Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective: We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design: We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results: Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions: Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD

Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by tissue transglutaminase autoantibodies and HLA

Aims: The aims were to estimate the diagnostic sensitivity and specificity of autoantibodies to tissue transglutaminase (IgA- and IgG-tTG), gliadin (AGA) and endomysium (EMA) in relation to human leukocyte antigen (HLA)-DQB1 alleles to identify silent celiac disease at diagnosis of type 1 diabetes. Methods: IgA- and IgG-tTG were measured in radioligand binding assays in 165 type 1 diabetic patients. Data on HLA-DQB1 were available for 148 patients and on both AGA and EMA for 164 patients. For patients considered positive for AGA or EMA, or both, an intestinal biopsy was suggested. HLA-DQB1 typing was carried out by polymerase chain reaction and hybridization with allele specific probes. Results: Three patients, left out from further study of antibodies, but not from HLA-DQB1 analysis, had treated celiac disease at diagnosis. Out of the other 162 type 1 diabetic patients tested, nine had IgA-tTG, six IgG-tTG, eight EMA, and 11 AGA. Biopsy was suggested for nine patients, of whom six showed villous atrophy, one did not and two refused to participate. Thus, silent celiac disease was probable in 8/162 and biopsy-verified in 6/162, where five patients were AGA-positive and six either EMA-, IgA-tTG- or IgG-tTG-positive. Of the 11 patients with celiac disease (three with treated and eight with silent celiac disease), 10 were HLA-DQB1-typed, of whom 65% (13/20) had the DQB1*02 allele, compared with 36% (100/276; p = 0.011) of those without celiac disease. IgA-tTG levels were higher in patients having either *02 or *0302 (0.6; −1.3–112.4 RU) compared with those not having these alleles (0.4; −0.7–3.4 RU; p = 0.023). Conclusion: IgA-tTG are HLA-DQB1*02-associated autoantibodies with high sensitivity and specificity for silent celiac disease at diagnosis of type 1 diabetes

Health-related quality of life is not impaired in children with undetected as well as diagnosed celiac disease : a large population based cross-sectional study

BACKGROUND: Knowledge regarding the health-related quality of life (HRQoL) of children with celiac disease remains limited and inconclusive. We investigated the HRQoL of three groups of 12-year-olds with: i) undetected celiac disease ii) clinically diagnosed celiac disease, and iii) without celiac disease. METHODS: A school-based cross-sectional multicenter screening study invited 18 325 children, whereof 68% consented to participate. Participants provided a blood sample, which was later analyzed for anti-tissue-tranglutaminase antibodies, and alongside filled in a questionnaire. When anti-tissue-tranglutaminase antibodies were elevated, a small intestinal biopsy verified the screening-detected celiac disease diagnosis. Self-reported HRQoL was measured using Kidscreen, a generic 52 items instrument with proven reliability and validity. Scores were linearly transformed into a 0-100 scale with higher values indicating better HRQoL. Mean values with standard deviations (mean +/- SD) were compared, and uni- and multivariate logistic regression models tested the odds of a low HRQoL among children with undetected or diagnosed celiac disease, respectively. RESULTS: Children with undetected celiac disease (n = 238) reported similar HRQoL as children without celiac disease (n = 12 037) (83.0 +/- 11.0 vs. 82.5 +/- 11.3, P = 0.51), and also similar HRQoL (82.2 +/- 12.2, P = 0.28) to that of children with diagnosed celiac disease (n = 90), of whom 92% were adherent to treatment. Having undetected celiac disease did not increase the odds of low overall HRQoL, independent of sex, area of residence, study year and occurrence of gastrointestinal symptoms (adjusted odds ratio 0.77, 95% CI 0.54-1.10). Comparable results were seen for diagnosed celiac disease cases (adjusted odds ratio 1.11, 95% CI 0.67-1.85) CONCLUSION: Children with undetected celiac disease reported comparable HRQoL as their peers with diagnosed celiac disease, and those without celiac disease, when reporting prior to receiving the diagnosis through screening. Thus, children with celiac disease, both untreated and diagnosed, perceive their HRQoL as unimpaired by their disease

Mass screening for celiac disease from the perspective of newly diagnosed adolescents and their parents : A mixed-method study

Background: Mass screening for celiac disease (CD) as a public health intervention is controversial. Prior to implementation, acceptability to the targeted population should be addressed. We aimed at exploring adolescents' and parents' experiences of having the adolescents' CD detected through mass screening, and their attitudes towards possible future mass screening. Methods: All adolescents (n = 145) with screening-detected CD found in a Swedish school-based screening study, and their parents, were invited to this study about one year after diagnosis. In all, 14 focus group discussions were conducted with 31 adolescents and 43 parents. Written narrative was completed by 91 adolescents (63%) and 105 parents (72%), and questionnaires returned by 114 parents (79%). Data were analyzed using qualitative content analysis. In addition, narratives and questionnaire data allowed for quantified measures. Results: Adolescents and parents described how they agreed to participate "for the good of others," without considering consequences for themselves. However, since the screening also introduced a potential risk of having the disease, the invitation was regarded as " an offer hard to resist." For the majority, receiving the diagnosis was described as "a bolt of lightning," but for some it provided an explanation for previous health problems, and "suddenly everything made sense." Looking back at the screening, the predominant attitude was "feeling grateful for being made aware," but some adolescents and parents also expressed "ambivalent feelings about personal benefits." Among parents, 92% supported future CD screening. The most common opinion among both adolescents and parents was that future CD mass screening should be "a right for everyone" and should be offered as early as possible. However, some argued that it should be "only for sufferers" with symptoms, whereas others were "questioning the benefits" of CD mass screening. Conclusions: Although the incentives to participate in the CD screening were partly non-personal, and diagnosis was met with surprise, adolescents and parents felt grateful that they were made aware. They welcomed future CD screening, but suggested that it should be conducted earlier in life. Thus, CD mass screening seemed acceptable to most of those who were diagnosed and their parents

Neck-specific training with a cognitive behavioural approach compared with prescribed physical activity in patients with cervical radiculopathy : a protocol of a prospective randomised clinical trial

Background: Patients with cervical radiculopathy often have neck- and arm pain, neurological changes, activity limitations and difficulties in returning to work. Most patients are not candidates for surgery but are often treated with different conservative approaches and may be sick-listed for long periods. The purpose of the current study is to compare the effectiveness of neck- specific training versus prescribed physical activity. Methods/Design: The current protocol is a two armed intervention randomised clinical trial comparing the outcomes of patients receiving neck specific training or prescribed physical activity. A total of 144 patients with cervical radiculopathy will be randomly allocated to either of the two interventions. The interventions will be delivered by experienced physiotherapists and last 14 weeks. The primary outcome variable is neck- and arm pain intensity measured with a Visual Analogue Scale accompanied with secondary outcome measures of impairments and subjective health measurements collected before intervention and at 3, 6, 12 and 24 months after base-line assessment. Discussion: We anticipate that the results of this study will provide evidence to support recommendations as to the effectiveness of conservative interventions for patients with cervical radiculopathy.Funding Agencies|Swedish Government through the Karolinska Institute; Swedish National School of Research Education in Health Care Sciences; Strategic Research Programme in Care Sciences; Stockholm County Council Funding ALF Medicine</p