17 research outputs found
Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype
Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled
asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and
single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of
action and process of response to omalizumab, and these could be used as predictive biomarkers
of response. We conducted an observational retrospective cohort study that included patients with
severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory
response after 12 months of treatment was defined as (1) Reduction 50% of exacerbations or no exacerbations,
(2) Improvement of lung function 10% FEV1, and (3) Reduction 50% of OCS courses
or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790,
rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A
(rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes
were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients
under treatment with omalizumab were recruited. After 12 months of treatment, the variables
associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22;
95% confidence interval [CI] = 0.95–19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27–547),
and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22–438.76). Reduction in oral corticosteroids
(OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91–0.99)
and blood eosinophil levels > 300 cells/ L (OR = 2.93; 95% CI = 1.01–9.29). Improved lung function
showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16;
95% CI = 2.45–79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12–117.15), GATA2 rs4857855-T
(OR = 15.98; 95% CI = 1.52–519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14–142.68; AG
vs. AA and OR = 7.46; 95% CI = 0.94–89.12; GG vs. AA). Meeting one response criterion was related
to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77–804.57), meeting two to age of asthma diagnosis
(OR = 0.93; 95% CI = 0.88–0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23;
95% CI = 3.31–100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01–9.92). The results of this study
show the possible influence of the polymorphisms studied on the response to omalizumab and the
clinical benefit that could be obtained by defining predictive biomarkers of treatment response.Instituto de Salud Carlos III (PT13/0010/0039)Biobank of the Hospital Universitario Virgen de las Nieves
Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis
Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.University of Granada and the FundaciĂłn de InvestigaciĂłn Biosanitaria de AndalucĂa Oriental
(FIBAO)Virgen de las Nieves University Hospital Biobank was supported by grants co-funded
by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039)
Impacto de la mutación homocigota en Nudix hidrolasa 15 sobre la mielosupresión con 6-mercaptopurina en una niña europea con leucemia linfoblástica aguda: A propósito de un caso
A 6-year-old girl diagnosed with intermediate-risk acute lymphoblastic leukemia (ALL) presented with severe myelotoxicity and multiple infections during phase IB induction treatment with 6-mercaptopurine (6-MP). In the subsequent treatment phases, which included 6-MP, the patient continued to show bone marrow aplasia and neutropenia, necessitating numerous dose adjustments and interruptions. The recommended dose was eventually reduced to 5 %. A pharmacogenetic analysis, conducted in induction phase IB, detected three single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene, and the phenotype of a normal metabolizer was observed. As a result of a second pharmacogenetic analysis, pathological polymorphisms were revealed in Nudix hydrolase 15 (NUDT15), which may explain the patient’s myelotoxicity. Hence, a pharmacogenetic analysis performed in advance would have been able to prevent her from suffering severe toxicity and/or treatment failure.Una paciente pediátrica de 6 años, diagnosticada de leucemia linfoblástica aguda (LLA) de riesgo intermedio, presenta milotoxicidad grave y mĂşltiples infecciones durante la fase de inducciĂłn IB del tratamiento con 6-mercaptopurina (6-MP). En las siguientes fases del protocolo de tratamiento, que incluĂa tambiĂ©n 6-MP, la paciente continĂşa mostrando aplasia de mĂ©dula Ăłsea y neutropenia, requiriendo numerosos ajustes de dosis e interrupciones. La dosis recomendada de 6-MP se reduce entonces al 5 %. El análisis farmacogenĂ©tico, realizado en la fase de inducciĂłn IB, detectĂł tres polimorfismos de nucleĂłtido Ăşnico (SNPs) en el gen que codifica para la enzima tiopurina S-metiltransferasa (TPMT), observándose un fenotipo de metabolizador normal para esta enzima. Como consecuencia, se requiriĂł de un segundo análisis farmacogenĂ©tico más completo, que revelĂł polimorfismos patolĂłgicos en el gen de la hidrolasa Nudix 15 (NUDT15), explicarĂa la mielotoxicidad observada en esta paciente. Por ello, un análisis farmacogenĂ©tico completo deberĂa llevarse a cabo con anterioridad al inicio de 6-MP y de manera rutinaria en la práctica clĂnica, para conseguir prevenir los efectos adversos graves y/o el fracaso terapĂ©utico
Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review
The objective of this systematic review was to provide a compilation of all the literature
available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved
in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival
(PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in
accordance with the PRISMA guidelines. It included all the literature published up to 1 November
2022 and was carried out in four databases (Medline [PubMed], Scopus,Web of Science, and Embase),
using the PICO strategy, with relevant keywords related to the objective. The quality of the studies
included was evaluated with an assessment tool derived from the Strengthening the Reporting
of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic
review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI
(rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play
a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as
well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC.
The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the
available evidence concerning the association between 13 SNPs in the main genes involved in the
vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1,
CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings
suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains
sparse for each of the polymorphisms examined, so these findings should be treated with caution.The Virgen de las Nieves University Hospital Biobank was supported by grants co-funded
by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039)
Effect of Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway on Susceptibility to Non-Small-Cell Lung Cancer
The pathogenesis of non-small-cell lung cancer (NSCLC) is complex, since many risk factors have been identified. Recent research indicates that polymorphisms in the metabolic pathway of vitamin D may be involved in both risk and survival of the disease. The objective of this study is to assess the effect of 13 genetic polymorphisms involved in the vitamin D metabolic pathway on the risk of suffering from NSCLC. We conducted an observational case-control study, which included 204 patients with NSCLC and 408 controls, of Caucasian origin, from southern Spain. The CYP27B1 (rs4646536, rs3782130, rs703842, rs10877012), CYP2R1 (rs10741657), GC (rs7041), CYP24A1, and VDR (BsmI, Cdx-2, FokI, ApaI, TaqI) gene polymorphisms were analyzed by real-time polymerase chain reaction. The logistic regression model, adjusted for smoking and family history of cancer, revealed that in the genotypic model, carriers of the VDR BsmI rs1544410-AA genotype were associated with a lower risk of developing NSCLC compared to the GG genotype (p = 0.0377; OR = 0.51; CI95% = 0.27-0.95; AA vs. GG). This association was maintained in the recessive model (p = 0.0140). Haplotype analysis revealed that the AACATGG and GACATGG haplotypes for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130, and rs10877012 polymorphisms were associated with a lower risk of NSCLC (p = 0.015 and p = 0.044 respectively). The remaining polymorphisms showed no effect on susceptibility to NSCLC. The BsmI rs1544410 polymorphism was significantly associated with lower risk of NSCLC and could be of considerable value as a predictive biomarker of the disease.ERDF funds (EU) from the Instituto de Salud Carlos III PT13/0010/003
Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease
Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels.
In addition to environmental risk factors, genetic predisposition increases the risk; this includes
alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying
vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular
disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR
gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted
comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The
genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and
Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic
discrimination using TaqMan® probes. The logistic regression analysis adjusted for body mass index
and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the
genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06–5.37; TT vs. CC) and the recessive model
(p = 0.0099; OR = 2.71; 95% CI = 1.31–6.07; TT vs. C). Haplotype analysis revealed that the haplotype
GAC (p = 0.047; OR = 0.34; 95% CI = 0.12–0.98) was associated with increased risk of CVD. The
VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No
influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232)
and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.ERDF funds (EU) from the Instituto de Salud Carlos III PT13/0010/003
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
Impacto de la mutación homocigota en Nudix hidrolasa 15 sobre la mielosupresión con 6-mercaptopurina en una niña europea con leucemia linfoblástica aguda: A propósito de un caso
Una paciente pediátrica de 6 años, diagnosticada de leucemia linfoblástica aguda (LLA) de riesgo intermedio, presenta milotoxicidad grave y mĂşltiples infecciones durante la fase de inducciĂłn IB del tratamiento con 6-mercaptopurina (6-MP). En las siguientes fases del protocolo de tratamiento, que incluĂa tambiĂ©n 6-MP, la paciente continĂşa
mostrando aplasia de médula ósea y neutropenia, requiriendo numerosos ajustes de dosis e interrupciones. La dosis recomendada de 6-MP se reduce entonces al 5 %. El análisis farmacogenético, realizado en la fase de inducción
IB, detectó tres polimorfismos de nucleótido único (SNPs) en el gen que codifica para la enzima tiopurina S-metiltransferasa (TPMT), observándose un fenotipo de metabolizador normal para esta enzima. Como consecuencia, se
requirió de un segundo análisis farmacogenético más completo, que reveló polimorfismos patológicos en el gen de
la hidrolasa Nudix 15 (NUDT15), explicarĂa la mielotoxicidad observada en esta paciente. Por ello, un análisis farmacogenĂ©tico completo deberĂa llevarse a cabo con anterioridad al inicio de 6-MP y de manera rutinaria en la práctica
clĂnica, para conseguir prevenir los efectos adversos graves y/o el fracaso terapĂ©utico.A 6-year-old girl diagnosed with intermediate-risk acute lymphoblastic leukemia (ALL) presented with severe myelotoxicity and multiple infections during phase IB induction treatment with 6-mercaptopurine (6-MP). In the subsequent treatment phases, which included 6-MP, the patient continued to show bone marrow aplasia and neutropenia, necessitating numerous dose adjustments and interruptions. The recommended dose was eventually
reduced to 5 %. A pharmacogenetic analysis, conducted in induction phase IB, detected three single-nucleotide
polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene, and the phenotype of a normal metab olizer was observed. As a result of a second pharmacogenetic analysis, pathological polymorphisms were revealed
in Nudix hydrolase 15 (NUDT15), which may explain the patient’s myelotoxicity. Hence, a pharmacogenetic analysis
performed in advance would have been able to prevent her from suffering severe toxicity and/or treatment failure.Funding: The Virgen de las Nieves University Hospital Biobank was supported by grants co-funded by ERDF funds
(EU) from the Instituto de Salud Carlos III (PT13/0010/0039)
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
Impact of Genetic Polymorphisms on the Metabolic Pathway of Vitamin D and Survival in Non-Small Cell Lung Cancer
Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population (p = 0.0233) and in the non-resected NSCLC subgroup (p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS (p = 0.0129) and rs7041 with PFS (p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS (p = 0.0048) and OS (p = 0.0089) and rs731236 and rs7975232 were associated with OS (p = 0.0005) and PFS (p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease