Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

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LD score regression distinguishes confounding from polygenicity in genome-wide association studies :

Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

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Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis

Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review

Objective:We compared the incidence of appendicitis or appendectomy across the world and evaluated temporal trends.Summary Background Data:Population-based studies reported the incidence of appendicitis.Methods:We searched MEDLINE and EMBASE databases for population-based studies reporting the incid

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The Global Incidence of Appendicitis: A Systematic Review of Population-based Studies.

Objective: This pilot study examines the potential efficacy of applying exosomes to excised keloid wound beds to modify and regulate the wound healing pathway, to promote scar-free healing and reduce keloid formation and recurrence. Method: The effect of human placental mesenchymal stem cell derived exosomes (XoGlo; Kimera Labs, Miami, FL) was studied on 21 patients. All patients had previous excision attempts of their keloids. In each case, the keloid recurred. Under current Institutional Review Board (IRB) approval, and with proper informed consent, patients in a pilot study, had their keloids excised with a CO 2 laser, exosomes immediately administered into the wound, and coverage with an amniotic membrane graft when appropriate. All patients were followed for recurrence. Results: Over the 2 years of follow-up 18 of 21 patients in the pilot study with keloid scars had no recurrence. Three patients of twenty-one developed a recurrence of their keloid scars within 2 months. All were African American. There was one female recurrence of a sternal keloid, one male recurrence on the face and one male recurrence on the neck. All recurrences were in hair bearing regions on the chest, face, and neck. When the process was repeated on the 3 recurrent keloids with the addition of laser hair removal, the 3 revision cases remained recurrence free. Conclusion: Exosomes appear to have a benefit in reducing the recurrence of keloid scars. It is hypothesized that the positive regenerative effects of exosomes override pro-fibrotic growth factors via anti-inflammatory and anti-fibrotic growth factors, especially TGFbeta 3, IL-10, IL-12, MMP-2, MMP-9 and TNF-alpha. These play a vital role in regulating “normal” wound healing and a “scarless” healing model. These studies have shown that with proper homing, exosomes illicit strong regenerative, immunomodulatory, anti-inflammatory, and anti-prostaglandin effects. They are also packed with the antifibrotic cytokines shown to be necessary for normal healing. The strong regenerative synergy of combining exosomes with amniotic membrane grafts which accelerate re-epithelialization and reduce inflammation are hypothesized to be the cornerstone to exosomes’ success at reducing the formation and recurrence of keloid scars in those patients with the genetic propensity to form them. This study examines the potential benefit of human, c-section donated, cultured fetal mesenchymal stem cell-derived exosomes in the treatment of keloid scars, after excision with the carbon dioxide laser. With larger surface area excisions, or when residual healthy cartilage was exposed, tissue coverage with amniotic membrane extracellular grafts was utilized. These grafts provide a scaffold for enhanced exosome performance in larger surface areas

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The Utilization of Human Placental, Fetal Mesenchymal Stem Cell Derived- Exosomes in Treating Keloid Scars

Exosome research continues to flourish. Subsequent knowledge surrounding indications, dose–response, safety, efficacy, and the ability to combine exosome treatment as a “skin primer”—for biostimulation modalities such as calcium hydroxylapatite (CaHA), platelet‐rich plasma (PRP), and platelet‐rich fibrin matrix (PRFM) is growing rapidly. The objective of this study was to develop safe, reproducible methods of improving topical exosome absorption to enhance the quality of skin either by themselves, or in combination with injectable CaHA.

Greg W. Chernoff

Papers

Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review

The Global Incidence of Appendicitis: A Systematic Review of Population-based Studies.

The Utilization of Human Placental, Fetal Mesenchymal Stem Cell Derived- Exosomes in Treating Keloid Scars

Combining topical dermal infused exosomes with injected calcium hydroxylapatite for enhanced tissue biostimulation