P0915 MECONIUM ILEUS IN CYSTIC FIBROSIS NEONATES IS ASSOCIATED WITH POLYMORPHIC MARKERS IN THE CALCIUM-ACTIVATED POTASSIUM CHANNEL (KCNN4) GENE
Bibliographic record
Abstract
Introduction: Cystic Fibrosis (CF) is an autosomal, recessive disease most common among Caucasians and caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Genotype-phenotype studies in CF suggest involvement of secondary genes (CF modifiers) in the pathophysiology of the disease. One of the early CF manifestations, meconium ileus (MI), is neonatal bowel obstruction present in a subset (15–20%) of CF patients. Relatively high concordance of MI among CF siblings suggests involvement of secondary genetic determinant(s) in this clinical feature. Our previous linkage studies identified the Cystic Fibrosis Modifier locus 1 (or CFM1) for MI on human chromosome 19q13. Methods: To assess association between polymorphic markers in the 19q13 chromosome region and MI trait in CF trios, family based association analysis using Transmission Disequilibrium Test (TDT) with the Pearson chi-square test has been performed. Results: Analyses of 18 markers in 19q13 revealed allelic association with MI for two markers: STR1 (D19S217 in the KCNN4 gene) and STR2 (D19S712 in the LOC284348 gene). A total of 398 pancreatic insufficient CF trios with or without MI were genotyped for these markers and analyzed for TDT. Both STRs showed a biased (60–65%) transmission of specific alleles (#4 in STR1 and #5 in STR2) to CF patients in the MI group and similar 59–61% non-transmission of the same alleles in the non-MI group. TDT showed significant association for both STRs (p=0.0013 and p=0.0031; respectively). Combined marker analysis also revealed a significant association, suggesting a chromosome background with #4 of STR1 and #5 of STR2 might carry a gene variant of CFM1 that would increase the risk of MI in CF patients. Analysis of 5 regional SNP markers in our study population revealed two most common haplotypes with the SNP core _ _ _ 2 1 1 _ (37%; haplotype A) and _ _ _ 1 2 2 _ (41%; haplotype B). Increased TDT association was detected for STR1(#4) on haplotype A with MI (p=0.0002). Conclusion: Since no TDT association was detected for haplotype A itself, we reason that the CFM1 gene mutation contributing to MI is probably present on chromosomes carrying the allele 4 of the D19S217 marker on the haplotype A background and that subsequent mutation analysis should be performed on a subset of CF patients carrying these chromosomes. The KCNN4 gene encoding intermediate conductance Ca-dependent potassium channel is currently the strongest candidate for the CFM1. Reference(S): We would like to thank the CF Modifier Collaborative Group for sharing samples and clinical data and the Canadian Cystic Fibrosis Foundation for support.
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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 | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".