Ulcerative Colitis: Almer S

Thiébaut R, Kotti S, Jung C, Merlin F, Colombel JF, Lemann M, Almer S, Tysk C, O'Morain M, Gassull M, Binder V, Finkel Y, Pascoe L, Hugot JP. · INSERM, U843, Hôpital Robert Debré, Université Paris Diderot, Paris, France. · Am J Gastroenterol. · Pubmed #19174806 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Bergquist A, Montgomery SM, Bahmanyar S, Olsson R, Danielsson A, Lindgren S, Prytz H, Hultcrantz R, Lööf LA, Sandberg-Gertzén H, Almer S, Askling J, Ehlin A, Ekbom A. · Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institute, Huddinge and Solna, Stockholm, Sweden. · Clin Gastroenterol Hepatol. · Pubmed #18674735 No free full text.

Abstract: BACKGROUND & AIMS: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. METHODS: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. RESULTS: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). CONCLUSIONS: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

Lindqvist M, Hindorf U, Almer S, Söderkvist P, Ström M, Hjortswang H, Peterson C. · Department of Medicine and Care, Division of Clinical Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. · Nucleosides Nucleotides Nucleic Acids. · Pubmed #17065060 No free full text.

Abstract: The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naïve patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35).

Hjortswang H, Järnerot G, Curman B, Sandberg-Gertzén H, Tysk C, Blomberg B, Almer S, Ström M. · Division of Gastroenterology and Hepatology, Department of Molecular and Clinical Medicine, Linköping University Hospital, Sweden. · Scand J Gastroenterol. · Pubmed #16990205 No free full text.

Abstract: OBJECTIVE: Assessment of health-related quality of life (HRQOL) is important in both clinical practice and clinical trials, and several multi-item questionnaires are currently in use. We have devised and evaluated a simplified four-item questionnaire, the Short Health Scale (SHS), representing each of four health dimensions: (a) symptom burden, (b) social function, (c) disease-related worry and (d) general well-being. MATERIAL AND METHODS: Three hundred patients with ulcerative colitis completed the SHS and three other HRQOL questionnaires (IBDQ, RFIPC and PGWB). Half of the patients repeated the questionnaires after 6 months - or earlier if disease activity changed. Test-retest reliability was derived from measurements of the SHS questions, 2 weeks apart, on 18 patients in remission. RESULTS: Patients in relapse scored higher on each of the four SHS questions than patients in remission (p < 0.001). Each of the four SHS scores were associated with results of their corresponding health dimension obtained with the other three questionnaires (rs=0.57-0.78, p < 0.001) (validity). The results of the SHS proved stable on repeated measurement with a 2-week interval in patients in remission (rs=0.71-0.91, p < 0.01) (test-retest reliability). Patients with a change in disease activity had a significant change in their SHS scores (p < 0.05) (responsiveness). CONCLUSIONS: The SHS is a valid, reliable and responsive measure of subjective health in patients with ulcerative colitis. It is simple to administer, quickly completed and the results do not need further calculations. The SHS can be used in clinical trials and in clinical practice to identify the patient's main problems affecting health.

Hindorf U, Lindqvist M, Peterson C, Söderkvist P, Ström M, Hjortswang H, Pousette A, Almer S. · Department of Clinical Sciences, Division of Gastroenterology, Faculty of Medicine, Lund University, 22185 Lund, Sweden. · Gut. · Pubmed #16543290 No free full text.

Abstract: BACKGROUND: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. AIM: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. PATIENTS: 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. METHODS: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. RESULTS: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11,450 pmol/8 x 10(8) red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015). CONCLUSIONS: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

Bodemar G, Kechagias S, Almer S, Danielson BG. · Division of Gastroenterology and Hepatology, Dept. of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, University Hospital, Linköping, Sweden. · Scand J Gastroenterol. · Pubmed #15180183 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD)-associated anaemia usually responds to intravenous iron. If not, additive treatment with erythropoietin has been proposed. The objective of the present retrospective study was to evaluate the effectiveness of treatment with iron sucrose alone. METHODS: Sixty-one patients with IBD and anaemia (average haemoglobin 97 g/L) were treated with iron sucrose (iron dose 1.4 +/- 0.5 g). The indications for iron sucrose were poor response and/or intolerance to oral iron. Treatment response was defined as an increase in haemoglobin of > or = 20 g/L or to normal haemoglobin levels (> or = 120 g/L). Two independent investigators retrospectively assessed laboratory variables, clinical findings, and concomitant medication. RESULTS: Two patients were transferred to other hospitals after treatment and therefore could not be evaluated. Fifty-four of the remaining 59 patients (91%) responded within 12 weeks. Sixty percent of the patients had responded within 8 weeks. Five patients had no or only a partial response to iron sucrose of which three had prolonged gastrointestinal blood losses. Eight patients with normal or elevated levels of ferritin could be considered to have anaemia of chronic disease, and all of them responded to iron sucrose. During a follow-up period of 117 +/- 85 (4-291) (mean +/- s (standard deviation) (range)) weeks 19 patients (32%) needed at least one second course of iron sucrose because of recurrent disease. CONCLUSIONS: Anaemia associated with IBD can be successfully treated with intravenously administered iron sucrose, provided that bowel inflammation is treated adequately and enough iron is given. Treatment with iron sucrose is safe. Follow-up of haemoglobin and iron parameters to avoid further iron deficiency anaemia is recommended.

Hjortswang H, Järnerot G, Curman B, Sandberg-Gertzén H, Tysk C, Blomberg B, Almer S, Ström M. · Division of Gastroenterology and Hepatology, Linköping University Hospital, Linköping, Sweden. · Eur J Gastroenterol Hepatol. · Pubmed #12923375 No free full text.

Abstract: OBJECTIVE: The aims of this study were to analyse the health-related quality of life of patients with ulcerative colitis and to assess in what way demographic and disease-related factors influence patients' experiences of this, in order to interpret the results of health-related quality of life assessment more correctly. PATIENTS AND METHODS: We carried out a cross-sectional evaluation of 300 consecutive patients with ulcerative colitis from the catchment areas of Linköping University Hospital and Orebro University Hospital in Sweden. Health-related quality of life was measured using four questionnaires: the IBDQ, the RFIPC, the SF-36 and the PGWB. Disease activity was evaluated using a one-week symptom diary, blood tests and rigid sigmoidoscopy. Demographic factors (gender, age, civil status, educational level), disease-related factors (disease duration, disease extent, disease activity) and presence of co-morbidity were obtained. RESULTS: Health-related quality of life was mainly impaired in the psychological and social areas and to a much lesser degree in physical areas. Patients with relapse had significantly more disease-related worries and concerns (the RFIPC), more impaired social functioning (the IBDQ and SF-36), and a lower feeling of well being (the IBDQ, the SF-36 and the PGWB). However, their physical function (SF-36) was no worse than patients in remission. Besides the symptom burden of the current disease, co-morbidity and female gender were associated with a lower health-related quality of life. CONCLUSION: To correctly interpret health-related quality of life assessments, it is necessary to consider co-morbidity and gender distribution in addition to the symptom burden of the disease studied.

Zouali H, Lesage S, Merlin F, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Christensen S, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Chamaillard M, Thomas G, Hugot JP, Anonymous00017, Anonymous00018. · Fondation Jean Dausset-CEPH, Paris, France. · Gut. · Pubmed #12477763 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Sjöwall C, Eriksson P, Almer S, Skogh T. · Department of Molecular and Clinical Medicine, Division of Rheumatology, Faculty of Health Sciences, University of Linköping, S-581 85 Linköping, Sweden. · J Autoimmun. · Pubmed #12419286 No free full text.

Abstract: The occurrence of antibodies to human C-reactive protein (CRP) was analysed by enzyme-linked immunosorbent assay (ELISA) in 56 patient sera known to contain antibodies to double-stranded DNA (dsDNA) and in 16 sera from patients with primary Sjögren's syndrome (SS), 15 rheumatoid arthritis, 31 Crohn's disease, and 37 ulcerative colitis. Eighty-seven per cent of the patients with anti-dsDNA antibodies had systemic lupus erythematosus (SLE) and the remaining had autoimmune hepatitis. The cut-off for positive anti-CRP test was set at the 95th percentile of 100 healthy blood donors. Twenty of 56 anti-dsDNA sera (36%) and two of 16 SS sera (13%) had antibodies reactive with human CRP, whereas all other samples were negative. Thirteen of 27 SLE patients (48%) were positive on at least one occasion. The sera containing anti-CRP antibodies only reacted with surface-bound antigen, but not with native CRP in solution. In conclusion, we found that autoantibodies to CRP are common in sera from patients with anti-dsDNA antibodies. It is not likely that this explains the relative failure of CRP response in patients with active SLE. However, it cannot be excluded that anti-CRP autoantibodies have other biological potentials of pathophysiological interest in SLE, for instance by binding to CRP deposited on cell and tissue surfaces.

Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP, Anonymous00210, Anonymous00211, Anonymous00212. · Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France. · Am J Hum Genet. · Pubmed #11875755 links to  free full text

Abstract: CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Levenstein S, Li Z, Almer S, Barbosa A, Marquis P, Moser G, Sperber A, Toner B, Drossman DA. · Gastroenterology Division, San Camillo-Forlanini Hospital, Rome, Italy. · Am J Gastroenterol. · Pubmed #11419836 No free full text.

Abstract: OBJECTIVE: The aim of this work was to study cross-cultural variations in the impact of inflammatory bowel disease (IBD) on health-related quality of life by an international comparison of disease-related concerns. METHODS: Item and factor scores on the Rating Form of Inflammatory Bowel Disease Patient Concerns and overall mean concern levels were compared by analysis of variance among 2002 IBD patients in eight countries. RESULTS: The overall level of concern varied from 51 out of 100 in Portugal to 19 in Sweden, with intermediate scores for Italy (43), Canada (40), United States (39), France (39), Austria (33), and Israel (25). Having surgery, an ostomy, the uncertain nature of the disease, and medication side effects were each rated among the first five in importance in six countries. Other items varied considerably. For example, concern regarding pain and suffering was high in Israel and low in Portugal, whereas concern over developing cancer was low in Italy. Concern over financial issues and access to high-quality health care were inversely associated with measures of national economic prosperity. CONCLUSIONS: 1) Cross-cultural comparisons of patient concerns related to IBD are feasible using translated scales. 2) Reporting tendencies vary greatly; within Europe, patients from southern countries report greater overall concern. 3) The complications and the variable evolution of disease elicit general concern, but the importance of specific issues varies among countries. 4) The reasons for national differences may have social, cultural, and/or economic determinants with relevance to the patient-physician relationship, patient education, and therapeutic decision making.

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. · Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France. · Nature. · Pubmed #11385576 No free full text.

Abstract: Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Hjortswang H, Järnerot G, Curman B, Sandberg-Gertzén H, Tysk C, Blomberg B, Almer S, Ström M. · Dept of Gastroenterology and Endocrinology, Linköping University, Sweden. · Scand J Gastroenterol. · Pubmed #11218243 No free full text.

Abstract: BACKGROUND: The Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease-specific health-related quality of life (HRQOL) questionnaire including four dimensions and a sum score. The aim of this study was to assess the internal and external validity, reliability, and sensitivity of a Swedish version of the IBDQ. METHODS: Three hundred consecutive patients with ulcerative colitis completed the IBDQ and three other health-related quality of life questionnaires (the Rating Form of IBD Patient Concerns (RFIPC), the Short Form-36 (SF-36) and the Psychological General Well-Being (PGWB) index). Disease activity was evaluated using a 1-week symptom diary, blood tests and rigid sigmoidoscopy. One hundred and fourteen patients filled in the questionnaire a second time, of whom 75 had been in stable remission for over 6 months and 39 had a significant clinical change in disease activity. RESULTS: Factor analysis of the 32 IBDQ items did not support the four dimensional scores. The dimensional scores had sufficient convergent validity, but low discriminative validity and homogeneity. The homogeneity was also low for the sum score. The inter-dimensional correlations were high. The concurrent validity was supported by correlations between the dimensional scores and other measures of disease activity and HRQOL. Patients in relapse scored significantly less on the sum score and the four dimensions compared to patients in remission. The test-retest correlations for the dimensional scores were 0.40-0.76. Patients with a change in disease activity during the 6-month follow-up period had a significant change in IBDQ scores not found in those who remained in remission. CONCLUSIONS: The Swedish version of the IBDQ had external validity and was shown to be a reliable and sensitive measure of HRQOL in ulcerative colitis, though there are some concerns regarding the internal validity. The use of a sum score was not supported and the questionnaire may benefit from a redivision of items into dimensions with better homogeneity and discriminative validity.

Lesage S, Zouali H, Colombel JF, Belaiche J, Cézard JP, Tysk C, Almer S, Gassull M, Binder V, Chamaillard M, Le Gall I, Thomas G, Hugot JP. · Fondation Jean Dausset/CEPH and Unité INSERM 434, 27 rue Juliette Dodu, 75010 Paris, France. · Gut. · Pubmed #11076876 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages. RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.

Hjortswang H, Almer S, Ström M. · Division of Gastroenterology and Hepatology, Linköping University, Sweden. · Eur J Gastroenterol Hepatol. · Pubmed #10524638 No free full text.

Abstract: OBJECTIVE: Health is a complex and multi-dimensional entity and is neither easily determined nor easily conveyed to others. Publications have often combined various variables of disease activity and health-related quality of life (HRQoL), used the variables interchangeably or utilized summation indices to compare health assessment. The aim of this study is to investigate the relationship between measurements of disease activity and HRQoL. STUDY: design Cross-sectional evaluation of disease activity and HRQoL. STUDY POPULATION: Two hundred and eleven consecutive patients with ulcerative colitis. SETTING: The catchment area of Linköping University Hospital. MEASUREMENTS: HRQoL was measured using two questionnaires, the Sickness Impact Profile (SIP) and the Rating Form of IBD Patient Concerns (RFIPC). Patients were also asked if they were 'feeling fit and well', as a measurement of general health perception. Disease activity was measured by means of symptom cards, laboratory tests and sigmoidoscopy. RESULTS: The correlations (Spearman's r (r5)) between variables of disease activity and HRQoL were low. 'Feeling fit and well' was best correlated to worries and concerns (the RFIPC, rs 0.32, P < 0.05), while there was a decreasing association with subjective functional status (the SIP, rs 0.31, P < 0.05), symptoms (stools per day, rs 0.15, not significant) and biological variables (endoscopy score, rs 0.04, not significant). CONCLUSION: The correlations between traditional measurements of disease activity and various measures of HRQoL are low. We therefore propose a system whereby the process is conceptualized using a 'network strategy', ordering the measurements of disease activity and HRQoL into five dimensions: biological variables, symptoms, functional status, worries and concerns, and health perceptions. We feel that this method of interpretation more accurately reflects the overall health of a group of patients with IBD than more traditional summation indices.