Greenson, Joel K.

Small intestinal biopsy interpretation has been the cornerstone for the diagnosis of celiac disease for over 50 years. Despite the existence of sensitive and specific serological tests, duodenal mucosal biopsies continue to be obtained in the vast majority of patients in whom a diagnosis of celiac disease is being considered. The accurate evaluation of these biopsies requires coordination and information sharing between the gastroenterologist, laboratory, and pathologist in order to optimize tissue sampling, preparation and interpretation. This document, a collaboration between the Rodger C. Haggitt Gastrointestinal Pathology Society and the North American Association for the Study of Celiac Disease, is intended to provide clinicians and pathologists with a summary of best practices in the use of endoscopy and biopsy for patients with suspected celiac disease. The authors present a comprehensive and critical appraisal of the literature with respect to the topics of endoscopic findings, best methods for the obtaining biopsies, completing the pathology form and pathologic assessment, including evaluating intraepithelial lymphocytes and villous architecture. A discussion of conditions with overlapping pathologic findings in duodenal mucosal biopsies is presented. In order to provide additional guidance for challenging situations, the authors include an appendix containing practical suggestions. This review may be utilized in interdisciplinary discussions to optimize care for patients with possible celiac disease.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.