Relationships between polymorphisms in EPHX2, CYP2J2, CYP2C9, and CYP2C8, white matter hyperintensities, and regional atrophy

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.