. Further studies will be required to confirm these results.Fundación de Investigación Biosanitaria de Andalucía Oriental (FIBAO)University of GranadaERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/003

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis

Abatacept (ABA) is used as a first-line treatment in patients diagnosed with moderate and severe rheumatoid arthritis (RA). The interindividual response to ABA therapy is very variable in these patients. The objective of our study was therefore to investigate the role of polymorphisms of the CTLA-4, CD80 and CD86 genes, as well as that of clinical factors of the disease, in the response toABAin patients with RA. A retrospective cohort study was carried out in 109 patients receiving treatment with ABA and diagnosed with RA. The genetic variables were analyzed using real-time PCR with TaqMan® probes. The patients were classified according to the European League Against Rheumatism (EULAR) criteria at 6 and 12 months from start of treatment. The independent variables associated with higher EULAR response were lower duration of previous biologic disease-modifying anti-rheumatic drugs and lower baseline values of the disease activity score 28 after 6 months of ABA treatment; and lower baseline patient’s visual analogue scale (PVAS) after 12 months. In addition, a significant association was found between duration of ABA treatment, non-administration of concomitant glucocorticoids and lower baseline values of the number of inflamed joints and erythrocyte sedimentation rate clinical variables, with remission of the disease after 6 months’ treatment with ABA. Finally, remission of the disease after 12 months’ treatment with ABA was associated with earlier age at start of ABA therapy and lower number of previous biologic therapies (BTs). The CTLA-4 rs5742909-T allele and the CTLA-4 rs231775-G allele were found to be associated with satisfactory EULAR response and low disease activity (LDA) after 12 months’ treatment with ABA (CTLA-4 rs5742909 T vs. CC; OR = 5.88; CI95% = 1.48–23.29 and OR = 4.75; CI95% = 1.35–17.94, respectively, and CTLA-4 rs231775 G vs. AA, OR = 3.48; CI95% = 1.20–10.09 and OR = 4.68; CI95% = 1.49–17.94, respectively). In conclusion, patients with RA treated with ABA showed better EULAR response and LDA rate when they had the CTLA-4 rs5742909-T or CTLA-4 rs231775-G polymorphisms; furthermore, this remission rate increased in patients that began ABA treatment earlier, those with a lower number of previous BTs and those with a lower PVAS value.University of GranadaFundación de Investigación Biosanitaria de Andalucía Oriental (FIBAO)ERDF funds (EU) from the Instituto de Salud Carlos III PT13/0010/003

<i>ABCC1</i>, <i>ABCG2</i> and <i>FOXP3</i>: Predictive Biomarkers of Toxicity from Methotrexate Treatment in Patients Diagnosed with Moderate-to-Severe Psoriasis

Background: Methotrexate (MTX) is one of the most extensively used drugs in the treatment of moderate-to-severe psoriasis (PS). However, it frequently must be suspended owing to the toxicity in certain patients. Objective: To evaluate the influence of ABCC1, ABCG2, and FOXP3 in the development of MTX toxicity in PS. Methods: Retrospective cohort study with 101 patients. Five single-nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction with TaqMan probes. Results: Patients carrying ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.04; 95% CI = 1.48–46.78; p = 0.015); FOXP3 rs376154-GT and GG genotypes (GT vs. TT/GG: OR = 3.86; 95% CI = 1.17–13.92; p = 0.031) and ABCG2 rs13120400-T allele (T vs. CC: OR = 8.33; 95% CI = 1.24–164.79; p = 0.059) showed a higher risk of developing more than one adverse effect. The toxicity analysis by subtypes showed that the ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.10; 95% CI = 1.69–46.63; p = 0.011) and FOXP3 rs376154-GT genotype (OR = 4.11; 95% CI = 1.22–15.30; p = 0.027) were associated with the appearance of asthenia. No association of the other ABCC1 polymorphisms (rs35592 and rs246240) with MTX toxicity was found. Conclusion: ABCC1, ABCG2, and FOXP3 polymorphisms can be considered to be risk biomarkers of toxicities in PS patients treated with MTX