RGD Reference Report - Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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

Authors: Choquet, Hélène  Trapani, Eliana  Goitre, Luca  Trabalzini, Lorenza  Akers, Amy  Fontanella, Marco  Hart, Blaine L  Morrison, Leslie A  Pawlikowska, Ludmila  Kim, Helen  Retta, Saverio Francesco 
Citation: Choquet H, etal., Free Radic Biol Med. 2016 Mar;92:100-109. doi: 10.1016/j.freeradbiomed.2016.01.008. Epub 2016 Jan 19.
RGD ID: 401960081
Pubmed: PMID:26795600   (View Abstract at PubMed)
PMCID: PMC4774945   (View Article at PubMed Central)
DOI: DOI:10.1016/j.freeradbiomed.2016.01.008   (Journal Full-text)


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 (>=5mm 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumancerebral cavernous malformation 1 exacerbatesIAGP DNA:silent mutation:CDS:p.L256L (rs5628) (human)RGD 
PtgisRatcerebral cavernous malformation 1 exacerbatesISOPTGIS (Homo sapiens)DNA:silent mutation:CDS:p.L256L (rs5628) (human)RGD 
PtgisMousecerebral cavernous malformation 1 exacerbatesISOPTGIS (Homo sapiens)DNA:silent mutation:CDS:p.L256L (rs5628) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanCerebral cavernous malformation exacerbatesIAGP DNA:silent mutation:CDS:p.L256L (rs5628)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ptgis  (prostaglandin I2 synthase)

Genes (Mus musculus)
Ptgis  (prostaglandin I2 (prostacyclin) synthase)

Genes (Homo sapiens)
PTGIS  (prostaglandin I2 synthase)


Additional Information