Introduction

Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and Ulcerative colitis (UC), is a group of chronic, relapsing disorders in the gastrointestinal tract. The disease mechanisms are largely unknown. We hypothesized that the interaction of genetic variants and tobacco smoking can influence the disease risk of IBD and impact the disease progression in CD and UC differently.

Aims & Methods

3530 IBD patients were included in the present study via Parelsnoer IBD Biobank (PSI), a Dutch prospective, nationwide biobank of IBD patients. Phenotypic data on smoking status at the time of diagnosis was obtained through the PSI questionnaire. Genome-wide genotyping was conducted on all PSI participants using the Global Screening Array and divided into two independent datasets, the discovery (N=990) and replication cohort (N=2540). Case-only study design was applied to estimate the interaction effects for IBD, CD, and UC separately with subsequent meta-analysis between discovery and replication cohorts.

Results

572 lead single nucleotide polymorphisms (SNPs) were demonstrated with interaction effect of smoking (meta-analysis P < 5e-5, heterogeneity Cochrane Q test P > 0.05). 30 interacting SNPs showed distinct opposite effects between CD and UC (the ratio of interaction effect sizes between CD and UC > 5 or < 0.1). Our analysis also confirmed 9 previously reported interacting SNPs in the regions of NOTCH4, TSBP1-AS1, HLA-DRA, HLA-DRA-HLA-DRB5, HLA-DRB9, DNMT3A, MUC22, and CCR3.

Conclusion

Our present study identified a large number of new interaction loci for IBD on a genome wide scale and shed new light on the disease mechanisms.

Disclosure

No conflict of interest

Introduction

Rare early onset cases of diabetes stem from single gene mutations, whereas frequent gene variants can also contribute to multifactorial diabetes, indicating shared disease mechanisms. Our recent study has identified ONECUT1 as a gene implicated in both monogenic and multifactorial diabetes, establishing it as crucial target for investigating fundamental signaling pathways in diabetes pathology [1,2]. However, numerous diabetic characteristics remain unexplained by typical genetic alterations, highlighting the underestimated significance of the non-coding genome. We have identified a neonatal diabetes patient carrying a heterozygous ONECUT1 truncating variant. Remarkably, the patient exhibited a phenotype akin to individuals with homozygous ONECUT1 truncating mutations. Upon further examination, we detected an additional heterozygous deletion in the non-coding genome, leading us to hypothesize that it could impact the regulation of the remaining ONECUT1 allele. Consequently, the dysregulation of the ONECUT1-dependent transcriptional machinery crucial for proper beta-cell development occurs, ultimately leading to the severe diabetic phenotype observed in the patient.

Aims & Methods

Following deletion of specific genomic regions in human embryonic stem cells, we initiated their differentiation into the pancreatic endocrine lineage and meticulously characterized the developmental stages.

Results

Importantly, we successfully replicated the patient’s diabetic phenotype, elucidating deficiencies in both pancreatic development and beta-cell functionality. The differentiation of pancreatic progenitors was notably hindered by the loss of the regulatory region associated with nearly complete ablation of ONECUT1. Moreover, the stem cell-derived islets exhibited a reduced number of beta-cells as well as impaired insulin secretion, even in heterozygous knockouts.

Conclusion

Altogether, our ongoing comprehensive mechanistic characterization provides insights into the precise role of the identified regulatory element in pancreatic beta-cell development and diabetes pathophysiology, emphasizing the significance of the non-coding genome. By unveiling unknown molecular pathomechanisms linked to alterations in regulatory sequences, we contribute to a deeper understanding of the pancreatic transcriptional network and establish the foundation for personalized diabetes treatment.

References

[1] Philippi, A., Heller, S., Costa, I.G. et al. Mutations and variants of ONECUT1 in diabetes. Nat Med 27, 1928–1940 (2021). https://doi.org/10.1038/s41591-021-01502-7
[2] Heller, S., Li, Z., Lin, Q. et al. Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Commun Biol 4, 1298 (2021). https://doi.org/10.1038/s42003-021-02818-3

Introduction

The clinical implications of portal vein thrombosis (PVT) on the prognosis of acute variceal bleeding (AVB) in cirrhosis remain under debate. Most studies have not been specifically designed to assess the severity of PVT.

Aims & Methods

This study aimed to evaluate the severity of PVT and its impact on outcomes in patients with cirrhosis and AVB. From January 2016 to December 2016, a total of 1541 consecutive cirrhotic patients admitted for AVB, with (n=432; 28.1%) or without PVT (n=1109; 71.9%), were included retrospectively. The degree of luminal obstruction was used to classify the grades of PVT according to Baveno VII criteria. The primary endpoint was 6-week mortality.

Results

During the follow-up period, 179 patients (11.6%) died within 6 weeks. Patients with PVT had a higher risk of 6-week mortality compared to those without PVT (18.3% vs 8.9%; HR 2.12, 95% CI 1.52–2.94, p <0.001). Among them, those with malignant main PVT had a significantly elevated risk (39.3% vs 9.2%; HR 4.86, 95% CI 2.74–8.62, p <0.001). In the non-malignant PVT cohort, only completely occlusive main PVT was associated with increased 6-week mortality (completely occlusive 26.1% vs cavernous transformation 9.7% vs partially occlusive 6.5% vs minimally occlusive 5.9% vs without PVT 9.2%, p = 0.023). These results were consistent across various relevant subgroups.

Conclusion

Our study demonstrates that PVT is linked to a poorer outcome in cirrhotic patients with AVB, particularly in cases of malignant main PVT and completely occlusive main PVT.

Disclosure

None of the authors have any conflict of interest.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a widespread clinical condition that affects about 1/4th adults globally. It can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). More than one-third of Egyptians are affected by NAFLD. Unfortunately, many patients diagnosed with NAFLD after cirrhosis has already occurred.
Single Nucleotide Polymorphisms (SNPs) associated with NAFLD have been proposed to identify the causal variants of the disease and also as potential pharmacological targets. Heritability of NAFLD estimates range from 20% to 70% based on ethnicity, and environmental factors. The first gene variant found to be a consistent genetic risk factor for NAFLD was Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409. In addition, other studies have shown that, Transmembrane 6 superfamily 2 (TM6SF2) rs58542926 and Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs9992651 also affect risk of NAFLD developmen. Some studies also show a role for Glucokinase regulatory protein (GCKR) rs1260326.

Aims & Methods

We aimed to investigate genetic risk factors for NAFLD occurrence in Egyptian patients.
Cases of clinically diagnosed NAFLD (n= 205) and controls (n= 187) were recruited. A subgroup of individuals with NAFLD that had progressed to liver fibrosis (n= 131) was compared with the control individuals. TaqMan-based genotyping assays were employed to explore the association of selected SNPs (PNPLA3 rs738409, TM6SF2 rs58542926, HSD17B13 rs9992651 and GCKR rs1260326) with NAFLD in Egyptian patients.

Results

NAFLD cases versus controls genotype data: rs738409 -genotype showed statistical significance. Univariate analysis for TM6SF2 rs58542926, HSD17B13 rs9992651, and GCKR rs1260326 did not show statistical significance.
After adjusting for the other risk factors -age, gender, BMI, and waist circumference, the association of PNPLA3 rs738409 -genotype, and allele models- with the variant G allele more common in NAFLD remained statistically significant with an increased odds ratio. PNPLA3 rs738409 GG carriers have 5.296 times NAFLD risk than CC carriers. For GCKR rs1260326 genotype model, after correction for the other risk factors, the variant T allele acquired statistical significance.
Fibrotic-NAFLD cases versus controls genotype data: Univariate analysis for PNPLA3 rs738409 showed statistical significance. The univariate analysis for TM6SF2 rs58542926, HSD17B13 rs9992651, and GCKR rs1260326 did not show statistical significance.
After adjusting for the other risk factors -age, gender, BMI, and waist circumference, the association of PNPLA3 rs738409 -genotype, and allele models remained statistically significance with an increased odds ratio. Of note, PNPLA3 rs738409 GG carriers have 9.267 times higher risk of Fibrotic-NAFLD than CC carriers.The association of HSD17B13 rs9992651 -genotype model-with the variant A allele protective against fibrosis acquired statistical significance and decreased odds ratio. Notably, HSD17B13 rs9992651 GA carriers have a fibrosis risk 0.487 times less than GG carriers. The association of GCKR rs1260326 -genotype model, after correction for the other risk factors acquired statistical significance and an increased odds ratio.

Conclusion

We discovered that in our study population, PNPLA3 rs738409 and GCKR rs1260326 variants increase the risk of NAFLD generally as well as its progression to fibrosis. On the other hand, the HSD17B13 rs9992651 variant may protect against fibrosis development in NAFLD.
Nehal Elmansoury shares the first authorship with Ahmed Kamal.