Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America. METHODS: Patients were diagnosed to have CD or UC using conventional radiologic, endoscopic, and/or histopathologic findings. Histological diagnosis was made by a single specialist gastrointestinal pathologist with a particular interest in IBD. Information regarding cigarette smoke exposure was obtained by administration of the Behavioral Risk Factor Surveillance System Survey (BRFSS) to all patients. Genomic DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 Single Nucleotide Polymorphisms (SNP) in NOD2, IL23r, OCTN1 genes along with IGR. RESULTS: Our cohort consists of 1196 patients: 435 controls, 485 CD patients, and 276 UC patients. Only patients with genotype data for at least 7 of 11 SNPs were included in our data analysis. The control groups for all 11 SNPs were in Hardy-Weinberg Equilibrium. In genotype-association SNP analysis, all NOD2 SNPs (rs5743293, rs2066844, rs2066845) and the IL23r SNP (rs11465804) showed a significant association to IBD (p < 0.03). A multiple gene-interaction analysis showed an association between NOD2 and IL23r with UC (p = 0.04). There were no associations between any OCTN1 and IGR SNPs and IBD in this cohort. A multivariable logistic regression analysis showed that female gender, "current" or "former" smoking status, family history of IBD, and NOD2 SNP minor alleles were associated with CD. CONCLUSION: IBD remains to be challenging to properly diagnose, characterize, and treat. Our study proposes a combined genetic, phenotypic, and environmental approach in an attempt to better understand IBD. Previously demonstrated associations between OCTN1 and IGR and IBD were not confirmed.

Crohn's disease in Caucasians and African Americans, as defined by clinical predictors and single nucleotide polymorphisms.

OBJECTIVES: To compare three aspects of Crohn's disease (CD) between African Americans and Caucasians: (1) demographic data and environmental factors affecting CD susceptibility, (2) disease presentation and clinical course, and (3) genetic susceptibility via the use of single nucleotide polymorphism (SNP) data for inflammatory bowel disease (IBD) susceptibility loci. METHODS: Clinical data and peripheral blood were obtained from 1032 patients (554 CD patients and 478 controls) derived from a clinically well-defined university-based medical and surgical digestive disease practice and included those who were diagnosed with IBD. Genomic DNA was extracted and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 SNPs, including the NOD2, IL-23r, OCTN 1, and the IGR gene variants. RESULTS: A total of 554 patients with CD were included in this study: 53 African Americans (10%), 485 Caucasians (87%), and 15 of other races (3%). The strongest demographic predictor of CD in African American patients was a family history of IBD. Ileocolic disease (L3) was the most common site involved in both African Americans and Caucasians, while the penetrating phenotype (B3) was the most common CD disease behavior in both races. Genotype association analysis showed a significant association between 2 IL23r gene SNPs and CD susceptibility in African Americans (p = .016 and .028, respectively). CONCLUSION: We believe this study is the first to report on genotype-phenotype associations in African American CD patients and compare findings to Caucasian CD patients within the same geographic area. We found no association between NOD2 gene SNPs and CD susceptibility in African Americans patients (p > .05).

Glucose and surgical sepsis: a study of underlying immunologic mechanisms.

BACKGROUND: Early clinical trials investigating the role of tightly controlled glucose levels showed marked benefit in survival of critically ill patients. However, a recent meta-analysis and large randomized controlled trial have failed to reproduce the benefit, showing instead substantially increased risk of dangerous hypoglycemia. We sought to investigate the effects of varying glucose concentrations on previously tested, prognostically significant, innate immune parameters, to define any potential effects of glucose at the cellular level. STUDY DESIGN: After formal approval and informed consent, venous blood samples were collected from young healthy volunteers. Up to 11 corresponding (same-subject) samples were incubated at 100, 350, or 600 mg/dL glucose concentrations and analyzed to determine human leukocyte antigen-DR surface receptor expression, cytokine release, phagocytic capacity, and formation of reactive oxygen species. Data are presented as mean +/- SEM. RESULTS: After incubation, the change in human leukocyte antigen-DR mean channel fluorescence from resting baseline values in lipopolysaccharide-stimulated monocytes was not significantly different between 100, 350, and 600 mg/dL (1,749 +/- 110; 1,748 +/- 120; and 1,725 +/- 96, respectively; p = 0.89). Tumor necrosis factor-alpha concentrations were significantly lower for samples incubated at higher glucose concentrations (179 +/- 50 pg/mL, 125 +/- 30 pg/mL, and 107 +/- 29 pg/mL; p < 0.05). The phagocytic capacity of the innate immune system was marginally enhanced by glucose. However, the formation of reactive oxygen species was markedly impaired by rising glucose (55% to 66% impairment; p < 0.05). CONCLUSIONS: Increasing glucose concentrations exert considerable opposing effects on several well-established innate immunologic processes. The opposing findings might contribute to recent clinical controversies. Physician judgment and experience are essential to imminent treatment of critically ill and perioperative surgical patients.