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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.
Zheng, T, Roda, G, Zabana, Y, Escudero-Hernández, C, Liu, X, Chen, Y, Camargo Tavares, L, Bonfiglio, F, Mellander, MR, Janczewska, I, et al
Journal of Crohn's & colitis. 2024;(3):349-359
Abstract
BACKGROUND AND AIMS Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.
Chan, SSM, Chen, Y, Casey, K, Olen, O, Ludvigsson, JF, Carbonnel, F, Oldenburg, B, Gunter, MJ, Tjønneland, A, Grip, O, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;(5):1048-1058
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Abstract
BACKGROUND AND AIMS It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. CONCLUSIONS In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.
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Prevalence of Celiac Disease in Patients With Iron Deficiency Anemia-A Systematic Review With Meta-analysis.
Mahadev, S, Laszkowska, M, Sundström, J, Björkholm, M, Lebwohl, B, Green, PHR, Ludvigsson, JF
Gastroenterology. 2018;(2):374-382.e1
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Abstract
BACKGROUND & AIMS Anemia is common in patients with celiac disease (CD) and a frequent mode of presentation. Guidelines recommend screening patients with iron-deficiency anemia (IDA) for CD. However, the reported prevalence of CD in patients with IDA varies. We performed a systematic review to determine the prevalence of biopsy-verified CD in patients with IDA. METHODS We performed a systematic review of articles published in PubMed Medline or EMBASE through July 2017 for the term "celiac disease" combined with "anemia" or "iron deficiency." We used fixed-effects inverse variance-weighted models to measure the pooled prevalence of CD. Meta-regression was used to assess subgroup heterogeneity. RESULTS We identified 18 studies composed of 2998 patients with IDA for inclusion in our analysis. Studies originated from the United Kingdom, United States, Italy, Turkey, Iran, and Israel. The crude unweighted prevalence of CD was 4.8% (n = 143). Using a weighted pooled analysis, we found a prevalence of biopsy-confirmed CD of 3.2% (95% confidence interval = 2.6-3.9) in patients with IDA. However, heterogeneity was high (I2 = 67.7%). The prevalence of CD was not significantly higher in studies with a mean participant age older or younger than 18 years or in studies with a mixed-sex vs female-predominant (≥60%) population. On meta-regression, year of publication, female proportion, age at CD testing, and prevalence in the general population were not associated with the prevalence of CD in patients with IDA. In the 8 studies fulfilling all our quality criteria, the pooled prevalence of CD was 5.5% (95% confidence interval = 4.1-6.9). CONCLUSIONS In a systematic review and meta-analysis, we found that approximately 1 in 31 patients with IDA have histologic evidence of CD. This prevalence value justifies the practice of testing patients with IDA for CD.