Relationships between polymorphisms in <i>EPHX2, CYP2J2, CYP2C9</i>, and CYP2C8, white matter hyperintensities, and regional atrophy
Bibliographic record
Abstract
Abstract Background White matter hyperintensities (WMH) of presumed vascular origin commonly coincide with neurodegeneration. Previous studies reported heterogeneous relationships between WMH and atrophy. Cytochrome P450s CYP2J2, CYP2C8, and CYP2C9 are involved in the vascular ischemic response and soluble epoxide hydrolase (EPHX2) metabolizes its products, which have been implicated in vascular pathology. Here we investigate potential effects of single nucleotide polymorphisms (SNPs) in these genes on WMH and atrophy. Method Patients with vascular cognitive impairment and/or neurodegenerative diagnoses were drawn from the Sunnybrook Dementia Study (NCT01800214), Vascular Brain Health (VBH) study, and the Brain‐Eye Amyloid Memory (BEAM) study. SNPs were genotyped using the Illumina Neurochip. Patients of European ancestry confirmed via principal components analysis were included. Variants in candidate genes were identified by variant IDs from dbSNP. Linkage‐disequilibrium‐based clumping on minor allele frequency (MAF) was applied via PLINK v1.9 (LD threshold: 0.2) to prioritize SNPs with higher MAF (removing SNPs with MAF<10%). Imaging (T1, T2/PD and FLAIR) was acquired at 3.0T for volumetric analysis using an in‐house segmentation (SABRE/Lesion Explorer). Linear regression models controlling for age, sex, Mini Mental State Exam, and head size were used to assess effects of the SNPs on WMH or atrophy, and effects of SNP×WMH interactions on atrophy in R. Genotypes were coded additively. Result Among included participants (n = 508, 71±11 years, 51% female), EPHX2 rs2741351 C/A (MAF = 16%) was associated with frontal (F = 3.54, p = 0.030), temporal (F = 5.86, p = 0.003), and global (F = 6.18, p = 0.002) atrophy. CYP2J2 C/T rs11572214 was associated with frontal (F = 3.99, p = 0.019) and global (F = 4.13, p = 0.017) atrophy. CYP2C8 rs11572174 G/A (MAF = 12%) was associated with deep WMH (F = 3.71, p = 0.025). EPHX2 rs2279591 C/T (MAF = 28%) moderated the association between periventricular WMH and temporal atrophy (F = 5.48, p = 0.004); CYP2C9 rs6583964 G/A (MAF = 47%) moderated the association between periventricular WMH and frontal atrophy (F = 3.74, p = 0.024); and CYP2J2 rs11572214 (MAF = 42%) moderated the association between deep WMH and temporal atrophy (F = 3.58, p = 0.029). Conclusion Genetic variation in the CYP450‐soluble epoxide hydrolase pathway was related to WMH and brain atrophy in people with cognitive impairment. The results suggest that this pathway may contribute to small vessel cerebrovascular disease, and to its impact on neurodegeneration.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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".