Contribution of higher risk genes and European admixture to Crohnʼs disease in African Americans:

African Americans (AA) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD

Diversity of O-Antigen Repeat Unit Structures Can Account for the Substantial Sequence Variation of Wzx Translocases

The most common system for synthesis of cell surface polysaccharides is the Wzx/Wzy-dependent pathway, which involves synthesis, on the cytoplasmic face of the cell membrane, of repeat units, which are then translocated to the periplasmic face by a Wzx translocase and then polymerized by Wzy to generate the polysaccharide. One such polysaccharide is O antigen, which is incorporated into lipopolysaccharide (LPS). The O antigen is extremely variable, with over 186 forms in Escherichia coli. Wzx proteins are also very diverse, but they have been thought to be specific only for the first sugar of the repeat units. However, recent studies demonstrated examples in which Wzx translocases have considerable preference for their native repeat unit, showing that specificity can extend well beyond the first sugar. These results appear to be in conflict with the early conclusions, but they involved specificity for side branch residues and could be a special case. Here we take six Wzx translocases that were critical in the earlier studies on the importance of the first sugar and assess their ability to translocate the Escherichia coli O16 and O111 repeat units. We use gene replacements to optimize maintenance of expression level and show that under these conditions the native translocases are the most effective for their native repeat unit, being, respectively, 64-fold and 4-fold more effective than the next best. We conclude that Wzx translocases are commonly adapted to their native repeat unit, which provides an explanation for the great diversity of wzx genes

Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients.

BackgroundPyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis.MethodsWe performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used.ResultsWe identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97).ConclusionCutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies

Clinical, Serologic, and Genetic Factors Associated with Pyoderma Gangrenosum and Erythema Nodosum in Inflammatory Bowel Disease Patients

OBJECTIVE: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. DESIGN: We performed a case control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD related serology was determined using ELISA and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. RESULTS: We identified a total 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN were available for serological analyses. Fewer male subjects were identified in the PG(+) (OR 0.6, p=0.009) and EN(+) groups (OR 0.31, p=0<0.0001). Colonic disease, previous IBD related surgery, and non-cutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared to controls. PG(+) was associated with ANCA seropositivity (p=0.03) and higher ANCA level (p=0.02) in CD. Genetic associations with PG included known IBD loci (IL8RA (p=0.00003), and PRDM1 (0.03)) as well as with USP15 (4.8×10(−6)) and TIMP3 (5.6 ×10(−7)). Genetic associations with EN included known IBD susceptibility genes (PTGER4 (p=8.8×10(−4)), ITGAL (0.03)) as well as SOCS5 (9.64×10(−6)), CD207 3.14×10(−6)), ITGB3 (7.56×10(−6)) and rs6828740 (4q26)(p <5.0 × 10(−8)). Multivariable models using clinical, serologic, and genetic parameters predicted PG (AUC 0.8) and EN (AUC 0.97). CONCLUSION: Cutaneous manifestations in IBD are associated with distinctive genetic characteristics as well as with the similar clinical characteristics including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Whether the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear. Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 µg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications

Contribution of higher risk genes and European admixture to Crohnʼs disease in African Americans

African Americans (AA) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD

Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

Contains fulltext : 88540.pdf (publisher's version ) (Closed access)Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.1 april 201

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk