Daniel Agardh

Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

BACKGROUND The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

A Report on the International Transglutaminase Autoantibody Workshop for Celiac Disease

OBJECTIVES:Measurement of transglutaminase autoantibodies (TGAA) is considered to be the most efficient single serologic test for celiac disease (CD) by the American Gastroenterological Association Institute. We hypothesized that a large international collaborative effort toward improving and standardizing TGAA measurement is both feasible and necessary. The primary aim of this workshop is to compare TGAA assays among various research and clinical laboratories to examine assay concordance and improve (and eventually standardize) the TGAA assay.METHODS:A total of 20 laboratories (5 commercial laboratories, 15 research and clinical laboratories) participated that included enzyme-linked immunosorbent assay (ELISA) and radiobinding assays. A total of 150 serum samples were distributed to each laboratory, with each laboratory receiving an equal aliquot that was coded and blinded, composed of 100 healthy control sera and 50 CD sera.RESULTS:Laboratory sensitivity ranged from 69% to 93% and specificity ranged from 96% to 100%. By receiver operator characteristic analysis, the area under the curve (C index) ranged from 0.9488 to 0.9904. When analyzing for linear correlation, r-squared was as high as 0.8882 but as low as 0.4244 for the celiac samples between different laboratories performing ELISA.CONCLUSIONS:This transglutaminase autoantibody workshop allows for larger-scale international participation for the purposes of improving and eventually standardizing the TGAA assay with subsequent workshops.

Cross-national comparisons of socioeconomic differences in the prevalence of leisure-time and occupational physical activity, and active commuting in six Asia-Pacific countries

Background This study describes physical activity patterns and their association with socioeconomic factors in six countries in the Asia-Pacific region, and examines whether physical activity associations with socioeconomic status follow similar patterns across the six countries. Methods Population-wide representative surveys of non-communicable disease risk factors and socioeconomic factors conducted in Australia, China, Fiji, Malaysia, Nauru and the Philippines between 2002 and 2006 were used. Survey respondents aged 18–64 years who provided information on their socioeconomic status (age, education, income, area of residence) and physical activity level in three domains (leisure-time, occupation, commuting) were included in the study (Australia N=15 786; China N=142 693; Fiji N=6763; Malaysia N=2572; Nauru N=2085; Philippines N=3307). Results Leisure-time physical activity increased with age in China, showed inverse associations for Fiji and Nauru men, and there were no age relationships in other countries. Individuals in China, Fiji and Malaysia living in urban areas, with higher educational attainment and affluence were physically active during leisure time but less active at work and during commuting compared to those in rural areas, with lower educational attainment and lower income. Conclusion There is a link between types of physical activity participation and socioeconomic factors in developing countries. Associations with socioeconomic indicators are likely to reflect economic growth. The findings strongly support the need for a comparable non-communicable risk factors surveillance system in developing countries.

HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM

Summary Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1*0301, DQA1*0501 and DQB1*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0401 -DQA1*03-DQB1*0302) are at greater risk of developing severe retinopathy. [Diabetologia (1996) 39: 1313–1317]

Prevalence of celiac disease: before and after a national change in feeding recommendations.

Objective. A national change in infant feeding recommendations was proposed in 1996 in Sweden: a slow introduction to gluten during weaning was stressed, the recommendation being introduction at 4 instead of 6 months of age. The aim of the present study was to compare the prevalence of celiac disease in healthy young children born before and after the new feeding recommendations in 1996. Material and methods. Sera from 679 children at a median age of 2.9 years (range 2.5–4.2 years) born between January 1996 and November 1997 were investigated with IgA-antigliadin antibodies (AGA) and IgA-endomysial autoantibodies (EMA) and compared with 690 age-matched children born between July 1992 and June 1993. Children with a positive test for EMA and AGA or EMA only were re-tested, and if positive at follow up, investigated with intestinal biopsy. Results. At baseline, 2.2% (15/679) children were positive for EMA and another 0.6% (4/679) for both EMA and AGA. One child refused to be re-tested and eight children were still EMA positive at follow-up. Intestinal biopsy was performed in seven children (one declined biopsy), of whom three showed total villous atrophy. Two children with EMA titers 1:640, respectively, refused further participation in the study, but were strongly suspected to have celiac disease. In total, 0.7% (5/679) (95% confidence interval (CI) = 0.1–1.4%) were considered to have celiac disease compared with 1.3% (9/690) (95% CI = 0.4–2.2%) in the control group (p=0.4217). In addition, 0.3% of the children were diagnosed with symptomatic celiac disease compared with 0.7% in controls (p=0.0134). Conclusions. The prevalence of symptomatic celiac disease declined after the infant dietary recommendations were introduced in 1996, but we could not find any difference in undiagnosed celiac disease between the screened children born before and those born after 1996.

Screening detects a high proportion of celiac disease in young HLA-genotyped children.

Background and Aims: Celiac disease is associated with tissue transglutaminase autoantibodies (tTGAb) and the human leukocyte antigen (HLA)–risk alleles DQB1*02 and DQB1*0302. The aim was to estimate the proportion of undiagnosed celiac disease in children with HLA risk at 3 years of age. Patients and Methods: From a population-based HLA-DQ screening study of newborns born between June 2001 and August 2004 in the southern part of Sweden, 6206 children with HLA-risk alleles were identified and asked to participate at a mean 3.3 ± 0.4 years of age. As controls, 7654 children with HLA-nonrisk alleles were asked to participate. In all, 1620 (26.1%) children with HLA risk and 1815 (23.7%) controls were screened for tTGAb using radioligand-binding assays. Celiac disease was established by intestinal biopsy in children with a confirmed positive tTGAb test. Results: Twenty-three children reported already having clinically diagnosed celiac disease and did not participate further. In children with HLA-risk genotypes, 73 of 1620 (4.5%, 95% CI 3.5%–5.5%) were tTGAb-positive compared with none of 1815 from the controls (P < 0.0001). Seventy-one children underwent biopsy (1 refused biopsy and 1 biopsy failed), of whom 56 of 1618 (3.5%, 95% CI 2.6%–4.4%) had damaged intestinal mucosa classified as celiac disease. The ratio between clinically and screening detected celiac disease in this study was 1:2.4 (23:56). Conclusions: The proportion of clinically undetected celiac disease may be particularly high among 3-year-old children with HLA-DQB1*02 and DQB1*0302 in Sweden, where these 2 HLA-risk alleles frequently occur.

Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort

BACKGROUND & AIMS Early nutrition may affect the risk of celiac disease. We investigated whether amount of gluten in diet until 2 years of age increases risk for celiac disease. METHODS We performed a 1-to-3 nested case-control study of 146 cases, resulting in 436 case-control pairs matched for sex, birth year, and HLA genotype generated from Swedish children at genetic risk for celiac disease. Newborns were annually screened for tissue transglutaminase autoantibodies (tTGA). If tested tTGA positive, time point of seroconversion was determined from frozen serum samples taken every 3 months. Celiac disease was confirmed by intestinal biopsies. Gluten intake was calculated from 3-day food records collected at ages 9, 12, 18 and 24 months. Odds ratios (OR) were calculated through conditional logistic regression. RESULTS Breastfeeding duration (median, 32 wk) and age at first introduction to gluten (median, 22 wk) did not differ between cases and tTGA-negative controls. At the visit before tTGA seroconversion, cases reported a larger intake of gluten than controls (OR, 1.28; 95% confidence interval [CI], 1.13-1.46; P = .0002). More cases than controls were found in the upper third tertile (ie, >5.0 g/d) before they tested positive for tTGA seroconversion than controls (OR, 2.65; 95% CI, 1.70-4.13; P < .0001). This finding was similar in children homozygous for DR3-DQ2 (OR, 3.19; 95% CI, 1.61-6.30; P = .001), heterozygous for DR3-DQ2 (OR, 2.24; 95% CI, 1.08-4.62; P = .030), and for children not carrying DR3-DQ2 (OR, 2.43; 95% CI, 0.90-6.54; P = .079). CONCLUSIONS The amount of gluten consumed until 2 years of age increases the risk of celiac disease at least 2-fold in genetically susceptible children. These findings may be taken into account for future infant feeding recommendations.

Clinical Features of Celiac Disease: A Prospective Birth Cohort

OBJECTIVES: To investigate clinical features of celiac disease (CD) and their association with risk factors for CD in a genetic risk birth cohort. METHODS: Children from 6 clinical centers in 4 countries positive for HLA-DR3-DQ2 or DR4-DQ8 were annually screened for tissue transglutaminase antibodies (tTGA) and assessed for symptoms by questionnaires. Associations of symptoms with anthropometrics, known risk factors for CD, tTGA levels, and mucosal lesions in those biopsied were examined. RESULTS: Of 6706 screened children, 914 developed persistent positive tTGA, 406 underwent biopsies, and 340 had CD. Compared with age-matched tTGA-negative children, those with persistent tTGA were more likely to have symptoms at 2 (34% vs 19%, P < .001) and 3 years of age (28% vs 19%, P = .009) but not at 4 years (27% vs 21%, NS). Z-scores for height, weight, and BMI did not differ between groups. In children with persistent tTGA, having ≥1 symptom was associated with family history of CD (odds ratio = 2.59, 95% confidence interval, 1.21–5.57) but not with age, gender, or HLA-DR3-DQ2 homozygosity. At seroconversion, tTGA levels were higher in symptomatic than asymptomatic children (P < .001), in those from CD families (P < .001), and in US participants (P < .001) but not associated with age, gender, or HLA genotype. tTGA levels correlated with severity of mucosal lesions both in symptomatic (r = 0.53, P < .001) and asymptomatic children (r = 0.22, P = .01). CONCLUSIONS: A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children.

Coeliac disease in children: a social epidemiological study in Sweden

Aim:  Little is known on the possible existence of socioeconomic and geographical differences in early coeliac disease (CD) risk. Therefore, we investigated these aspects in children before age two.

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

Abstract: 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.