Genome-wide Genotyping of Cerebral Cavernous Malformation Type 1 Individuals to Identify Genetic Modifiers of Disease Severity

2020 ◽  
pp. 77-84
Author(s):  
Hélène Choquet ◽  
Helen Kim
Keyword(s):  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Genetic Modifiers ◽  
Genome Wide

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

2016 ◽  
Vol 92 ◽  
pp. 100-109 ◽  
Author(s):  
Hélène Choquet ◽  
Eliana Trapani ◽  
Luca Goitre ◽  
Lorenza Trabalzini ◽  
Amy Akers ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Matrix Metalloproteinase ◽  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Genetic Modifiers

Abstract T P154: Association of Common Variants in Immune Response Genes with Severity of Familial Cerebral Cavernous Malformation Type 1

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Hélène Choquet ◽  
Jeffrey Nelson ◽  
Ludmila Pawlikowska ◽  
Charles E. McCulloch ◽  
Amy Akers ◽  
...  
Keyword(s):  
Immune Response ◽  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Common Variants ◽  
Immune Response Genes ◽  
Minor Alleles ◽  
And Gender ◽  
Familial Cerebral Cavernous Malformation

Objective: Familial Cerebral Cavernous Malformation type 1 (fCCM1) is an autosomal dominant disease caused by KRIT1 mutations and characterized by brain lesions, which increase in number over time for unknown reasons. Inflammation and altered expression of immune response genes have been observed in human CCM lesions. We investigated whether common variants in immune response genes are associated with fCCM1 disease severity, as manifested by greater lesion burden. Methods: Lesion burden was assessed on susceptibility-weighted MR imaging for 178 fCCM1 subjects, all carriers of the founder common Hispanic mutation (CHM, Q455X in KRIT1 ) and recruited as part of the Brain Vascular Malformation Consortium study. We selected 321 variants in 12 immune response genes up-regulated in human CCM lesions and represented on the Affymetrix Axiom® Genome-Wide LAT-1 Human Array. Linear regression analyses under an additive model were performed to assess association of genotype with log-lesion burden residuals, after adjustment for age at enrollment and gender. P -values were generated using 100,000 permutations to account for family structure and multiple testing. Results: Lesion burden (range: 0-713; mean ± SD: 60.5 ± 116.3) was highly variable. The minor alleles at rs2272022 ( CD200 ), rs75223220 ( CD68 ), rs57767447 and rs12587347 ( IGH ), and rs13053345 ( IGL ) were associated with more lesions (≥32%, P <0.05) at baseline, independent of age and gender. The minor alleles at rs7639471 ( CD200 ), rs9901675 ( CD68 ), rs5759959 ( GUSP11 ), rs10147756 and rs7144404 ( IGH ), and rs987710 ( IGL ) were associated with fewer lesions (≤45%, P <0.05). Variants in CD247 , CD3G , HLA-DRB1 , IGJ , LOC390714 , MS4A1 and SDC1 were not significantly associated with lesion burden. Conclusions: Several common variants in immune response genes are associated with lesion burden in fCCM1-CHM subjects. Further studies are needed to confirm whether CD200, CD68, GUSP11, IGH and IGL genes influence fCCM1 disease severity.

scholarly journals Association of Cardiovascular Risk Factors with Disease Severity in Cerebral Cavernous Malformation Type 1 Subjects with the Common Hispanic Mutation

2013 ◽  
Vol 37 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Hélène Choquet ◽  
Jeffrey Nelson ◽  
Ludmila Pawlikowska ◽  
Charles E. McCulloch ◽  
Amy Akers ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
The Common

Abstract 196: Polymorphisms in Cerebral Cavernous Malformation Signaling Pathway Genes Associated With Severity of Cerebral Cavernous Malformation Type 1

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Hélène Choquet ◽  
Ludmila Pawlikowska ◽  
Jeffrey Nelson ◽  
Charles E McCulloch ◽  
Amy Akers ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Neurological Deficits ◽  
Lesion Count ◽  
Large Lesion ◽  
Genes Encoding ◽  
Dominant Disease ◽  
Familial Cerebral Cavernous Malformation

Objective: Familial cerebral cavernous malformation (CCM) is an autosomal dominant disease caused by mutations in CCM1 , CCM2 or CCM3 , and characterized by multiple brain lesions that can lead to intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same mutation can manifest variable symptoms and severity of disease, suggesting the influence of modifiers. As the three CCM proteins form a trimeric complex in vitro and interact with many other proteins, we hypothesized that variants in CCM1-2-3 and in other genes encoding proteins involved in CCM signaling modify disease severity, as manifested by ICH and greater total or large lesion counts. Methods: We analyzed 188 Hispanic CCM1 patients harboring the common Hispanic mutation (CHM, CCM1 Q455X). ICH and lesion counts at enrollment were obtained by clinical assessment and MRI. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 504 variants (MAF≥1%) within +/- 5kb of 42 genes for association with ICH, total and large (≥5 mm in diameter) lesion counts, adjusting for age, gender and family structure. Results: At baseline, 30.3% of CCM1-CHM patients had a history of ICH. Mean total lesion count was 60.1 ± 115.0 (range 0 to 713). Mean large lesion count was 4.9 ± 8.7 (range 0 to 104). Two NTRK1 variants (rs41267423 and rs1800879) as well as SLMAP rs7621574 and PCDHGA1 rs17097189 were significantly associated with ICH ( P ≤0.014). Suggestive associations with ICH ( P ≤0.05) were observed for additional 15 variants in 11 genes. RAP1GAP rs2625408 was associated with both total and large lesion counts ( P ≤0.004) and additional 4 variants in 4 genes were associated with one of these phenotypes. No single variant was associated with both ICH and total or large lesion count; however, different variants in RAP1GAP and KDR genes were associated with all three phenotypes tested. Conclusions: Variants in genes involved in CCM signaling may contribute to variability in CCM1 disease severity. Genotypes that replicate in other cohorts might be useful as predictors in clinical management.

Cerebral Cavernous Malformation Type 1 with Retinal Blood Vessel Tortuosity and Krit1 Gene Mutation

2019 ◽  
Vol 72 (7-8) ◽  
pp. 273-277
Author(s):  
Kalmár Tibor ◽  
Maróti Zoltán ◽  
Vadvári Árpád ◽  
Halmosi Ágnes ◽  
Kálovits Ferenc ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Gene Mutation ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Retinal Blood Vessel ◽  
Vessel Tortuosity

scholarly journals Polymorphisms in Inflammatory and Immune Response Genes Associated with Cerebral Cavernous Malformation Type 1 Severity

2014 ◽  
Vol 38 (6) ◽  
pp. 433-440 ◽  
Author(s):  
Hélène Choquet ◽  
Ludmila Pawlikowska ◽  
Jeffrey Nelson ◽  
Charles E. McCulloch ◽  
Amy Akers ◽  
...  
Keyword(s):  
Immune Response ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Immune Response Genes
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