Manuel Díaz-Rubio

Symptoms of gastro-oesophageal reflux: prevalence, severity, duration and associated factors in a Spanish population

Aim : To measure the prevalence of gastro‐oesophageal reflux symptoms and to identify associated factors in a representative sample of the Spanish population.

Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug‐metabolising enzymes. Two amino‐acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti‐inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.

Myenteric antiplexus antibodies and class II HLA in achalasia.

Achalasia, a motor disorder of the esophagus, is accompanied by autoimmune phenomena that could be playing a role in the pathogenesis of the disease. Our objective was to establish the genotypic frequency of the HLA-DR and DQ alleles in patients with achalasia and to establish their relationship with the presence of myenteric antiplexus antibodies in our geographic area. A total of 92 patients diagnosed with achalasia and two control groups with 275 healthy subjects were studied for HLA typing and 40 for autoantibodies determination. The myenteric antiplexus antibodies were positive in 50 patients (54.3%) and in 3 healthy subjects (7.5%) (P < 0.001). The patients showed a significantly higher frequency of DQA1*0103 and DQB1*0603 than was found in the controls. The heterodimer DQA1*0103–DQB1*0603 was increased in the patients [odds ratio (OR) = 2.57]. In regard to the association between the HLA DQA1 and DQB1 alleles and the antiplexus antibodies, these antibodies were found in greater prevalence in those patients with the DQA1*0103 and DQB1*0603 alleles, and the differences were statistically significant (OR = 3.17 and OR = 5.82, respectively). All of the women and 66.7% of the men with achalasia and the DQB1*0603 allele or the DQA1*0103–DQB1*0603 heterodimer were positive for antibodies.

Manifestaciones extraintestinales en la enfermedad inflamatoria intestinal: diferencias entre la enfermedad de Crohn y la colitis ulcerosa

Fundamento y objetivo: La prevalencia de las manifestaciones extraintestinales (MEI) en la enfermedad inflamatoria intestinal (EII) varia en funcion de las areas geograficas, el tipo de EII, la localizacion, la duracion de la enfermedad y el tratamiento y la rapidez en el diagnostico. El objetivo de este trabajo ha sido determinar la prevalencia de las principales MEI en la EII y las diferencias existentes entre la enfermedad de Crohn (EC) y la colitis ulcerosa (CU). Pacientes y metodo: Estudio prospectivo en el que se incluyo a 566 pacientes con EII (295 con EC y seguimiento medio de 11,6 anos [extremos: 2-32 anos] y 271 con CU y seguimiento medio de 10,4 anos [extremos: 2-36 anos]. Los datos referidos a las MEI y tests de laboratorio se obtuvieron en el momento del diagnostico y durante las visitas posteriores. Resultados: La aparicion de al menos una MEI se observo en el 46,6% de los pacientes. Las MEI fueron frecuentes tanto en la CU (51,5%) como en la EC (42,2%). Las manifestaciones hepatobiliares (odds ratio [OR] = 1,91; intervalo de confianza [IC] del 95%, 1,15-3,16), la enfermedad tromboembolica venosa (OR = 4,26; IC del 95%, 1,3-15,4) y las artralgias (OR = 1,59; IC del 95%, 1,01-2,5) fueron mas frecuentes en la CU que en la EC. El eritema nodoso (OR = 2,35; IC del 95%, 1,13-5,0) y las artritis perifericas (OR = 1,95; IC del 95%, 1,02-3,74) fueron mas frecuentes en la EC. La prevalencia de las manifestaciones oculares y del resto de manifestaciones articulares no difirio entre la CU y la EC. Conclusiones: La prevalencia de las MEI en los pacientes con EII espanoles es una de las mas altas publicadas. La frecuencia del tipo de MEI es diferente entre los pacientes con EC y CU, un aspecto que es importante conocer para realizar un diagnostico adecuado de la EII y de sus complicaciones.

Burden of Illness in Irritable Bowel Syndrome Comparing Rome I and Rome II Criteria

AbstractObjectives: To evaluate the burden of illness in irritable bowel syndrome (IBS), in terms of resource utilisation (direct and indirect) and health-related quality of life (HR-QOL), in individuals with IBS who meet Rome I and Rome II criteria. Methods: A cross-sectional study, carried out by personal interview, on a representative sample (n = 2000) of the Spanish population. Individuals with suspected IBS were identified via a screening question and subsequently given an epidemiological questionnaire to complete. The questionnaire collected information on IBS symptoms, resource utilisation, and HR-QOL [Medical Outcomes Study 36-item Short Form (SF-36)]. Results: Sixty-five individuals met Rome II criteria for IBS, while 146 individuals met exclusively Rome I criteria. Of Rome II individuals, 67.7% had consulted some type of healthcare professional in the previous 12 months, compared with only 41.8% of those individuals meeting exclusively Rome I criteria (p < 0.001). In the same vein, similar findings were observed (p < 0.01) for the variables: ‘diagnostic tests’ (35.4 vs 17.1%); ‘drug consumption’ (70.8 vs 45.2%); and ‘reduced performance in main activity’ (60 vs 27.4%). Compared with the general population, the study sample reported significantly worse HR-QOL scores in four dimensions of the SF-36 (‘bodily pain’, ‘vitality’, ‘social functioning’ and ‘role-emotional’. Additionally, individuals meeting Rome II criteria reported worse HR-QOL scores than those individuals meeting exclusively Rome I criteria, especially in the ‘bodily pain’ and ‘general health’ dimensions. Conclusions: The burden of illness in IBS is important and correlated to the diagnostic criteria employed. Individuals who met Rome II criteria reported a higher level of resource utilisation and worse HR-QOL than individuals meeting exclusively Rome I criteria.

Prevalence of mutations of the NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn disease

Background: We assessed the prevalence of R702W, G908R, and L1007fs coding mutations in the NOD2/CARD15 gene and the genotype–phenotype relation in Spanish patients with Crohn disease. Methods: A cohort of 204 unrelated patients with Crohn disease and 140 healthy controls were studied. The phenotype was established before commencement of genotyping. Genotyping of the R702W, G908R, and L1007fs gene polymorphisms of NOD2/CARD15 was performed by two independent laboratories using different techniques. In the case of discordant results, specific sequencing of DNA strands was performed. Results: At least one mutation was present in 32.8% of patients compared to 10.7% in controls (OR = 4.08, 95% CI 2.21 to 7.50). In patients with Crohn disease, the frequency of R702W, G908R, and L1007fs carriers was 13.7%, 8.3%, and 14.2%, respectively. Compound heterozygotes and homozygotes occurred in 3.4% and 2.9% of patients and in none of the controls. The correlation of genotype–Vienna classification showed a significant association with ileal disease (RR = 1.61, 95% CI 1.21–2.15, P = 0.001) and an inverse association with colonic localization (RR = 0.29, 95% CI 0.11–0.80, P = 0.007). There was a significant association between G908R carriership and previous appendectomy, surgical interventions, and stricturing behavior. A gene‐dosage effect on phenotypic characteristics was not observed. Conclusions: In a Spanish population from Madrid, mutations of the NOD2/CARD15 gene were a marker of susceptibility to Crohn disease and were associated with ileal disease. Carriers of the G908R mutation showed a stricturing disease behavior, history of appendectomy, and surgical interventions over the course of the disease.

MDR1 gene: susceptibility in Spanish Crohn's disease and ulcerative colitis patients.

Background: The multidrug resistance MDR1 gene codes for a membrane transporter associated with inflammatory bowel disease. The polymorphism Ala893Ser/Thr (G2677T/A) previously showed significant association with Crohns disease (CD) and the Ile1145Ile (C3435T) with ulcerative colitis (UC). We studied the association of both polymorphisms in an independent population to reveal the impact of the MDR1 gene on predisposition to inflammatory bowel disease. Methods: Case‐control study with 321 CD and 330 UC white Spanish patients recruited from the same center, and 352 healthy ethnically matched controls. Results: A significant association of MDR1 C3435T with CD was observed (CC vs (CT + TT): P = 0.007; OR [95% CI] = 1.58 [1.12‐2.23]). A CD susceptibility haplotype 2677T/C3435 was identified. No difference between UC patients as a whole and controls could be detected. Conclusions: New evidence supports the role of the MDR1 gene on CD susceptibility. Therefore, considering our results and those from others, the MDR1 gene behaves as a common risk factor for both CD and UC. We discovered that the C3435 allele conferring susceptibility to CD is different from the described 3435T UC risk allele.

Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease.

OBJECTIVES:Genome-wide association studies have reported the role of the interleukin (IL) 2–IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs).METHODS:Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohns disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case–control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry.RESULTS:The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44–0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58–0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58–0.92)).CONCLUSIONS:Polymorphisms within the IL2–IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.

Splitting irritable bowel syndrome: from original Rome to Rome II criteria.

OBJECTIVES:Diagnosis of irritable bowel syndrome (IBS) and other functional bowel disorders (FBD) is based on symptom evaluation. Clinical criteria have changed over time, yielding different proportions of subjects fulfilling diagnostic requirements. According to new diagnostic criteria (Rome II), subjects considered some years ago to have IBS no longer do so. The aim of this article is to evaluate how patients diagnosed as having IBS according to original Rome criteria have been split, and to which clinical diagnosis they belong today.METHODS:Two hundred and eleven subjects meeting original Rome IBS diagnostic criteria were studied: 65 also met Rome II criteria while 146 did not. Subjects were extracted from an epidemiological survey, using home-based personal interviews, on 2,000 subjects randomly selected as representative of the Spanish population. Clinical complaints, personal well-being, resource utilization, and health-related quality of life (HRQOL) were compared.RESULTS:Of the subjects meeting original Rome but not Rome II criteria, the present diagnosis should be: 40%“minor” IBS (IBS symptoms of less than 12 wk duration), 37% functional constipation, 12% alternating bowel habit, 7% functional diarrhea, 3% functional abdominal bloating, and 1% unspecified functional bowel disorder (FBD). Thus, 52 subjects (36%) should not be diagnosed with IBS because they really had other FBD, 59 (40%) because of symptoms consistent with IBD diagnosis but not the required duration or frequency, and 35 (24%) because of symptoms consistent with some other FBD diagnosis but not meeting the required duration. Clinical complaints, personal well-being, resource utilization, and HRQOL were more severely affected in IBS than in other FBD as a group, and in “major” rather than in “minor” forms.CONCLUSIONS:Many subjects meeting original Rome criteria for IBS do not meet Rome II criteria: approximately one quarter of subjects do not have sufficient symptom duration or frequency to be diagnosed with IBS and almost half are now considered as having other (“major” or “minor”) FBD.

Role of the MHC2TA gene in autoimmune diseases

Objectives: Expression of major histocompatibility complex (MHC) class II genes is almost exclusively regulated by the class II transactivator. A promoter polymorphism (−168A/G, rs3087456) in the MHC2TA gene was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction in a northern European population. However, no evidence of association of this MHC2TA variant with the two autoimmune diseases could be subsequently detected in independent cohorts. Aim: To test the aforementioned single nucleotide polymorphism and another G→C change (nt1614 from coding sequence, rs4774) to analyse the haplotype pattern in this MHC2TA gene. Methods: A case–control study was performed with 350 patients with rheumatoid arthritis, 396 patients with multiple sclerosis, 663 patients with inflammatory bowel disease (IBD) and 519 healthy controls from Madrid. Genotyping was ascertained by using TaqMan assays-on-demand on a 7900HT analyser, following the manufacturer’s suggestions (Applied Biosystems, Foster City, California, USA). Haplotypes were inferred with the expectation–maximisation algorithm implemented by the Arlequin software. Results: No independent association with these autoimmune diseases was found for either polymorphism in the Spanish cohorts tested. However, when haplotypes were compared between patients with rheumatoid arthritis and controls, a significant difference in their overall frequency distribution was observed, evidencing a protective haplotype (−168A/1614C, p = 0.006; odds ratio (OR) 0.7) and a risk haplotype (−168G/1614C, p = 0.019; OR 1.6). Patients with multiple sclerosis mirrored these results, but no effect on IBD was identified. Conclusions: The MHC2TA gene influences predisposition to rheumatoid arthritis and multiple sclerosis, but not to IBD. The −168G allele is not an aetiological variant in itself, but a genetic marker of susceptibility/protection haplotypes.