A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

Causes of death in people with celiac disease spanning the pre- and post-serology era: a population-based cohort study from Derby, UK.

OBJECTIVES: The objective of the study was to compare cause-specific mortality risks in the periods before and after the introduction of accurate and specific serological tests for diagnosing celiac disease. METHODS: This was a prospective cohort study of people with celiac disease diagnosed in Southern Derbyshire, United Kingdom, from the late 1950s onward, and followed-up from 1978 until death or 31 December 2006. Standardized mortality ratios (SMRs) were calculated for all-cause mortality and various cause-specific groups concentrating on the period commencing 2 years after diagnosis of celiac disease. RESULTS: A total of 1,092 celiac patients (of whom 90% were incident) contributed 10,152 person-years of follow-up beyond 2 years of diagnosis and 142 deaths. A statistically significant increase in all-cause mortality was observed (SMR 1.37; 95% confidence interval (CI) 1.16-1.62), along with an increase in deaths from cancer (SMR 1.61; 95% CI 1.19-2.13), digestive disease (SMR 2.19; 10 deaths, 4 due to liver disease), and respiratory disease (SMR 1.57; 21 deaths, 11 due to pneumonia). The overall increase in mortality risk was higher for males (SMR 1.86; 95% CI 1.45-2.34) than it was for females (SMR 1.10; 95% CI 0.86-1.38). When results were stratified by period of diagnosis (pre-1990, 1990-1999, and 2000 onward), we found no evidence of differing all-cause mortality between cases diagnosed within these periods. CONCLUSIONS: Mortality in people with celiac disease has not materially changed over the 25 years of this study with the introduction of serological tests to aid diagnosis. The excess overall mortality we observed was partly explained by deaths from cancer, digestive disease, and respiratory diseases, of which the majority were deaths from pneumonia, supporting existing guidelines that advise pneumococcal vaccination for celiac patients.

Mortality in coeliac disease: a population-based cohort study from a single centre in Southern Derbyshire, UK.

OBJECTIVE: With the advent of screening tests, it was hypothesised that milder cases of coeliac disease coming to diagnosis might have reduced risk of mortality. An earlier publication did not support this view. We have re-examined this issue employing a larger number of patients followed for a further 8 years. DESIGN: Patients with coeliac disease from Southern Derbyshire, UK, were followed prospectively from 1978 to 2014 and included those diagnosed by biopsy and serology. Causes of death were ascertained. Standardised mortality ratios were calculated for all deaths, cardiovascular disease, malignancy, accidents and suicides, respiratory and digestive disease. Ratios were calculated for individual causes. Analysis centred on the postdiagnosis period that included follow-up time beginning 2 years from the date of coeliac disease diagnosis to avoid ascertainment bias. Patients were stratified according to date of diagnosis to reflect increasing use of serological methods. RESULTS: All-cause mortality increase was 57%. Mortality in the serology era declined overall. Mortality from cardiovascular disease, specifically, decreased significantly over time. Death from respiratory disease significantly increased in the postdiagnosis period. The standardised mortality ratio for non-Hodgkin's lymphoma was 6.32, for pneumonia 2.58, for oesophageal cancer 2.80 and for liver disease 3.10. Survival in those who died after diagnosis increased by three times over the past three decades. CONCLUSIONS: Serological testing has impacted on the risk of mortality in coeliac disease. There is an opportunity to improve survival by implementing vaccination programmes for pneumonia and more prompt, aggressive treatments for liver disease.

Epidemiology of coeliac disease in a single centre in Southern Derbyshire 1958-2014.

OBJECTIVE: To determine trends in diagnosis of coeliac disease (CD) in patients attending a single centre 1958-2014 and provide figures for prevalence and incidence in those born in Derby city over 4 decades. To explore a link between deprivation and prevalence and characteristics of CD in Asians. DESIGN: An unselected, consecutive series of 2410 adult patients with CD diagnosed in the catchment area of the Derby hospitals was identified. 1077 born within Derby city identified by postcodes was used to determine changes in prevalence and incidence over 4 decades. 191 patients were Asian. Population numbers were obtained from National Census information. RESULTS: In the quinquennium 2010-2014, 20 times more patients were diagnosed than during 1975-1979. 27% were diagnosed at ≥60 years. A paucity of diagnoses in young men was observed. Women were diagnosed most often in age band ≥35<45, 15 years earlier than men. The largest increase in diagnosis rates occurred in young women and the elderly. In 2014, overall prevalence was 1:188; women 1:138. 4.6% of the variation was attributed to deprivation. Diagnosis rates in Asians increased markedly although only 5% were diagnosed at ≥60 years, much lower than for whites. CONCLUSIONS: The dramatic increase in number of patients with CD presents challenges for follow-up and new models of care need to be explored. Healthcare workers should be alert to the diagnosis in young men and elderly Asians. A dedicated coeliac clinic is an excellent facility to increase diagnosis rates.

Coeliac disease: further evidence that biopsy is not always necessary for diagnosis.

OBJECTIVES: Growing evidence supports the view that the diagnosis of coeliac disease (CD) can be made by serological tests alone, although this approach is still not widely accepted. We previously showed in retrospective and prospective studies that in adults an IgA-tissue transglutaminase antibody cut-off can be defined above which the positive predictive value for CD is 100%. Following a change in the analytical method for measuring the antibody, our objectives were to re-examine this finding in a larger series of adults to ascertain whether a diagnosis of CD can be reliably made in a proportion of patients without the need for small bowel biopsy and to re-evaluate the diagnostic guidelines used in our centre. PATIENTS AND METHODS: A retrospective analysis was done in an unselected series of 270 adult patients who had small bowel biopsies and serum IgA-tissue transglutaminase antibody levels measured from 2009 to 2014. RESULTS: At an IgA-tissue transglutaminase antibody cut-off greater than 45 U/ml (>8×upper limit of normal+2SDs) the positive predictive value for CD in this cohort was 100%; 40% of cases were above this cut-off. CONCLUSION: We have verified that a diagnosis of CD can be reliably made in a high proportion of adults based on serology alone using the IgA-tissue transglutaminase antibody method specified. These results add to the body of evidence that small bowel biopsy should no longer be considered mandatory for the diagnosis of CD. On the basis of these results the diagnostic guidelines in our centre have been modified.

European multi-centre study on coeliac disease and non-Hodgkin lymphoma.

INTRODUCTION: Coeliac disease (CD) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but there is little information about whether this is true for clinically silent CD. OBJECTIVE: To investigate the frequency of CD in two European populations; one with NHL and another derived from the general population. METHODS: A prospective, multi-centre, case-control study in 10 European countries was conducted between May 1998 and April 2001. A total of 1446 consecutive patients with newly diagnosed NHL aged over 18 years was collected. The control group consisted of a population of 9676 individuals who were screened for CD. The number of patients with a previous diagnosis of CD and those with silent CD detected by screening were determined in the two groups. RESULTS: The patients with CD had a significantly increased risk of developing NHL [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.9]. This risk was only present in patients with CD diagnosed clinically before the study (OR 3.3, 95% CI 1.4-7.9), but not in those with silent CD detected by screening (OR 1.3, 95% CI 0.6-2.7). CONCLUSION: Patients with CD have an increased risk of developing NHL, although this is lower than previously thought. Clinically silent CD is rare in patients with NHL.

Risk of morbidity in contemporary celiac disease.

Celiac disease is one of the most common chronic diseases encountered in the Western world with a serological prevalence of approximately 1%. Since it is so common, much comorbidity will occur either as associations or simply by chance, or as complications of the disorder. Many of the published studies purporting to establish the frequency of these occurrences have been limited by factors such as the source and number of patients considered, choice of control groups and ascertainment bias. Recent epidemiological studies have attempted to minimize these sources of error and provide more reliable information. Autoimmune diseases constitute clinically important associations, of which Type 1 diabetes mellitus and thyroid disorders are the most important. Several liver disorders, including primary biliary cirrhosis and primary sclerosing cholangitis, are also associated. The frequency of malignant complications of celiac disease is much lower than earlier studies have indicated, with lymphoma increased by approximately fivefold and the absolute number of tumors is small. The increase in fracture risk in celiac disease is only modest. Although neurological and psychiatric conditions affect celiac patients, no disorder specifically associated with celiac disease has been identified. Reproductive problems have been overexaggerated. It is important that these co-morbidities are recognized because if not, symptoms will be falsely attributed to deliberate or inadvertent ingestion of gluten, rather than prompt a search for a second diagnosis. Furthermore, in a patient with an established diagnosis that is considered falsely to account for the whole clinical picture, celiac disease is likely to remain undetected.

Newly identified genetic risk variants for celiac disease related to the immune response.

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

Association of celiac disease and intestinal lymphomas and other cancers.

Celiac disease (CD) is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, and of the esophagus. Enteropathy-associated T-cell lymphoma (EATL) is a rare form of high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine that is specifically associated with CD. This NHL subtype arises in patients with either previously or concomitantly diagnosed CD. In a subgroup of patients, there is progressive deterioration of a refractory form of CD. EATL derives from a clonal proliferation of intraepithelial lymphocytes and is often disseminated at diagnosis. Extraintestinal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal sinus, and brain. The outlook of EATL is poor. Recent studies indicated that (1) CD is associated with a significantly increased risk for NHL, especially of the T-cell type and primarily localized in the gut (EATL); (2) the CD-lymphoma association is less common than previously thought, with a relative risk close to 3; (3) CD screening is not required in patients with NHL of any primary site at the onset, unless suggested by specific findings (T-cell origin and/or primary gut localization). The risk of NHL associated with clinically milder (or silent) forms could be lower than in typical cases of CD. Several follow-up studies suggest that the GFD protects from cancer development, especially if started during the first years of life. Strict adherence to the GFD seems to be the only possibility of preventing a subset of rare but very aggressive forms of cancer.