Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

INTRODUCTION: To determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. RESULTS: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; p = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (p = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (p = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. CONCLUSIONS: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status

Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

INTRODUCTION: A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. RESULTS: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. CONCLUSIONS: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status.This study was supported by a grant from ‘Fondo de Investigaciones Sanitarias’ PI12/00193 (Spain). RLM is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III at the Spanish Ministry of Health (Spain) (CD12/00425). FG and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013).Ye

Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population

Bases genéticas de la enfermedad de Behçet. Estudio multicéntrico en población española

La enfermedad de Behçet (BD) es una vasculitis sistémica de curso crónico y recidivante cuyos síntomas principales son las aftas orales, ulceras genitales y lesiones oculares. Es una enfermedad de base inmunológica clasificada como de patrón mixto porque en su origen se encuentran implicados elementos tanto del sistema inmune innato (enfermedad autoinflamatoria) como adaptativo (enfermedad autoinmune). Se trata de una enfermedad compleja que se desencadena en individuos genéticamente susceptibles mediante el concurso de determinados factores medioambientales. Dentro de los factores genéticos que influyen en la predisposición a desarrollar esta enfermedad, el más conocido y fuertemente asociado en diferentes poblaciones es una molécula del complejo mayor de histocompatibilidad (MHC) humano (HLA) de clase I, concretamente HLA-B51. Por esta razón, la región HLA ha sido ampliamente analizada mediante estudios caso-control aunque no está claro si otras moléculas de clase I pudieran tener asociación independiente con la enfermedad. Pero además, la región HLA explica sólo el 20-30% de la carga genética de la enfermedad por lo que la búsqueda de genes implicados en la predisposición y evolución de esta patología es objeto de investigación. El abordaje de este tipo de estudios se puede hacer con o sin hipótesis a priori; en cualquier caso, el desarrollo de la tecnología ha permitido el avance en sistemas de genotipado masivo y la identificación de nuevas variantes genéticas implicadas en diversas patologías. Si bien, los estudios de replicación son imprescindibles para validar las asociaciones en diferentes poblaciones. El objetivo general de nuestro trabajo ha sido profundizar en el conocimiento de las bases genéticas de la enfermedad de Behçet y los objetivos específicos que nos hemos planteado son: 1) determinar el papel de diferentes moléculas HLA de clase I en la predisposición a padecer la enfermedad y 2) establecer si determinados genes situados fuera de la región HLA, previamente relacionados con la enfermedad, se asocian con esta patología en nuestra población. En cuanto al diseño experimental se trata de un estudio multicéntrico de casos y controles en el que se incluyeron 315 pacientes diagnosticados de BD según los criterios del Grupo Internacional de la enfermedad de Behçet de 1990 y 377 controles sanos. El tipaje de los loci HLA-A*, B* y C* se realizó utilizando técnicas de ¿polimerase chain reaction¿ (PCR) y ¿specific sequence oligonucleotide probe¿ (SSOP) y el genotipado del resto de los genes mediante el estudio de ¿single nucleotide polymorphism¿ (SNP) con PCR a tiempo real y sondas TaqMan®. En cuanto a los resultados, además de B*51, diferentes grupos alélicos HLA-B se encontraron relacionados con la enfermedad: B*57 como factor de riesgo y B*35 como factor de protección. La región HLA-A muestra asociación independiente con la predisposición a padecer la enfermedad. En este sentido, el grupo alélico HLA-A*03 se comportaría como factor de protección en nuestra población. Finalmente, la región HLA-C no se encuentra asociada independientemente con la enfermedad ya que la asociación detectada es consecuencia del desequilibrio de ligamiento entre esta región y la región HLA-B. Con respecto a los genes no-HLA incluidos en el estudio, IL23R, IL10 y ERAP1 se encuentran asociados con la enfermedad en nuestra población, mientras que descartamos que otros genes, concretamente: CPVL, TRD3, UBASH3B, TRD7 y LOC100129342 jueguen un papel importante en la predisposición a padecer esta enfermedad. Diferentes genes que codifican moléculas relacionadas con la inmunidad adaptativa, así como con la inmunidad innata, pueden contribuir a la predisposición a padecer la enfermedad de Behçet. El estudio de los genes involucrados en el desarrollo de esta patología puede contribuir a mejorar el conocimiento de la etiopatogénesis de la enfermedad y por tanto, ayudar al diagnóstico de la misma, así como a la predicción del curso clínico de la enfermedad y al desarrollo de nuevas dianas terapéuticas

¿Violencia obstétrica en España, realidad o mito? 17.000 mujeres opinan

ObjetivoInvestigar la calidad percibida por las mujeres atendidas con motivo de un parto, cesárea o aborto en centros sanitarios españoles, y su satisfacción con distintos aspectos tanto humanos como técnicos de los cuidados recibidos.Material y MétodoEstudio descriptivo retrospectivo utilizando una encuesta online anónima difundida a través de redes sociales sobre la atención recibida durante su proceso obstétrico.ResultadosSe obtuvo una muestra de 17.677 respuestas. La atención por parte de los sanitarios obtuvo una nota media de 6,9 sobre 10. El 45,8 % de las mujeres opinaron que los sanitarios no solicitaron su consentimiento informado antes de cada técnica realizada y el 49 % que no tuvieron posibilidad de aclarar dudas o expresar miedos. El 38% percibieron que durante el parto recibieron procedimientos que no necesitaban y/o podían ser perjudiciales para su salud. El 34 % de las mujeres opinaron que habían sufrido violencia obstétrica.ConclusionesEl nacimiento de un nuevo hijo/a o su pérdida son eventos que dejan una importante huella en la salud física, psíquica y emocional de una mujer y de su familia. Los/as agentes de salud debemos reflexionar sobre el impacto generado por nuestros cuidados, la necesidad de basarlos en evidencia científica, y la obligación de respetar los derechos de la mujer y su bebé, aunque ni siquiera los conozca o los llegue a exigir. Los resultados de esta encuesta identifican una serie de áreas en las que pueden y deben mejorarse las prácticas de atención obstétrica, incluyendo el trato.ObjectiveTo investigate the quality of obstetric care as perceived by women in the context of giving birth, a cesarean section or miscarriage/stillbirth in health centers in Spain, and their satisfaction with different aspects of the attention received, both human and technical.Materials and methodRetrospective descriptive study based on an anonymous online survey about the care received during the obstetric process.ResultsA sample of 17,677 answers was obtained. Healthcare professionals were awarded an average of 6.9 points out of 10. 45.8 % of women believed that healthcare professionals did not ask for their informed consent before every procedure and 49 % did not have the opportunity to clarify doubts or express fears. 38 % perceived that they received unnecessary or potentially dangerous procedures during labor. Finally, 34 % believed they had suffered obstetric violence.ConclusionsThe birth or loss of a baby are events that leave a deep mark on the physical, psychological and emotional health of women and their families. Healthcare professionals should reflect upon the impact of our care, the need to base it on scientific evidence and the duty to respect women’s and children’s rights, even if they do not know these rights nor demand them. The results of this survey contribute to drawing up a guideline and identifying a series of fields in which obstetric attention, including treatment, can and must be improved.ObjetivoInvestigar la calidad percibida por las mujeres atendidas con motivo de un parto, cesárea o aborto en centros sanitarios españoles, y su satisfacción con distintos aspectos tanto humanos como técnicos de los cuidados recibidos.Material y MétodoEstudio descriptivo retrospectivo utilizando una encuesta online anónima difundida a través de redes sociales sobre la atención recibida durante su proceso obstétrico.ResultadosSe obtuvo una muestra de 17.677 respuestas. La atención por parte de los sanitarios obtuvo una nota media de 6,9 sobre 10. El 45,8 % de las mujeres opinaron que los sanitarios no solicitaron su consentimiento informado antes de cada técnica realizada y el 49 % que no tuvieron posibilidad de aclarar dudas o expresar miedos. El 38% percibieron que durante el parto recibieron procedimientos que no necesitaban y/o podían ser perjudiciales para su salud. El 34 % de las mujeres opinaron que habían sufrido violencia obstétrica.ConclusionesEl nacimiento de un nuevo hijo/a o su pérdida son eventos que dejan una importante huella en la salud física, psíquica y emocional de una mujer y de su familia. Los/as agentes de salud debemos reflexionar sobre el impacto generado por nuestros cuidados, la necesidad de basarlos en evidencia científica, y la obligación de respetar los derechos de la mujer y su bebé, aunque ni siquiera los conozca o los llegue a exigir. Los resultados de esta encuesta identifican una serie de áreas en las que pueden y deben mejorarse las prácticas de atención obstétrica, incluyendo el trato

Association of the AIRE gene with susceptibility to rheumatoid arthritis in an European population: a case control study

Abstract Introduction AIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus. Recently, the AIRE gene was identified as a genetic risk factor for rheumatoid arthritis (RA) in genome wide association (GWA) studies performed in the Japanese population. According to the available data this association is restricted to the Asian population. However, different facts could influence the lack of association in Caucasian populations. The aim of this study was to further investigate the possible role of the AIRE gene in susceptibility to RA in a Caucasian population. Methods A total of 472 Spanish Caucasian RA patients and 475 ethnically matched controls were included in the study. Three single-nucleotide polymorphisms (SNPs) (rs2776377, rs878081 and rs1055311) with a minor allele frequency >0.05 in the Caucasian population which were not included in the high-throughput platforms used in the GWA studies performed in susceptibility to RA, and two SNPs (rs2075876 and rs1800520) associated with RA in the Japanese population, were selected and genotyped using TaqMan assays. Results No significant differences in the distribution of the alleles of rs2776377, rs2075876, rs1055311 and rs1800520 SNPs between RA patients and controls were observed. Nevertheless, the frequency of the C allele of rs878081 was significantly higher among RA patients (80.5% vs. 74.6% in the control group, pc = 0.012, OR = 1.41, 95%CI 1.13-1.75). Regarding the distribution of the rs878081 genotypes, a higher frequency of CC homozygous individuals was found in the RA patient group (65.56% vs. 56.47% in the control group, pc = 0.013, OR = 1.47, 95%CI 1.12-1.93). The in silico analysis predicted lower affinity to the binding-site of a motif of the transcription NF-κB family and lower transcription levels of AIRE gene for the rs878081C risk variant Conclusions Our findings suggest that the AIRE gene is associated with susceptibility to RA in the Spanish population. Probably, this association has not been detected in the European population in the GWA studies because the earliest high-throughput platforms did not include SNP suitable markers (e.g. rs878081).This work was supported by Fondo de Investigaciones Sanitarias (FIS 10/1701), Fondos FEDER, Plan Andaluz de Investigación (PAI CTS-0197) and Consejería de Salud de la Junta de Andalucía (Exp. 0260/08).Peer Reviewe

HLA and non-HLA genes in Behçet¿s disease: a multicentric study in the Spanish population

Abstract Introduction According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet’s disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations. Methods This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ2 test. Results In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population. Conclusion Different HLA specificities are associated with Behçet’s disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease.This work was supported by Fondo de Investigaciones Sanitarias (10/1701), Fondos FEDER, Plan Andaluz de Investigación (CTS-0197 and CTS-180), Red Enfermedades Inflamatorias y Reumáticas RD08/0075/0013 and Consejería de Salud de la Junta de Andalucía (PI0411/2010). LOF is the recipient of a fellowship (FI11/00547).Peer Reviewe

Epistatic interaction of ERAP1 and HLA-B in Behcet disease: A replication study in the Spanish population

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population