A35 GENOME WIDE ASSOCIATION STUDY OF ABNORMAL INTESTINAL PERMEABILITY IN HEALTHY FIRST DEGREE RELATIVES OF CROHN’S PATIENTS
Bibliographic record
Abstract
Increased intestinal permeability (IP) is thought to be a risk factor for the development of inflammatory bowel disease (IBD). Our recent study has demonstrated that known IBD risk-associated single nucleotide polymorphisms (SNPs) were not associated with IP, while smoking status and age were two independent factors associated with increased IP. To identify other genetic loci influencing IP, we performed a genome wide association study (GWAS) among healthy first-degree relatives of CD patients with increased and normal IP. IP was measured with high-pressure liquid chromatography of timed urine collection after ingestion of two saccharide probes, lactulose and mannitol. For each subject, the lactulose–mannitol ratio (LacMan ratio) was calculated as the fractional excretion of lactulose divided by that of mannitol. A LacMan ratio >0.025 was considered as abnormal IP. Genotyping was performed using the HumanCoreEXOME chip and ImmunoChip platform. Imputation was performed using the Michigan server using the Haplotype Reference Consortium v1.1 panel. Imputation was quality controlled and SNPs with a minor allele frequency < 5% or R square <0.3 were removed. Associations were tested using the gee framework that accounts for family correlation, age (age squared), gender, smoking, and the first three genetic principal components. LacMan ratio was log(10) transformed before statistical analysis. A total of 1,075 healthy individuals enrolled in the Gene-environment-microbe (GEM) cohort study with both IP and genotyping data were included. In this cohort 17.8% of individuals had abnormal IP. A total of 7.8 million SNPs were imputed and 5.7 million SNPs were included in the analysis after quality control. When the data were not dichotomized (abnormal versus normal IP) the genomic inflation was of 1.03 compared to 1.04 using dichotomized data. No SNP reached genome wide significance (P> 5 × 10–8). However 58 loci showed suggestive associations e.g. SGCG, RBFOX3, PSMG1, DAB2, SVIL (p<9.1 × 10–6). We did not find robust genetic wide associations with IP. Although multivariate analysis controlling for major contributing factors to IP showed only a few SNP with nominal association these failed to reach the conventional GWAS threshold (P< 5 × 10–8). This may be due to the power of the study with only 1,075 subjects. Submitted on behalf of behalf of the CCC IBD GEM Project research team. CCC, CIHRThe Helmsley Charitable Trust
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".