Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

Abstract

Background

Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.

Methods

Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5 mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 ‘common Hispanic mutation’ (CCM1–CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.

Results

The CYP superfamily showed a trend toward association with total lesion count ( P=0.057) and large lesion count ( P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count ( P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH ( P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.

Conclusions

Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.

Graphical abstract

Highlights

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  Inter-individual variability in oxidative stress-related genes may impact CCM1 disease severity.

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  CYP4 and CYP8 families were associated with either large lesion or total lesion count, while CYP46 and MMP Stromelysin families were associated with ICH.

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  Single SNPs in CYP4F8, CYP4F11, CYP4F12, CYP8A1, CYP19A1, CYP27A1, CYP27B1, CYP46A1 and CYP51A1 genes showed significant associations with at least one disease severity phenotype.

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  A single SNP in the MMP3 gene was strongly associated with ICH.

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  CYP and MMP SNPs associated with CCM1 disease severity could serve as early objective predictors of disease susceptibility and outcome.