Clara Cieza-Borrella

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

A genetic variant in the microRNA-146a gene is associated with susceptibility to alcohol use disorders.

BACKGROUND Polymorphisms in the microRNA (miRNA) regulatory pathways are novel functional genetic variants whose association with alcoholism susceptibility has not been previously studied. Given the potential relationship between certain miRNAs and alcohol use disorders (AUDs), this study was designed to explore the association between two polymorphisms within hsa-miR-146a and hsa-miR-196a2 genes and susceptibility to these diseases. METHODS Three hundred and one male patients with AUDs and 156 sex-matched healthy volunteers were enrolled. Polymorphisms were genotyped using TaqMan(®) PCR assays. Allele and genotype frequencies were compared between groups and logistic regression analysis was also performed to analyze the model of inheritance. RESULTS There was a significantly higher prevalence of allele C carriers (47.8%) of the miR-146a G>C polymorphism (rs2910164) among patients with AUDs when compared with controls (35.9%), and multivariable logistic regression analysis showed that the C allele was associated with these AUDs (OR=1.615, 95% CI 1.067-2.442; P=0.023). Neither the genotype nor the allele distribution of miR-196a2 polymorphism (rs11614913) was significantly different between groups. CONCLUSIONS This is the first genetic association study to explore the relationship of miRNA polymorphisms with AUDs and to show an association of the miR-146a C>G rs2910164 allelic variant with this disease.

VEGF A (rs699947 and rs833061) and VEGFR2 (rs2071559) Gene Polymorphisms are not Associated with AMD Susceptibility in a Spanish Population

Abstract Purpose: Age-related macular degeneration (AMD) is a multifactorial disease due to interaction between genetic and environmental factors. Increased angiogenesis plays a central role in AMD development. Previous studies on the potential link between AMD and vascular endothelial growth factor (VEGFA) and vascular endothelial growth factor receptor (VEGFR) have yielded conflicting results. We have analysed if polymorphisms in genes coding for VEGFA and VEGFR are associated to susceptibility to suffer AMD in a cohort of Spanish subjects. Patients and Methods: We obtained peripheral blood samples from 151 patients with diagnosis of exudative AMD. We also studied 91 healthy subjects matched by age. We studied VEGFA rs699947 and rs833061, and VEGFR2 rs2071559 polymorphisms using real-time PCR with TaqMan probes. Results: We did not find statistically significant differences in genotypic distribution of VEGF rs699947 and rs833061 polymorphisms between patients and controls. However, analysis of VEGFR2 rs2071559 polymorphism shows that carriers of GG genotype are more frequent in subjects with AMD (p: 0.032; Odds Ratio(OR): 1.933; confidence interval (CI): 1.053–3.549), but, when corrected by Bonferroni testing, the result was found to be not significant. Conclusion: Our study shows that VEGFA rs699947 and rs833061 and VEGFR2 rs2071559 polymorphisms do not modify the risk of suffering AMD in a Spanish population.

Association of Lysyl Oxidase-Like 1 Gene Polymorphisms in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population

Abstract Purpose: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG). Materials and methods: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing. Results: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p = 3.36 × 10−5, OR = 5.71, 95% CI: 2.30–14.18; p = 3.38 × 10−5, OR = 6.91, 95% CI: 2.51–19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p = 2.50 × 10−4, OR = 2.18, 95% CI: 1.43–3.33; p = 1.21 × 10−2, OR = 2.13, 95% CI: 1.75–3.85 respectively). No significant association between XFS/XFG and the rs1048661 was observed. The GGT haplotype composed of all three risk alleles was determined to be significantly associated with pseudoexfoliation. The genotypic and allelic distributions of the three SNPs were similar between XFS and XFG. Conclusions: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe. However rs1048661 SNP did not show an association with XFS.

CFH (rs1410996), HTRA1 (rs112000638) and ARMS2 (rs10490923) Gene Polymorphisms are Associated with AMD Risk in Spanish Patients

ABSTRACT Purpose: Age-related macular degeneration (AMD) is the main cause of legal blindness in the western adult population. We investigated the association between SNPs located in CFH, ARMS2 and HTRA1 and AMD in Spanish patients. Patients and Methods: We obtained peripheral blood samples from 121 patients with a diagnosis of AMD (84 exudative and 37 atrophic) at the Department of Ophthalmology of the University Hospital of Salamanca. We took 91 subjects as a control group. We studied a single nucleotide polymorphism (SNP) in each patient for each of the genes associated with high susceptibility to developing AMD using Real-time PCR with TaqMan probes for CFH and ARMS2 polymorphisms and PCR-RFLP for HTRA1 polymorphism. Results: We observed a statistically significant difference between patients and controls in the distribution of CFH rs1410996 genotypes, patients homozygous for the C-allele have twice the risk of developing the disease (p = 0.010; OR = 2,176 (1.194–3.964)). The analysis of ARMS2 rs10490923 polymorphism also showed differences in allelic distribution between the case and control groups (p < 0.001). Carriers of the T-allele appear more frequently in the group of patients (p < 0.001; OR = 3.340 (1.848–6.060)). Our results also confirm significant differences in the distribution of HTRA1 rs112000638 polymorphism with an increased representation of the G-allele in the patient’s group (p < 0.001; OR = 6.254(3.463–12.280)). Our study also indicates that TTGG ARMS2/HTRA1 (rs10490923/rs112000638) haplotype increases the risk of developing AMD by 9 times. Conclusions: Our results show that genotypes of ARMS2 (rs10490923), HTRA1 (rs112000638) and CFH (rs1410996) polymorphisms are related to an increased risk of suffering AMD in Spanish patients.

Prognostic value of telomere length in acute coronary syndrome.

Telomere and telomerase are involved in cellular and organismal ageing and have been related to human diseases. Coronary artery disease is one of the most common age-related health problems in developed countries. Nevertheless, the specific role of cellular ageing in this process is still unclear. In this study, we analyze the possible prognostic value of telomere length and telomerase polymorphisms in a population of 150 middle aged males (mean age 62 ± 7) admitted for acute coronary syndrome who were followed up for more than 600 days. Peripheral blood samples were obtained and relative and comparative qPCR was used to measure telomere length and real time PCR to study the polymorphisms. Two prognostic combined events were defined. Long telomere length was revealed as an independent predictor (protector) of combined event presentation during long term follow up in our patients.

Cognitive outcome and gamma noise power unrelated to neuregulin 1 and 3 variation in schizophrenia

BackgroundNeuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1–4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance.MethodsWe obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype.ResultsContrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia.ConclusionsDespite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia.

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

BackgroundProstate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.MethodsWe sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.ResultsProtein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.ConclusionsInherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.

Early-onset type 2 diabetes mellitus is associated to HNF4A T130I polymorphism in families of central Spain

Purpose Type 2 diabetes mellitus (type 2 DM) and maturity-onset diabetes of the young present some similar clinical and biochemical characteristics that make them difficult to differentiate. Currently, the polymorphism T130I (rs1800961) in the HNF4A (hepatocyte nuclear factor 4A) gene has been described as a risk factor to type 2 DM and shows an autosomal dominant inheritance pattern associated to β-cell function decrease. The aim of the present work was to characterize the phenotypic profile of the T130I carrier and noncarrier relatives included in 3 unrelated families. Methods We studied GCK, HNF1A, and HNF4A genes by polymerase chain reaction and sequencing in 3 unrelated subjects from Valladolid, Spain, in which maturity-onset diabetes of the young was suspected. We collected genetic, clinical, and biochemical data from these subjects and their relatives in order to check the presence of the T130I polymorphism. Results The heterozygous T130I mutation was the unique functional gene variation that could explain diabetes phenotype. We observed significant differences in glucose metabolism, lipid profile, and Homeostasis Model Assessment index when we compared T130I mutation carriers and noncarriers. Diabetes diagnosed in T130I mutation carriers was related to stressful situations in an earlier age and tightly associated with gestational diabetes. Fasting plasma glucose and HbA1c levels increased with age in all carriers (r = 0.69 and r = 0.66, P < 0.01), respectively. Conclusions Our study supports the T130I variant in HNF4A as a major susceptibility genotype associated with early-onset type 2 DM. Healthy carriers of this mutation require a stricter control in the population of central Spain.

Pharmacokinetic drug evaluation of vorapaxar for secondary prevention after acute coronary syndrome

ABSTRACT Introduction: Vorapaxar is the first protease-activated receptor-1 inhibitor approved for clinical use. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infarction or symptomatic peripheral artery disease. Areas covered: This article reviews the pharmacokinetics of vorapaxar and its potential use in secondary prevention after an acute coronary syndrome. Expert opinion: Vorapaxar inhibits platelet aggregation mediated by thrombin. This effect is carried out without affecting to coagulation parameters and bleeding times. This drug has showed a significant reduction of cardiovascular events in patients with chronic atherosclerosis but not during the admission for an acute coronary syndrome. The rate of major bleeding found in patients treated with vorapaxar in randomized trials was consistently higher than placebo in most of the analyzed subgroups. For this reason, cautious evaluation of risk-benefit profiles should be required before prescribing this drug.