Roel Heijmans - Academia.edu (original) (raw)

Papers by Roel Heijmans

World Journal of Gastroenterology, 2007

AIM: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patie... more AIM: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients. METHODS: A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies). RESULTS: Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or-DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassifi ed into euthyroidism in ten (5%; 95% CI 2-9), subclinical hypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis. CONCLUSION: The data from a Dutch population confi rm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recommended.

Journal of Crohn's and Colitis Supplements, 2008

Background: Health-related quality of life (HRQoL) is an essential outcome of any health care int... more Background: Health-related quality of life (HRQoL) is an essential outcome of any health care intervention. Disease specific HRQoL measurements are used to evaluate the impact of symptoms in a specific disease. To be able to compare the relative impacts of different diseases, however, generic HRQoL measures, such as the 15D or the EQ-5D, should be preferred. Methods: We investigated the impact of a chronic condition (Colitis ul-cerosa=CU, Crohn' s disease=CD, colon polyps=CoPO or colon cancer=CoCA) on HRQoL in patients attending surveillance colonoscopy. 331 patients (75 CU, mean age±SD 46±13 yr; 70 CD, 41±15 yr; 103 CoPo, 63±10 yr and 83 CoCa, 67±10 yr) filled in the15 dimensional, generic 15D HRQoLquestionnaire within two weeks prior to the colonoscopy and 6 and 12 months after colonosocopy. Linear regression analysis was used to compare the baseline HRQoL of the studied groups taking also age and gender into account. Results: Mean±SD total 15D score (on a 0-1 scale) was 0.90±0.08 in CU, 0.89±0.08 in CD, 0.86±0.11 in CoPo and 0.88±0.10 in CoCa patients. Standardizing for age and sex, the only statistically significant difference in the baseline total 15D score was observed between the CU and CoPO groups (p=0.030). No difference was found between groups in the dimensions of hearing, sleeping, eating, speech, elimination, usual activities, vitality, mental function, depression, distress. CU patients had less discomfort, and better mobility, seeing, breathing and sexual function than CoPo patients. Ca patients had less distress than CD or CoPo patients and more sexual dysfunction than CU or CD patient. No difference between CU and CD in different dimensions was found. Only age and the total 15D at the first measurement predicted the change in 15D score at 6 and 12 months mesurements, whereas no difference was found in the 15D change between groups. Conclusions: CU and CD patients attending surveillance colonoscopy have similar general HRQoL than patients followed after curative colon cancer treament, whereas patients with colon polyps have slightly worse HRQoL.

Drugs of today (Barcelona, Spain : 1998), 2009

Susceptibility to Chlamydia trachomatis infections is 40% host based. microRNA-146a is a negative... more Susceptibility to Chlamydia trachomatis infections is 40% host based. microRNA-146a is a negative regulator of Tolllike receptor (TLR) signaling and possesses functional polymorphisms which decrease the production of premiR-146a and mature miR-146a. Single nucleotide polymorphisms (SNPs) in NLRP3 are associated with decreased NLRP3 expression and hypoproduction of interleukin (IL)-1beta. We investigated whether the SNPs miR-146a G>C (rs2910164), NLRP3 C>T (rs4925663) and G>A (rs12065526) are associated with the susceptibility to and severity of C. trachomatis infection. The genotypes of three SNPs were tested in two cohorts: cohort 1 consists of Dutch women (n = 318) attending a sexually transmitted disease (STD) clinic and cohort 2 (n = 277) consists of subfertile (n = 184) and healthy Finnish women (n=93). While in cohort 1 the analyzed SNPs were not associated with the susceptibility to C. trachomatis infections (C. trachomatis-positive vs. C. trachomatis-negative), we s...

International Journal of Immunogenetics, 2006

Tumour necrosis factor (TNF)-α is an important proinflammatory cytokine that has been implicated ... more Tumour necrosis factor (TNF)-α is an important proinflammatory cytokine that has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The promoter TNF-857 C→T single nucleotide polymorphism (SNP) is functional through the binding to the transcription factor octamer transcription factor-1 (OCT-1). In order to investigate the frequency of this SNP in Israeli Jewish IBD patients, we analysed a cohort of wellcharacterized patients, 153 with Crohn's disease (CD) and 78 with ulcerative colitis (UC) and 188 healthy controls individually matched for age, sex and ethnicity. Forty-one per cent of the patients were of Ashkenazi and 48% were of non-Ashkenazi background. The remaining 11% were of mixed Ashkenazi-non-Ashkenazi background. Patients and controls were genotyped for the TNF-857 SNP by Taqman technology. Stratification for the CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC mutations took place in 136 CD patients. Carrier frequency of TNF-857T between CD and controls (36% vs. 40%; P = 0.556; OR: 1.18, 95% CI 0.74-1.88), or between UC and controls (41% vs. 37%; P = 0.743; OR: 0.85, 95% CI 0.45-1.62) did not differ significantly. Neither did stratifying for the presence of at least one of the common CARD15 mutations result in a significant difference between CD and controls. No associations were found between TNF-857T and CD phenotype as defined by the Vienna classification, perianal disease or extra-intestinal disease irrespective of CARD15 carrier status. In conclusion, it appears that TNF-857 SNP does not contribute to susceptibility of IBD, neither does it define the phenotype of CD in Israeli Jewish IBD patients.

Inflammatory Bowel Diseases, 2008

kinase 2 (JAK2) mutations have been described in several Philadelphia-negative myeloproliferative... more kinase 2 (JAK2) mutations have been described in several Philadelphia-negative myeloproliferative disorders (MDP) as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis, conditions complicated by thrombosis. 1 The point mutation in JAK2 encodes a valine-tophenylalanine change at position 617 (JAK2 V617F) and confers constitutive tyrosine kinase activity. 2 It has been suggested that thrombosis in MPD may be due to JAK2 mutation. Moreover, screening for JAK2 V617F has been carried out in a series of splanchnic, cerebral, and leg deep vein thromboses (DVTs) without overt MDP. 3,4 Results from these studies indicate that the JAK2 V617F mutation in the absence of overt MDP is highly associated with splanchnic vein thrombosis and sporadically with cerebral thrombosis. Thromboembolism is a diseasespecific extraintestinal manifestation of inflammatory bowel disease (IBD) 5 that develops as the result of multiple interactions between acquired and genetic risk factors. Arterial and venous thromboembolism is the most important complication, representing a significant cause of morbidity and mortality in IBD patients. The most commonly detected risk factors for thrombophilia in this disease are factor V R506Q (Leiden) mutation, plasminogen activator inhibitor gene polymorphism, hyperhomocysteinemia, and antiphospholipid antibod

Inflammatory Bowel Diseases, 2010

The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the imm... more The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the immune response. The FcgR2a*519GG and FcgR3a*559CC genotypes have been associated with several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, nephritis, and possibly to type I diabetes, and celiac disease. In a large multicenter, two-stage study of 6570 people, we tested whether the FcgR2a and FcgR3a genes were also involved in inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). We genotyped the FcgR2a*A519G and FcgR3a*A559C functional variants in 4205 IBD patients in six well-phenotyped Caucasian IBD cohorts and 2365 ethnically matched controls recruited from the Netherlands, Spain, and New Zealand. In the initial Dutch study we found a significant association of FcgR2a genotypes with IBD (P-genotype = 0.02); while the FcgR2a*519GG was more common in controls (23%) than in IBD patients (18%; odds ratio [OR] = 0.75; 95% confidence interval [CI] 0.61-0.92; P = 0.004). This association was corroborated by a combined analysis across all the study populations (Mantel-Haenszel [MH] OR = 0.84; 0.74-0.95; P = 0.005) in the next stage. The Fcgr2a*GG genotype was associated with both UC (MH-OR = 0.84; 0.72-0.97; P = 0.01) and CD (MH-OR = 0.84; 0.73-0.97; P = 0.01), suggesting that this genotype confers a protective effect against IBD. There was no association of FcgR3a*A559C genotypes with IBD, CD, or UC in any of the three studied populations. The FcgR2a*519G functional variant was associated with IBD and reduced susceptibility to UC and to CD in Caucasians. There was no association between FcgR3a*5A559C and IBD, CD or UC.

Genes and Immunity, 2011

Interferon-b (IFNb) therapy is effective in approximately half of the patients with relapsing-rem... more Interferon-b (IFNb) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNb treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNb compared with patients carrying the respective G-alleles (P ¼ 0.0006 and P ¼ 0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNb treatment (P ¼ 0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P ¼ 0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNb treatment and MRI-based non-responder status was observed (P ¼ 0.103 and P ¼ 0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P ¼ 0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNb therapy that might have relevance as biomarker to predict the response to IFNb in multiple sclerosis.

Gastroenterology, 2009

Inflammatory bowel disease (IBD), a chronic disorder affecting the intestinal mucosa, normally pr... more Inflammatory bowel disease (IBD), a chronic disorder affecting the intestinal mucosa, normally presents as either of two subphenotypes, Crohn's disease (CD) or ulcerative colitis (UC). The complex genetic basis of IBD has been highlighted by recent genome-wide association studies (GWAs) and although several susceptibility loci for CD (including NOD2, 5q31, Il23R, ATG16L1, MST1, TNFSF15, ECM1) and recently also for UC, have been replicated in more than one study, some of the reported associations have been found only in single study to date. Aims: To investigate variants of four previously reported susceptibility loci (NELL1, C10ORSF67, TNFRSF6B and ECM1) in a Italian samples with CD or UC and healthy controls (HC) and search for potential correlation with clinical phenotypes in patients with adult and pediatric onset of disease. Results: The polymorphisms rs1793004 in 11p15.1 (NELL1), rs1398024 in 10q12.2 (C10ORSF67), rs4809330 in 20q13 (TNFRSF6B), rs3737240 (T130M) and rs13294 (G290S) in ECM1 gene were tested in 762 CD (439 male) with a mean age at diagnosis of 31 yrs (range 1-79), 1071 UC (627 male) with a mean age at diagnosis of 31 yrs (range 1-83) and 552 HC, by using the TaqMan allelic discrimination method. No significant difference for either allele and genotype frequencies of the selected SNPs was found in both CD and UC patients compared with controls (MAF: rs1793004 21% in CD and UC vs 24% in HC; rs1398024 27% in UC vs 26% in HC; rs4809330 24% in CD, 22% in UC vs 25% in HC; rs3737240 42% in UC vs 40% in HC; rs13294 43% in UC vs 40% in HC). The frequencies remained still not significant different for all variants after stratifying the cohort in adult (CD: 618 patients > 18 yrs at diagnosis; UC: 794 patients >18 yrs at diagnosis) and pediatric-onset patients, although for T130M a week association in UC pediatric-onset patients (164 pts) in both allele (P=0.043; OR 1.29, CI 1.01-1.66) and genotype (P=0.045; OR 1.47, CI 1.01-2.15) frequencies, was found. No correlation with any clinical sub-phenotypes for all loci was observed. Conclusions: The investigated SNPs on the identified loci 11p15.1, 10q12.2 and 20q13 and ECM1 gene, have no significant role in disease susceptibility in IBD Italian population. However, a weak association with variation 130M and UC pediatric-onset patients, was found.

Clinical Microbiology and Infection, 2011

The management of the ongoing lymphogranuloma venereum epidemic in industrialized Western countri... more The management of the ongoing lymphogranuloma venereum epidemic in industrialized Western countries caused by Chlamydia trachomatis variant L2b still needs improvements in diagnosis, therapy and prevention. We therefore developed the first rapid C. trachomatis variant L2b-specific polymerase chain reaction to circumvent laborious ompA gene sequencing.

The American Journal of Human Genetics, 2008

The two main phenotypes of inflammatory bowel disease (IBD)-Crohn's disease (CD) and ulcerative c... more The two main phenotypes of inflammatory bowel disease (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p IBD 1.9 3 10 À8 ; OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p ¼ 9.19 3 10 À4). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p IBD ¼ 3.25 3 10 À5 ; OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.

Microorganisms, 2019

Background: Sexually transmitted infections (STIs), like Chlamydia trachomatis and Neisseria gono... more Background: Sexually transmitted infections (STIs), like Chlamydia trachomatis and Neisseria gonorrhoeae (CT and NG, respectively) are linked to an important sexual and reproductive health (SRH) burden worldwide. Behavior is an important predictor for SRH, as it dictates the risk for STIs. Assessing the behavior of a population helps to assess its risk profile. Methods: Study participants were recruited at a gynecology outpatient department (OPD) in the Allahabad district in Uttar Pradesh India, and a questionnaire was used to assess demographics, SRH, and obstetric history. Patients provided three samples (urine, vaginal swab, and whole blood). These samples were used to identify CT and NG using PCR/NAAT and CT IgG ELISA. Results: A total of 296 women were included for testing; mean age was 29 years. No positive cases of CT and NG were observed using PCR/NAAT. A 7% (22/296) positivity rate for CT was observed using IgG ELISA. No positive association was found between serology and s...

GENES AND IMMUNITY, 2004

Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. Recently, fun... more Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. Recently, functional polymorphisms in IL-12p40 (IL12B) were found to be associated with susceptibility to several autoimmune diseases. Similarly, variation in IL12B might be involved in susceptibility to Crohn's disease (CD), a chronic inflammatory bowel disorder associated with high IL-12 expression. We searched for additional polymorphism in IL12B and genotyped a large cohort of CD patients. Differential in vitro secretors of IL-12 were tested for polymorphism. Polymorphisms were analyzed using the intrafamilial transmission disequilibrium test (TDT) and by case-control analysis. A novel polymorphism was strongly associated with differential expression of IL-12. However, no association with susceptibility to CD was seen for this and other polymorphisms. The high level of conservation is consistent with the key regulatory role of IL-12. The lack of association with IL12B makes it unlikely that this gene is directly involved in the susceptibility to CD.

World Journal of Gastroenterology, 2007

AIM: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patie... more AIM: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients. METHODS: A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies). RESULTS: Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or-DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassifi ed into euthyroidism in ten (5%; 95% CI 2-9), subclinical hypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis. CONCLUSION: The data from a Dutch population confi rm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recommended.

Journal of Crohn's and Colitis Supplements, 2008

Background: Health-related quality of life (HRQoL) is an essential outcome of any health care int... more Background: Health-related quality of life (HRQoL) is an essential outcome of any health care intervention. Disease specific HRQoL measurements are used to evaluate the impact of symptoms in a specific disease. To be able to compare the relative impacts of different diseases, however, generic HRQoL measures, such as the 15D or the EQ-5D, should be preferred. Methods: We investigated the impact of a chronic condition (Colitis ul-cerosa=CU, Crohn' s disease=CD, colon polyps=CoPO or colon cancer=CoCA) on HRQoL in patients attending surveillance colonoscopy. 331 patients (75 CU, mean age±SD 46±13 yr; 70 CD, 41±15 yr; 103 CoPo, 63±10 yr and 83 CoCa, 67±10 yr) filled in the15 dimensional, generic 15D HRQoLquestionnaire within two weeks prior to the colonoscopy and 6 and 12 months after colonosocopy. Linear regression analysis was used to compare the baseline HRQoL of the studied groups taking also age and gender into account. Results: Mean±SD total 15D score (on a 0-1 scale) was 0.90±0.08 in CU, 0.89±0.08 in CD, 0.86±0.11 in CoPo and 0.88±0.10 in CoCa patients. Standardizing for age and sex, the only statistically significant difference in the baseline total 15D score was observed between the CU and CoPO groups (p=0.030). No difference was found between groups in the dimensions of hearing, sleeping, eating, speech, elimination, usual activities, vitality, mental function, depression, distress. CU patients had less discomfort, and better mobility, seeing, breathing and sexual function than CoPo patients. Ca patients had less distress than CD or CoPo patients and more sexual dysfunction than CU or CD patient. No difference between CU and CD in different dimensions was found. Only age and the total 15D at the first measurement predicted the change in 15D score at 6 and 12 months mesurements, whereas no difference was found in the 15D change between groups. Conclusions: CU and CD patients attending surveillance colonoscopy have similar general HRQoL than patients followed after curative colon cancer treament, whereas patients with colon polyps have slightly worse HRQoL.

Drugs of today (Barcelona, Spain : 1998), 2009

Susceptibility to Chlamydia trachomatis infections is 40% host based. microRNA-146a is a negative... more Susceptibility to Chlamydia trachomatis infections is 40% host based. microRNA-146a is a negative regulator of Tolllike receptor (TLR) signaling and possesses functional polymorphisms which decrease the production of premiR-146a and mature miR-146a. Single nucleotide polymorphisms (SNPs) in NLRP3 are associated with decreased NLRP3 expression and hypoproduction of interleukin (IL)-1beta. We investigated whether the SNPs miR-146a G>C (rs2910164), NLRP3 C>T (rs4925663) and G>A (rs12065526) are associated with the susceptibility to and severity of C. trachomatis infection. The genotypes of three SNPs were tested in two cohorts: cohort 1 consists of Dutch women (n = 318) attending a sexually transmitted disease (STD) clinic and cohort 2 (n = 277) consists of subfertile (n = 184) and healthy Finnish women (n=93). While in cohort 1 the analyzed SNPs were not associated with the susceptibility to C. trachomatis infections (C. trachomatis-positive vs. C. trachomatis-negative), we s...

International Journal of Immunogenetics, 2006

Tumour necrosis factor (TNF)-α is an important proinflammatory cytokine that has been implicated ... more Tumour necrosis factor (TNF)-α is an important proinflammatory cytokine that has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The promoter TNF-857 C→T single nucleotide polymorphism (SNP) is functional through the binding to the transcription factor octamer transcription factor-1 (OCT-1). In order to investigate the frequency of this SNP in Israeli Jewish IBD patients, we analysed a cohort of wellcharacterized patients, 153 with Crohn's disease (CD) and 78 with ulcerative colitis (UC) and 188 healthy controls individually matched for age, sex and ethnicity. Forty-one per cent of the patients were of Ashkenazi and 48% were of non-Ashkenazi background. The remaining 11% were of mixed Ashkenazi-non-Ashkenazi background. Patients and controls were genotyped for the TNF-857 SNP by Taqman technology. Stratification for the CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC mutations took place in 136 CD patients. Carrier frequency of TNF-857T between CD and controls (36% vs. 40%; P = 0.556; OR: 1.18, 95% CI 0.74-1.88), or between UC and controls (41% vs. 37%; P = 0.743; OR: 0.85, 95% CI 0.45-1.62) did not differ significantly. Neither did stratifying for the presence of at least one of the common CARD15 mutations result in a significant difference between CD and controls. No associations were found between TNF-857T and CD phenotype as defined by the Vienna classification, perianal disease or extra-intestinal disease irrespective of CARD15 carrier status. In conclusion, it appears that TNF-857 SNP does not contribute to susceptibility of IBD, neither does it define the phenotype of CD in Israeli Jewish IBD patients.

Inflammatory Bowel Diseases, 2008

kinase 2 (JAK2) mutations have been described in several Philadelphia-negative myeloproliferative... more kinase 2 (JAK2) mutations have been described in several Philadelphia-negative myeloproliferative disorders (MDP) as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis, conditions complicated by thrombosis. 1 The point mutation in JAK2 encodes a valine-tophenylalanine change at position 617 (JAK2 V617F) and confers constitutive tyrosine kinase activity. 2 It has been suggested that thrombosis in MPD may be due to JAK2 mutation. Moreover, screening for JAK2 V617F has been carried out in a series of splanchnic, cerebral, and leg deep vein thromboses (DVTs) without overt MDP. 3,4 Results from these studies indicate that the JAK2 V617F mutation in the absence of overt MDP is highly associated with splanchnic vein thrombosis and sporadically with cerebral thrombosis. Thromboembolism is a diseasespecific extraintestinal manifestation of inflammatory bowel disease (IBD) 5 that develops as the result of multiple interactions between acquired and genetic risk factors. Arterial and venous thromboembolism is the most important complication, representing a significant cause of morbidity and mortality in IBD patients. The most commonly detected risk factors for thrombophilia in this disease are factor V R506Q (Leiden) mutation, plasminogen activator inhibitor gene polymorphism, hyperhomocysteinemia, and antiphospholipid antibod

Inflammatory Bowel Diseases, 2010

The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the imm... more The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the immune response. The FcgR2a*519GG and FcgR3a*559CC genotypes have been associated with several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, nephritis, and possibly to type I diabetes, and celiac disease. In a large multicenter, two-stage study of 6570 people, we tested whether the FcgR2a and FcgR3a genes were also involved in inflammatory bowel disease (IBD), which includes Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD) and ulcerative colitis (UC). We genotyped the FcgR2a*A519G and FcgR3a*A559C functional variants in 4205 IBD patients in six well-phenotyped Caucasian IBD cohorts and 2365 ethnically matched controls recruited from the Netherlands, Spain, and New Zealand. In the initial Dutch study we found a significant association of FcgR2a genotypes with IBD (P-genotype = 0.02); while the FcgR2a*519GG was more common in controls (23%) than in IBD patients (18%; odds ratio [OR] = 0.75; 95% confidence interval [CI] 0.61-0.92; P = 0.004). This association was corroborated by a combined analysis across all the study populations (Mantel-Haenszel [MH] OR = 0.84; 0.74-0.95; P = 0.005) in the next stage. The Fcgr2a*GG genotype was associated with both UC (MH-OR = 0.84; 0.72-0.97; P = 0.01) and CD (MH-OR = 0.84; 0.73-0.97; P = 0.01), suggesting that this genotype confers a protective effect against IBD. There was no association of FcgR3a*A559C genotypes with IBD, CD, or UC in any of the three studied populations. The FcgR2a*519G functional variant was associated with IBD and reduced susceptibility to UC and to CD in Caucasians. There was no association between FcgR3a*5A559C and IBD, CD or UC.

Genes and Immunity, 2011

Interferon-b (IFNb) therapy is effective in approximately half of the patients with relapsing-rem... more Interferon-b (IFNb) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNb treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNb compared with patients carrying the respective G-alleles (P ¼ 0.0006 and P ¼ 0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNb treatment (P ¼ 0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P ¼ 0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNb treatment and MRI-based non-responder status was observed (P ¼ 0.103 and P ¼ 0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P ¼ 0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNb therapy that might have relevance as biomarker to predict the response to IFNb in multiple sclerosis.

Gastroenterology, 2009

Inflammatory bowel disease (IBD), a chronic disorder affecting the intestinal mucosa, normally pr... more Inflammatory bowel disease (IBD), a chronic disorder affecting the intestinal mucosa, normally presents as either of two subphenotypes, Crohn's disease (CD) or ulcerative colitis (UC). The complex genetic basis of IBD has been highlighted by recent genome-wide association studies (GWAs) and although several susceptibility loci for CD (including NOD2, 5q31, Il23R, ATG16L1, MST1, TNFSF15, ECM1) and recently also for UC, have been replicated in more than one study, some of the reported associations have been found only in single study to date. Aims: To investigate variants of four previously reported susceptibility loci (NELL1, C10ORSF67, TNFRSF6B and ECM1) in a Italian samples with CD or UC and healthy controls (HC) and search for potential correlation with clinical phenotypes in patients with adult and pediatric onset of disease. Results: The polymorphisms rs1793004 in 11p15.1 (NELL1), rs1398024 in 10q12.2 (C10ORSF67), rs4809330 in 20q13 (TNFRSF6B), rs3737240 (T130M) and rs13294 (G290S) in ECM1 gene were tested in 762 CD (439 male) with a mean age at diagnosis of 31 yrs (range 1-79), 1071 UC (627 male) with a mean age at diagnosis of 31 yrs (range 1-83) and 552 HC, by using the TaqMan allelic discrimination method. No significant difference for either allele and genotype frequencies of the selected SNPs was found in both CD and UC patients compared with controls (MAF: rs1793004 21% in CD and UC vs 24% in HC; rs1398024 27% in UC vs 26% in HC; rs4809330 24% in CD, 22% in UC vs 25% in HC; rs3737240 42% in UC vs 40% in HC; rs13294 43% in UC vs 40% in HC). The frequencies remained still not significant different for all variants after stratifying the cohort in adult (CD: 618 patients > 18 yrs at diagnosis; UC: 794 patients >18 yrs at diagnosis) and pediatric-onset patients, although for T130M a week association in UC pediatric-onset patients (164 pts) in both allele (P=0.043; OR 1.29, CI 1.01-1.66) and genotype (P=0.045; OR 1.47, CI 1.01-2.15) frequencies, was found. No correlation with any clinical sub-phenotypes for all loci was observed. Conclusions: The investigated SNPs on the identified loci 11p15.1, 10q12.2 and 20q13 and ECM1 gene, have no significant role in disease susceptibility in IBD Italian population. However, a weak association with variation 130M and UC pediatric-onset patients, was found.

Clinical Microbiology and Infection, 2011

The management of the ongoing lymphogranuloma venereum epidemic in industrialized Western countri... more The management of the ongoing lymphogranuloma venereum epidemic in industrialized Western countries caused by Chlamydia trachomatis variant L2b still needs improvements in diagnosis, therapy and prevention. We therefore developed the first rapid C. trachomatis variant L2b-specific polymerase chain reaction to circumvent laborious ompA gene sequencing.

The American Journal of Human Genetics, 2008

The two main phenotypes of inflammatory bowel disease (IBD)-Crohn's disease (CD) and ulcerative c... more The two main phenotypes of inflammatory bowel disease (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p IBD 1.9 3 10 À8 ; OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p ¼ 9.19 3 10 À4). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p IBD ¼ 3.25 3 10 À5 ; OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.

Microorganisms, 2019

Background: Sexually transmitted infections (STIs), like Chlamydia trachomatis and Neisseria gono... more Background: Sexually transmitted infections (STIs), like Chlamydia trachomatis and Neisseria gonorrhoeae (CT and NG, respectively) are linked to an important sexual and reproductive health (SRH) burden worldwide. Behavior is an important predictor for SRH, as it dictates the risk for STIs. Assessing the behavior of a population helps to assess its risk profile. Methods: Study participants were recruited at a gynecology outpatient department (OPD) in the Allahabad district in Uttar Pradesh India, and a questionnaire was used to assess demographics, SRH, and obstetric history. Patients provided three samples (urine, vaginal swab, and whole blood). These samples were used to identify CT and NG using PCR/NAAT and CT IgG ELISA. Results: A total of 296 women were included for testing; mean age was 29 years. No positive cases of CT and NG were observed using PCR/NAAT. A 7% (22/296) positivity rate for CT was observed using IgG ELISA. No positive association was found between serology and s...

GENES AND IMMUNITY, 2004

Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. Recently, fun... more Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. Recently, functional polymorphisms in IL-12p40 (IL12B) were found to be associated with susceptibility to several autoimmune diseases. Similarly, variation in IL12B might be involved in susceptibility to Crohn's disease (CD), a chronic inflammatory bowel disorder associated with high IL-12 expression. We searched for additional polymorphism in IL12B and genotyped a large cohort of CD patients. Differential in vitro secretors of IL-12 were tested for polymorphism. Polymorphisms were analyzed using the intrafamilial transmission disequilibrium test (TDT) and by case-control analysis. A novel polymorphism was strongly associated with differential expression of IL-12. However, no association with susceptibility to CD was seen for this and other polymorphisms. The high level of conservation is consistent with the key regulatory role of IL-12. The lack of association with IL12B makes it unlikely that this gene is directly involved in the susceptibility to CD.