Real-life data of immune recovery using bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed people living with HIV. Results at 48-96†weeks of RETROBIC Study.

BACKGROUND: Switching strategy with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) has become a gold standard for people living with HIV (PLWH), achieving high efficacy and safety rates. However, data regarding immune status in long-term real-life cohorts of pretreated patients are needed. METHODS: We performed a multicentre, non-controlled, retrospective study in virologically suppressed PLWH switching to B/F/TAF. We evaluated CD4+, CD8+ and CD4+/CD8+ ratio, efficacy and safety at weeks 48 and 96. RESULTS: The study comprised 1966 PLWH from 12 hospitals in Spain, of whom 80% were men, and the median age was 51.0 [42.0-57.0] years. The median time of HIV infection was 18.0 [10.0-27.0] years. No significant changes in CD4+, CD8+ T cells, or CD4+/CD8+ were observed after 96 weeks. Nevertheless, in women at weeks 48 and 96, we found a significant increase of CD4+ T cells and a significant decrease in CD8+ T cells. In patients ≥60 years at week 96, CD4 T cells significantly increased and CD8+ T cells significantly decreased at week 48. The on-treatment analysis revealed HIV-RNA <50 copies/mL in 95.6% (1700/1779) and 96.7% (1312/1356) of patients at weeks 48 and 96, respectively. The rates increased to 99.2% (1765/1779) and 99.7% (1352/1356) when considering HIV-RNA <200 copies/mL. No resistance mutations were detected in virologic failures. B/F/TAF discontinuations accounted for 10.2% (200). Simplification was the most common reason for discontinuation in 3.8% (74) of patients. CONCLUSION: In long-term virologically controlled PLWH, B/F/TAF achieved high efficacy rates and slightly improved immune status in women and individuals aged 60 and over after 48 and 96 of switching.

Functional assessment of the BMPR2 gene in lymphoblastoid cell lines from Graves' disease patients.

In this study, we analysed the possible influence of the c.419-43delT BMPR2 variant in patients with Graves' disease (GD), in a molecular basis, focusing our efforts on possible alterations in the mRNA processing and synthesis. The molecular assessment of this variant in patients with GD would shed light on the association between the BMPR2 gene and the disease. The variant was detected in 18%, 55% and 10% of patients with pulmonary arterial hypertension, GD and in general population, respectively. Patients with GD fold change showed increased BMPR2 expression when matched against the controls, with a mean of 4.21 ± 1.73 (P = 0.001); BMPR2 was overexpressed in the analysed cell cycle stages. Fold change analysis of variant carriers and non-carriers showed slight overexpression and differences between phases, but none of them were statistically significant. BMPR2 expression was confirmed in the lymphoblastoid cell lines (LCLs) with a molecular weight of 115 kD, and no differences between variant carriers and non-carriers were detected. To conclude, the BMPR2 variant c.419-19delT appears in high frequency in patients with GD, and independently of its presence, BMPR2 is overexpressed in the LCLs from the GD patients tested. This increase could be paired with the described decreased expression of transforming growth factor-ß1 in thyroid tissue from patients with GD.

Functional analysis by minigene assay of putative splicing variants found in Bardet-Biedl syndrome patients.

Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare diseases belonging to the group of ciliopathies. Although mutational screening studies of BBS/ALMS cohorts have been extensively reported, little is known about the functional effect of those changes. Thus, splicing variants are estimated to represent 15% of disease-causing mutations, and there is growing evidence that many exonic changes are really splicing variants misclassified. In this study, we aimed to analyse for the first time several variants in BBS2, ARL6/BBS3, BBS4 and ALMS1 genes predicted to produce aberrant splicing by minigene assay. We found discordance between bioinformatics analysis and experimental data when comparing wild-type and mutant constructs. Remarkably, we identified nonsense variants presumably resistant to nonsense-mediated decay, even when a premature termination codon would be introduced in the second amino acid (p.(G2*) mutation in ARL6/BBS3 gene). As a whole, we report one of the first functional studies of BBS/ALMS1 variants using minigene assay, trying to elucidate their role in disease. Functional studies of variants identified in BBS and ALMS patients are essential for their proper classification and subsequent genetic counselling and could also be the start point for new therapeutic approaches, currently based only on symptomatic treatment.

Mutational and clinical analysis of the ENG gene in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterized by a capillary wedge pressure ≤ 15 mmHg and a mean pulmonary arterial pressure ≥ 25 mmHg at rest. PAH can be idiopathic, heritable or associated with other conditions. The aim of this study was to analyze the Endoglin (ENG) gene and assess the influence of the c.572G > A (p.G191D) mutation in patients with idiopathic or associated PAH. The correlation between the pathogenic mutations and clinical and functional parameters was further analyzed. RESULTS: Sixteen different changes in the ENG gene were found in 44 out of 57 patients. After in silico analysis, we classified eight mutations as pathogenic in 16 of patients. The c.572G>A (p.G191D) variation was observed in ten patients, and the analysis for the splicing process using hybrid minigenes, with pSPL3 vector to assess splicing alterations, do not generate a new transcript. Age at diagnosis (p = 0.049) and the 6-min walking test (p = 0.041) exhibited statistically significant differences between carriers and non-carriers of pathogenic mutations. Patients with pathogenic mutations exhibited disease symptoms 8 years before non-carriers. Five patients with pathogenic mutations were carriers of another mutation in the BMPR2 or ACVRL1 genes. CONCLUSIONS: We present a series of PAH patients with mutations in the ENG gene, some of them not previously described, exhibiting clinical and hemodynamic alterations suggesting that the presence of these mutations may be associated with the severity of the disease. Moreover, genetic analysis in patients with PAH may be of clinical relevance and indicates the complexity of the genetic background.

Efficacy and Safety of Two-Drug Regimens with Dolutegravir plus Rilpivirine or Lamivudine in HIV-1 Virologically Suppressed People Living with HIV.

BACKGROUND: The high effectiveness and safety of the two-drug (2DRs) strategy using dolutegravir (DTG) plus lamivudine (3TC) have led to international guidelines recommending their use for treatment-naive HIV patients. In virologically suppressed patients, de-escalating from 3DRs to DTG plus either rilpivirine (RPV) or 3TC has shown high rates of virological suppression. OBJECTIVES: This study aimed to compare the real-life data of two multicenter Spanish cohorts of PLWHIV treated with DTG plus 3TC (SPADE-3) or RPV (DORIPEX) as a switch strategy, not only in terms of virological suppression, safety, and durability but also in terms of immune restoration. The primary endpoint was the percentage of patients with virological suppression on DTG plus 3TC and DTG plus RPV at weeks 24 and 48. The secondary outcomes included the proportion of patients who experienced the protocol-defined loss of virological control by week 48; changes in immune status in terms of CD4+ and CD8+ T lymphocyte counts and the CD4+/CD8+ ratio; the rate, incidence, and reasons for discontinuation of treatment over the 48-week study period; and safety profiles at weeks 24 and 48. METHODS: We conducted a retrospective, observational, multicenter study of 638 and 943 virologically suppressed HIV-1-infected patients in two cohorts who switched to 2DRs with DTG plus RPV or DTG plus 3TC. RESULTS: The most frequent reasons for starting DTG-based 2DRs were treatment simplification/pill burden or drug decrease. The virological suppression rates were 96.9%, 97.4%, and 99.1% at weeks 24, 48, and 96, respectively. The proportion of patients with virological failure over the 48-week study period was 0.01%. Adverse drug reactions were uncommon. Patients treated with DTG+3TC increased CD4, CD8, and CD4/CD8 parameters at 24 and 48 weeks. CONCLUSIONS: We conclude that DTG-based 2DRs (combined with 3TC or RPV) in clinical practice were effective and safe as a switching strategy, with a low VF and high viral suppression rates. Both regimens were well tolerated, and ADR rates were low, including neurotoxicity and induced treatment discontinuations.

Dolutegravir Plus 3TC in Virologically Suppressed PLWHIV: Immunological Outcomes in a Multicenter Retrospective Cohort in Spain during the COVID-19 Pandemic.

Dolutegravir (DTG) based dual therapies for treating PLWHIV are a standard of care nowadays. Switching to DTG and lamivudine (3TC) safety and efficacy were proven in TANGO randomized clinical trial. This multicenter retrospective study included 1032 HIV virologically suppressed patients switching to DTG+3TC from 13 Spanish hospitals. DTG+3TC provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. The analysis for paired data showed an increase in CD4+ cell count. A statistically significant increase in CD4+ lymphocyte count was found in those without comorbidities in the three-time series analyzed [average increase at 24 weeks: 48.7 (SD: 215.3) vs. 25.8 (SD: 215.5), p-value = 0.050; a mean increase at 48 weeks: 75.1 (SD: 232.9) vs. 42.3 (SD: 255.6), p-value = 0.003; a mean increase at 96 weeks: 120.1 (SD: 205.0) vs. 63.8 (SD:275.3), p-value = 0.003]. In conclusion, our cohort demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy.

Real-life cohort experience after implementing HIV pre-exposure prophylaxis for one year in northwest Spain.

Introduction: Pre-exposure prophylaxis (PrEP) has become a useful tool to reduce the transmission of human immunodeficiency virus (HIV) in key populations. In this article we assessed the effectiveness, safety, adherence, sexually transmitted infections (STIs) dynamics, and frequency of anal dysplasia among a real-life cohort of PrEP users in Northwest Spain. Methods: A retrospective cohort study was undertaken in the Alvaro-Cunqueiro Hospital, Vigo which included every individual who started daily emtricitabine/tenofovir-disoproxil-fumarate (FTC/TDF) between November-2019 and October-2021. Clinical and epidemiological data were obtained from the patient's medical records. The effectiveness and safety of FTC/TDF were assessed by HIV serology and renal function monitoring every 3 months. Anal, urethral, and oropharyngeal exudates were collected quarterly after the baseline visit. Results: A total of 126 individuals were considered eligible, most of the participants had previously been diagnosed with a STI (60.3%), 22% had consumed recreational drugs in the year prior, and 13% had engaged in chemsex. At the end of the follow-up, no cases of HIV infection were detected; 3 patients had discontinued FTC/TDF because of side effects but none of them had presented renal toxicity. In addition, the diagnosis of STIs during the follow-up was common (100 cases in 54 patients). Moreover, engagement in chemsex was more common within this latter group (22 vs. 6%, p = 0.013). Among the study population included in the anal screening programme, the frequency of dysplasia was 9%. Conclusions: FTC/TDF was effective, safe, and tolerable in a real-life cohort; adherence remained high throughout the study period (79%). However, a high number of STIs were diagnosed, especially among patients who engaged in chemsex.

Dolutegravir plus rilpivirine: benefits beyond viral suppression: DORIPEX retrospective study.

ABSTRACT: Switching dual therapy with dolutegravir (DTG) plus rilpivirine (RPV) was assessed in the SWORD-1 and SWORD-2 studies. Real-life data regarding the immunological impact of this approach on CD4+ and CD8+ T lymphocyte counts and the CD4/CD8 ratio are scarce. We evaluated this strategy on the basis of clinical practice data.A multicentric retrospective cohort study.Treatment-experienced virologically suppressed HIV-1-infected patients who were switched to DTG plus RPV were included. Using different models for paired data, we evaluated the efficacy and immune status in terms of CD4+ and CD8+ T-cell counts and CD4/CD8 ratio at 24 and 48 weeks of treatment.The study population comprised of 524 patients from 34 centers in Spain. Men accounted for 76.9% of patients, with a median age of 53 years. Patients receiving DTG plus RPV reached weeks 24 and 48 in 99.4% and 83.8% of cases, respectively, with only three (0.57%) virological failures. We found a significant decrease in CD8+ T-cell count (log OR -40) at week 24 and an increase in CD4+ T-cell count at week 48 (log OR +22.8). In acquired immunodeficiency syndrome-diagnosed patients, we found a significant increase in the CD4+ T-cell count at week 48 (log OR = 41.7, P = .0038), but no significant changes in the CD8+ T-cell count (log OR = -23.4, P = .54). No differences were found in the CD4/CD8 ratio between the acquired immunodeficiency syndrome subgroup and sex or age.In patients with controlled treatment, dual therapy with DTG plus RPV slightly improved the immune status during the first 48 weeks after switching, not only in terms of CD4+ T-cell count but also in terms of CD8+ T-cell count, with persistently high rates of viral control.

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.

Pulmonary arterial hypertension associated to systemic erythematosus lupus: molecular characterization of 3 cases. / Hipertensión arterial pulmonar asociada a lupus eritematoso sistémico: caracterización molecular de 3 casos.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension associated with systemic lupus erythematosus (PAH-SLE) is a rare disease with a low incidence rate. In this study, PAH related genes and genetic modifiers were characterised molecularly in patients with PAH-SLE. PATIENTS AND METHODS: Three patients diagnosed with PAH-SLE and 100 control individuals were analysed after signing an informed consent. RESULTS: Two out of the three analysed patients with PAH-SLE were carriers of pathogenic mutations in the genes BMPR2 and ENG. After an in silico analysis, pathogenic mutations were searched for in control individuals and different databases, with negative results, and they were thus functionally analysed. The third patients only showed polymorphisms in the genes BMPR2, ACVRL1 and ENG. Several genetic variants and genetic modifiers were identified in the three analysed patients. These modifiers, along with the pathogenic mutations, could lead to a more severe clinical course in patients with PAH. CONCLUSIONS: We present, for the first time, patients with PAH-SLE carrying pathogenic mutations in the main genes related to PAH and alterations in the genetic modifiers.

Mutational screening in genes related with porto-pulmonary hypertension: An analysis of 6 cases. / Cribado mutacional en genes relacionados con la hipertensión portopulmonar: análisis de 6 casos.

INTRODUCTION: Portopulmonary hypertension (PPH) is a rare disease with a low incidence and without a clearly-identified genetic component. The aim of this work was to check genes and genetic modifiers related to pulmonary arterial hypertension in patients with PPH in order to clarify the molecular basis of the pathology. PATIENTS: We selected a total of 6 patients with PPH and amplified the exonic regions and intronic flanking regions of the relevant genes and regions of interest of the genetic modifiers. RESULTS: Six patients diagnosed with PPH were analyzed and compared to 55 healthy individuals. Potentially-pathogenic mutations were identified in the analyzed genes of 5 patients. None of these mutations, which are highly conserved throughout evolution, were detected in the control patients nor different databases analyzed (1000 Genomes, ExAC and DECIPHER). After analyzing for genetic modifiers, we found different variations that could favor the onset of the disease. CONCLUSIONS: The genetic analysis carried out in this small cohort of patients with PPH revealed a large number of mutations, with the ENG gene showing the greatest mutational frequency.

Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a progressive disease that causes the obstruction of precapillary pulmonary arteries and a sustained increase in pulmonary vascular resistance. The aim was to analyze functionally the variants found in the BMPR2 gene and to establish a genotype-phenotype correlation. mRNA expression studies were performed using pSPL3 vector, studies of subcellular localization were performed using pEGFP-N1 vector and luciferase assays were performed using pGL3-Basic vector. We have identified 30 variants in the BMPR2 gene in 27 of 55 patients. In 16 patients we detected pathogenic mutations. Minigene assays revealed that 6 variants (synonymous, missense) result in splicing defect. By immunofluorescence assay, we observed that 4 mutations affect the protein localization. Finally, 4 mutations located in the 5'UTR region showed a decreased transcriptional activity in luciferase assays. Genotype-phenotype correlation, revealed that patients with pathogenic mutations have a more severe phenotype (sPaP p = 0.042, 6MWT p = 0.041), a lower age at diagnosis (p = 0.040) and seemed to have worse response to phosphodiesterase-5-inhibitors (p = 0.010). Our study confirms that in vitro expression analysis is a suitable approach in order to investigate the phenotypic consequences of the nucleotide variants, especially in cases where the involved genes have a pattern of expression in tissues of difficult access.

Methylation Analysis of the BMPR2 Gene Promoter Region in Patients With Pulmonary Arterial Hypertension. / Análisis de la metilación de la región promotora del gen BMPR2 en pacientes con hipertensión arterial pulmonar.

INTRODUCTION: Pulmonary arterial hypertension is characterizated by obstruction of the pulmonary arteries. The gene mainly related to pathology is the bone morphogenetic protein receptor type II (BMPR2). The aim of this study was to analyze the methylation pattern of the BMPR2 promoter region in patients and controls. METHODS: We used Methyl Primer Express(®) v.1.0 and MatInspector softwares to analyze this region. Genomic DNA obtained from the peripheral blood of patients and controls was modified with sodium bisulphite. Methylation was analyzed using methylation-specific PCR. DNA treated with CpG methyltransferase was used as a positive control for methylation and H1299 cell culture DNA was used as positive control for gene expression. RESULTS: We identified a CpG island, which may have been methylated, in the BMPR2 promoter region, in addition to NIT-2 (global-acting regulatory protein), sex-determining region Y) and heat shock factor transcription factor binding sites. We found no evidence of methylation in patients and controls. No methylated CpG sites were identified in H1299 cells expressing the BMPR2 gene. CONCLUSIONS: The BMPR2 promoter region is the most suitable for study because of the high number of transcription factor binding sites that could alter gene function. No evidence of methylation was detected in this region in patients and controls.

Complex inheritance in Pulmonary Arterial Hypertension patients with several mutations.

Pulmonary Arterial Hypertension (PAH) is a rare and progressive disease with low incidence and prevalence, and elevated mortality. PAH is characterized by increased mean pulmonary artery pressure. The aim of this study was to analyse patients with combined mutations in BMPR2, ACVRL1, ENG and KCNA5 genes and to establish a genotype-phenotype correlation. Major genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Genotype-phenotype correlation was performed. Fifty-seven (28 idiopathic PAH, 29 associated PAH group I) were included. Several mutations in different genes, classified as pathogenic by in silico analysis, were present in 26% of PAH patients. The most commonly involved gene was BMPR2 (12 patients) followed by ENG gene (9 patients). ACVRL1 and KCNA5 genes showed very low incidence of mutations (5 and 1 patients, respectively). Genotype-phenotype correlation showed statistically significant differences for gender (p = 0.045), age at diagnosis (p = 0.035), pulmonary vascular resistance (p = 0.030), cardiac index (p = 0.035) and absence of response to treatment (p = 0.011). PAH is consequence of a heterogeneous constellation of genetic arrangements. Patients with several pathogenic mutations seem to display a more severe phenotype.

[Pulmonary arterial hypertension associated with human immunodeficiency virus infection: study of 4 cases]. / Hipertensión arterial pulmonar asociada a infección por el virus de la inmunodeficiencia humana: análisis de 4 casos.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare and progressive disease that can be inherited as autosomal dominant form. The BMPR2, ACVRL1 and ENG genes are main genes involved in the pathology. PAH associated to human immunodeficiency virus (HIV) is another rare disease with a low incidence, prevalence and survival. The main objective of this analysis was to study the clinical and molecular characteristics of PAH associated to HIV patients. PATIENTS: We present 4 cases of HIV patients who developed PAH and have been treated with ambrisentan. RESULTS: Pathogenic mutations have been identify in analyzed genes in 3 of the four analyzed patients. In addition, these patients present other changes classified as benign after a thorough in silico analysis. We identified some changes in genetic modifiers that predispose to these patients to more severe phenotype. CONCLUSIONS: The clinical analysis can help to define monitoring for these patients and the administration of appropriate treatment. These patients also have shown several pathogenic mutations.

Pulmonary arterial hypertension associated with hereditary spherocytosis and splenectomy in a patient with a mutation in the BMPR2 gene.

There is some question about the relationship between hereditary spherocytosis (HS) and pulmonary arterial hypertension, even associated with splenectomy. The finding of BMPR2 mutations in our patient suggests that other factors are necessary for the development of the disease, and perhaps, the incidence of pulmonary hypertension is not increased in patients with HS.

Molecular and clinical analysis of TRPC6 and AGTR1 genes in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze 5'UTR region in canonical transient receptor potential isoform 6 (TRPC6) and 3'UTR region in Angiotensin II type I receptor (AGTR1) genes in patients with idiopathic and associated PAH. Correlation among mutations and clinical and functional parameters was further analyzed. METHODS: Analysis of TRPC6 and AGTR1 genes was performed by polymerase chain reaction (PCR) and direct sequencing. We used a non-parametric test to determine if significant differences were found between the groups studied and chi-square test to compare clinical and hemodynamic variables among genotypes. RESULTS: Fifty five patients and fifty two controls were included in this study. We found statistically significant differences for c.1-361A > T (p = 0.0077), c.1-254C > G (p < 0.0001) and c.1-218C > T (p = 0.0021) in TRPC6 gene and c.1166A > C (p < 0.001) in AGTR1 gene, between patients and controls. Idiopathic PAH patients (IPAH) and controls presented significant differences for all 3 TRPC6 polymorphisms (p = 0.020), (p = 0.002) and (p = 0.008) respectively, and also showed differences for AGTR1 gene (p < 0.001). In associated PAH (APAH) patients we found statistical differences for c.1-254C > G (p < 0.001) and c.1-218C > T (p = 0.001) in TRPC6 gene and c.1166A > C (p = 0.001) in AGTR1 gene. Several clinical and hemodynamic parameters showed significant differences between carriers and non-carriers of these single nucleotide polymorphisms (SNPs). Nineteen patients were carriers of all 3 SNPs in TRPC6 gene and presented a more severe phenotype with differences in mean pulmonary arterial pressure (p = 0.016), systolic pulmonary arterial pressure (p = 0.040), cardiac index (p < 0.001) and 6 minute walking test (p = 0.049). 16 of these patients harbored the SNP in AGTR1 gene. These patients showed differences in age at diagnosis (p = 0.049), mean pulmonary arterial pressure (p = 0.033), cardiac index (p = 0.002) and 6 minute walking test (p = 0.039). CONCLUSIONS: PAH is a rare disease with pulmonary vascular remodeling caused in part by a heterogeneous constellation of genetic arrangements. This study seems to suggest that c.1-361A > T, c.1-254C > G and c.1-218C > T polymorphisms in TRPC6 gene and c.1166A > C polymorphism in AGTR1 could have a role in the development of this disease.

Pulmonary arterial hypertension and portal hypertension in a patient with hereditary hemorrhagic telangiectasia.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare disease that could be inherited with an autosomal dominant pattern. Mutations in BMPR2 gene are described in over 70% of cases, although other genes are involved in lesser extend in PAH. Hereditary hemorrhagic telangiectasia (HHT) is another rare autosomal dominant disease. PAH is a rare complication of HHT that occurs in less than 1% of cases. Liver cirrhosis with portal hypertension is also associated with the presence of PAHs in 1-2% of cases. PATIENTS: We present here a patient with HHT who developed PAH shortly after showing portal hypertension. RESULTS: Some genes (BMPR2, ACVRL1, ENG) seem to play an important role in PAH pathogenesis. We analyzed these genes, detecting mutations in BMPR2 gene (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) and ENG (c.498G>A (Q166Q)). The patient also had 3 polymorphisms in the TRPC6 gene (c.1-361A>T, c.1-254C>G, c.1-218C>T). CONCLUSIONS: The study of these genes will help us to identify and track individuals susceptible for developing PAH associated with other diseases.

[K198N polymorphism in the EDN1 gene in patients with pulmonary arterial hypertension]. / Estudio del polimorfismo K198N en el gen EDN1 en pacientes afectados con hipertensión arterial pulmonar.

BACKGROUND AND OBJECTIVE: In pulmonary arterial hypertension (PAH) an association with a polymorphism in the endothelin gene (EDN1) has been described. The main objective of this study was to analyze the polymorphism K198N in the gene EDN1 in patients with PAH, correlating the results with clinical and hemodynamic parameters. PATIENTS AND METHODS: We compared 41 patients diagnosed with idiopathic and associated PAH of group i with 50 healthy controls. Polymerase chain reaction and direct sequencing were used to analyze the polymorphism K198N. We compared the genotype distribution and searched for a correlation with clinical, hemodynamic and therapeutic response. RESULTS: Genotype GG was present in 42% of patients in this study and 65% of controls. The GT+TT genotypes appeared in 58% of patients and in 35% of controls. Statistically significant differences between patients and controls (P=.032) were detected, with a relative risk in carriers of having the T allele of 2.51 (95% CI 1.07 to 5.86). The analysis by PolyPhen software defined K198N change as pathogenic. No significant differences in the response to treatment at medium term were found. CONCLUSIONS: The genotype analysis of the EDN1 gene polymorphism shows statistically significant differences in patients with PAH compared to healthy individuals. Individuals carrying at least one T allele exhibit a higher relative significant risk to develop HAP.

Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze the Bone Morphogenetic Protein Receptor 2 (BMPR2), Activin A type II receptor like kinase 1 (ALK1/ACVRL1) and potassium voltage-gated channel, shakerrelated subfamily, member 5 (KCNA5) genes in patients with idiopathic and associated PAH. Correlation among pathogenic mutations and clinical and functional parameters was further analyzed. METHODS AND RESULTS: Forty one patients and fifty controls were included in this study. Analysis of BMPR2, ACVRL1 and KCNA5 genes was performed by polymerase chain reaction (PCR) and direct sequencing. Fifty one nucleotide changes were detected in these genes in 40 of the 41 patients; only 22 of these changes, which were classified as pathogenic, have been detected in 21 patients (51.2%). Ten patients (62.5%) with idiopathic PAH and 10 (40%) with associated PAH showed pathogenic mutations in some of the three genes. Several clinical and hemodynamics parameters showed significant differences between carriers and non-carriers of mutations, being more severe in carriers: mean pulmonary artery pressure (p = 0.043), pulmonary vascular resistence (p = 0.043), cardiac index (p = 0.04) and 6 minute walking test (p = 0.02). This differences remained unchanged after adjusting for PAH type (idiopathic vs non idiopathic). CONCLUSIONS: Pathogenic mutations in BMPR2 gene are frequent in patients with idiopathic and associated PAH group I. Mutations in ACVRL1 and KCNA5 are less frequent. The presence of these mutations seems to increase the severity of the disease.