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

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 that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count. Methods: Hispanic CCM1 patients (n = 188) harboring the founder Q455X ‘common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways. Results: At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean w standard deviation (SD) of 60.1 w 115.0 (range 0-713) for total lesions and 4.9 w 8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE = 0.31), 0.81 (SE = 0.17), and 0.48 (SE = 0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p ≤ 0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p = 0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count. Conclusions: These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sam...

Peripheral Plasma Vitamin D and Non-HDL Cholesterol Reflect the Severity of Cerebral Cavernous Malformation Disease

“…Patients' histories and previously adjudicated relevant disease parameters were obtained during their clinical visit and stored prospectively in a secure database for subsequent analysis [1,9,14].…”

“…A relevant disease biomarker might reflect chronic disease aggressiveness over the patient's lifetime, or more acute clinical activity [3,9,14]. We considered validated features of chronic disease aggressiveness including a history of multiple adjudicated clinically overt hemorrhages, early age of clinical onset or high lesion burden in familial cases.…”

“…Some patients remain asymptomatic, while others are disabled from recurrent bleeds and/or high lesion burden [4]. Early age of lesion onset, multiple hemorrhages and increased lesion burden have been correlated in various studies with chronic disease severity [5][6][7][8][9]. Features of acute disease aggressiveness include clinically overt hemorrhage, CCM lesion growth and the genesis of new lesions [10,11].…”

“…Another study indicated that proinflammatory genotypes [9] and low BMI [14] may be associated with greater aggressiveness of familial CCM cases harboring a common CCM1 muta- Research Article Girard, Khanna, Shenkar et al tion. Additionally, the inflammatory cells and their cytokines are modulated by vitamin D [15].…”

Neurocysticercosis, familial cerebral cavernomas and intracranial calcifications: differential diagnosis for adequate management

“…In the United States, mainly in the State of New Mexico and southwestern regions, there has been described a high frequency of a Common Hispanic Mutation of the gene CCM1/KRIT1 (Q455X, rs 267607203) in families of Mexican heritage up to the point where most insurance companies are paying for its screening 19 . The New Mexico CCM cohort recently reported a study searching for association between inflammatory biomarkers and aggressiveness of the disease, with most patients having multiple lesions and epilepsy as the main symptoms 20 .…”