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(Stroke. 2004;35:2294.)
© 2004 American Heart Association, Inc.

Original Contributions

Polymorphisms in Genes Involved in Inflammatory and Angiogenic Pathways and the Risk of Hemorrhagic Presentation of Brain Arteriovenous Malformations

Ludmila Pawlikowska, PhD; Mary N. Tran, PhD; Achal S. Achrol, BS; Charles E. McCulloch, PhD; Connie Ha, BS; Denise L. Lind, PhD; Tomoki Hashimoto, MD; Jonathan Zaroff, MD; Michael T. Lawton, MD; Douglas A. Marchuk, PhD; Pui-Yan Kwok, MD PhD William L. Young, MD for the UCSF BAVM Study Project

From the Cardiovascular Research Institute (L.P., C.H., D.L.L., P.Y.K.), Departments of Anesthesia and Perioperative Care and Center for Cerebrovascular Research (M.N.T., A.A., T.H., W.L.), Departments of Epidemiology and Biostatistics (C.E.M.), Neurological Surgery (M.T.L.), and Medicine (J.Z.), University of California, San Francisco, Calif; and the Department of Genetics (D.A.M.), Duke University Medical Center, Durham, NC.

Correspondence to Dr William L. Young, UCSF, 1001 Potrero Avenue, Rm3C-38, San Francisco, CA 94110. E-mail ccr{at}anesthesia.ucsf.edu

	Abstract

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Background and Purpose— Accurate estimates of intracranial hemorrhage (ICH) risk in patients harboring brain arteriovenous malformation (BAVM) are needed to evaluate interventional strategies and to help guide clinical management. Identification of genetic polymorphisms associated with ICH would facilitate risk stratification in BAVM patients.

Methods— We identified patients with BAVM and documented clinical presentation, demographic data, venous drainage pattern, and BAVM size. Patients were genotyped for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes. Association of genotype with risk of hemorrhagic BAVM presentation was evaluated using logistic regression analysis.

Results— We genotyped 180 patients with BAVM (53% female, 57% white, mean age at diagnosis 35±17 years, 41% presenting with ICH). BAVM patients homozygous for the interleukin 6 (IL6)–174G allele had a greater risk of ICH presentation (OR, 2.62, P=0.003) than IL6–174C carriers. In a multivariate logistic regression model, IL6–174G>C genotype, small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation. A similar univariate trend was noted for the TNF-308 GG genotype (P=0.055). The other polymorphisms genotyped were not associated with ICH.

Conclusions— A polymorphism in the inflammatory cytokine IL6, but not polymorphisms in angiogenesis-related genes, was associated with ICH presentation of BAVM. Further studies are needed to define the role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage.

Key Words: cerebral hemorrhage • genetic epidemiology • vascular malformations

	Introduction

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Brain arteriovenous malformations (BAVM) are an important cause of hemorrhagic stroke in young adults, but their pathogenesis remains poorly understood.¹ Because of appreciable risk in the interventional treatment of BAVMs, better estimates for intracranial hemorrhage (ICH) risk in patients harboring BAVM would inform selection of interventional strategies. Although BAVM features associated with ICH have been identified,² additional robust and reproducible indices are needed.

Genetic variation may influence the pathogenesis and the clinical course of BAVM. Identification of genetic polymorphisms associated with clinical course would facilitate risk stratification as well as illuminate the underlying biology. Molecular studies of BAVM tissue have revealed an altered expression profile compared with normal tissue, including upregulated expression of genes involved in angiogenesis and inflammation.¹ Based on these clues and on findings in related disorders,^3,4 we hypothesized that polymorphisms in genes implicated in angiogenic or inflammatory pathways may predispose to BAVM vascular instability and be associated with initial clinical presentation with ICH.

We genotyped 14 polymorphisms in genes associated with inflammatory and angiogenic pathways in 180 BAVM patients and examined the association of each genotype with risk of hemorrhagic presentation.

	Materials and Methods

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Subjects
Beginning in June 2000, all patients with BAVM evaluated at the University of California San Francisco (UCSF) who gave informed consent for genotyping had blood samples drawn and were entered into an ongoing prospective registry.⁵

The primary outcome was clinical presentation with ICH, defined as presentation with evidence of hemorrhage as a symptomatic event with signs of new intracranial blood on computed tomography or magnetic resonance imaging. Patients presenting with a seizure, focal ischemic deficit, or headache without any imaging evidence of hemorrhage, or patients in whom BAVM was detected during evaluation of unrelated symptoms, were coded as unruptured.

Demographic and clinical characteristics, including BAVM size and venous drainage pattern, were taken from the UCSF BAVM registry, as previously described.^5,6

Polymorphism Selection
Polymorphisms in the coding regions or promoters of genes implicated in inflammatory (IL6, IL10, TNF) and angiogenic (ANGPT2, FLT4, KDR, VEGF) pathways were selected for analysis based on literature review and sequence database searches (Unigene and dbSNP). The rationale for selection of each polymorphism is shown in Table 1. The TIE2 gene (coding exons flanked by at least 10 base pairs of intronic sequence and 1300 base pairs of the promoter) was sequenced in 26 anonymous control individuals (52 alleles) to identify common polymorphisms. One polymorphism resulting in an amino acid substitution and 2 promoter polymorphisms altering predicted transcription factor binding sites were identified (Transcription Element Search System, http://www.cbil.upenn.edu/tess) and selected for genotyping (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Functional Rationale for Polymorphism Selection.

Genotyping
Genomic DNA was extracted from peripheral blood lymphocytes using a salt modification method (Gentra Systems). Polymorphism-spanning fragments were amplified by the polymerase chain reaction (PCR) and genotyped by template-directed dye-terminator incorporation assay with fluorescence polarization detection,⁷ using the AcycloPrime-FP kit (Perkin-Elmer). Plates were read on the En- Vision fluorescence polarization plate reader (Perkin-Elmer). We used published PCR primer sequences for ANGPT2 G735A, VEGF-2578C>A, and IL6-572G>C,^8–10 and designed primers for other assays. PCR conditions and primer sequences are shown in Table I, available online at http://www.strokeaha.org. Genotyping was performed by investigators blinded to clinical status.

Statistical Analysis
Each polymorphism genotyped was coded as a dichotomous variable (most frequent homozygous genotype versus other) and tested for association with hemorrhagic presentation using ². Uncorrected probability values are reported in Table 2; significance levels were adjusted for multiple testing using the Bonferroni correction within the inflammatory and angiogenic functional groups; adjusted significance level is reported only for the significant association. The polymorphism found to have a significant association with ICH presentation, IL6–174G>C, was selected for logistic regression, controlling for age, race and sex, analysis to estimate prediction of BAVM hemorrhage risk. Adherence of genotype distribution to Hardy-Weinberg equilibrium was tested by ² in the full cohort and also in the largest ethnic subgroup (white).

View this table: [in this window] [in a new window]   TABLE 2. Association of Mode of BAVM Presentation With Demographic and BAVM Characteristics and With Polymorphisms in Genes Related to Inflammation and Angiogenesis

	Results

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Table 2 shows the demographic and BAVM characteristics and genotypes of the study cohort. Of the 180 patients genotyped, 40.6% presented with hemorrhage and 59.4% with unruptured BAVM. ICH presentation was not significantly associated with race/ethnicity or gender, but was associated with age at diagnosis (t test, P=0.048), exclusively deep venous drainage (², P<0.001), and small BAVM size (², P=0.005), as previously reported.²

Of the 14 polymorphisms genotyped, six (IL6–174G>C and IL6–572G>C, FLT4 3437G>A, KDR 1174T>C, TIE2–126InsG and TIE2–571G>T) were not in Hardy-Weinberg equilibrium in the full cohort (P<0.05). Within the largest race/ethnic subcohort (whites), all but 1 of these 6 variants (KDR 1174T>C, a very rare variant) were in equilibrium. These results suggest that ethnic stratification and small sample size likely explain the departures from Hardy-Weinberg equilibrium within the ethnically diverse study cohort.

The GG genotype of the IL6–174G>C polymorphism was significantly associated with ICH presentation: (², uncorrected P=0.003); this association survived correction for multiple testing within the inflammatory functional group (adjusted significance threshold: P=0.01). IL6–174C minor allele frequency was lower in patients presenting with hemorrhage than in patients with unruptured BAVM (0.19 versus 0.34, ² P=0.003). The association of the TNF-308G>A polymorphism with ICH presentation did not reach significance (uncorrected P=0.055). TNF–308A minor allele frequency was lower in patients presenting with ICH than in patients with unruptured BAVM (0.065 versus 0.13, ², P=0.07). ICH presentation was not significantly associated with any polymorphisms in angiogenesis-related genes.

We genotyped 2 IL6 promoter polymorphisms; unlike IL6–174G>C, the more distal IL6–572G>C polymorphisms was not itself significantly associated with ICH presentation. However, the 2 polymorphisms were associated with each other among unruptured (², P=0.001) and hemorrhagic (², P=0.01) cases.

We evaluated the association of the IL6–174G>C variant with demographic and BAVM characteristics (Table 3). Exclusively deep venous drainage was associated with hemorrhagic presentation regardless of IL6–174G>C genotype (C carriers, P=0.031; GG, P=0.001). BAVM size was significantly associated with ICH presentation in IL6–174 GG homozygotes (P=0.004) but not in C carriers (P=0.65). IL6–174G>C genotype was not significantly associated with TNF–308G>A genotype.

View this table: [in this window] [in a new window]   TABLE 3. Association of IL6–174G>C Genotype With Demographic and BAVM Characteristics, and With TNF–308G>A Genotype

In univariate logistic regression analysis, risk of ICH presentation was increased for patients with IL6–174 GG genotype, small BAVM size, and exclusively deep venous drainage (Table 4). In multivariate analysis, controlling for age, gender, and race/ethnicity, IL6–174 GG genotype (OR, 2.43; CI, 1.04 to 5.68), small BAVM size (OR, 2.36; CI, 1.12 to 4.96), and exclusively deep venous drainage (OR, 5.01; CI, 1.64 to 15.3) remained significant predictors of hemorrhagic presentation (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Impact of IL6–174G>C Genotype, BAVM Size and Type of Venous Drainage on Risk of Hemorrhagic Presentation

View this table: [in this window] [in a new window]   TABLE I. Oligonucleotide Primer Sequences for PCR Amplification and TDI Genotyping

	Discussion

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We describe here the first demonstration of an association between genotype and clinical behavior of BAVMs. The GG genotype of the IL6–174G>C promoter polymorphism is associated with an almost 3-fold increase in risk of presentation with ICH. Thus, patients carrying the C allele appear protected.

The multifunctional cytokine IL6 is produced by many tissues, including endothelium, and is a key mediator of the acute phase inflammatory response. IL6 expression is regulated largely at the level of transcription.¹¹ Promoter constructs containing the IL6–174G allele showed higher stimulated activity in vitro.^12,13 Because this activity was cell-type-dependent, its physiological significance is unclear, given that promoter function in vivo depends on extended DNA sequence context and chromatin structure.

In vivo studies of the effect of IL6–174G>C genotype on systemic IL6 levels and inflammatory phenotypes have yielded controversial results. In apparent contradiction to in vitro findings, patients with abdominal aortic aneurysms and the GG genotype had lower plasma IL6 levels and reduced cardiovascular mortality from small aneurysms.¹⁴ Similarly, peak IL6 levels after coronary bypass surgery were lower in GG patients than in C carriers.¹⁰ The IL6–174C allele was found to be associated with susceptibility to myocardial infarction¹⁵ and with impaired endothelial function.¹⁶ Conversely, other studies found the IL6–174 GG genotype to be associated with higher postoperative IL6 levels and inferior coronary bypass outcomes,¹⁷ increased intima-media thickness of the carotid arterial wall (a measure of systemic asymptomatic atherosclerosis),¹⁸ history of ischemic stroke,¹⁹ and with peripheral artery occlusive disease.²⁰ Among stroke patients, IL6–174G-containing haplotypes were associated with higher systemic serum IL6 levels, as well as with higher stimulated IL6 transcription in vitro.²¹

The association of the IL6–174 GG genotype with BAVM hemorrhagic presentation implicates inflammatory processes in the cause of BAVM rupture. Cytokines mediate induction of matrix metalloproteinases (MMP), which degrade extracellular matrix around blood vessels and can damage endothelial cells;²² MMP9 has been found to be abnormally expressed in BAVMs.¹ Local IL6 release by endothelial cells within the BAVM nidus may therefore contribute to vascular wall instability by stimulating release and activation of MMP.^23,24 If the IL6–174G allele increases local IL6 production, then BAVM hemorrhage may result from MMP-mediated weakening of the vascular wall already compromised by hemodynamic stress.

Alternatively, if, as suggested by some studies, the IL6–174G allele is associated with less vigorous IL6 response, these results raise the intriguing possibility that BAVM hemorrhage might be related to the inability to mount a successful inflammatory response to an inciting event that challenges the vascular wall. Elucidation of the specific mechanistic impact of the IL6–174GG genotype on BAVM biology requires investigation of IL6 expression and localization in BAVM endothelium and in neighboring normal tissue via immunocytochemistry, as well as correlation of in situ IL6, TNF, and MMP expression patterns.

In vitro and in vivo studies suggest that cooperative interactions among 4 promoter polymorphisms influence IL6 expression.^13,21 The controversy over which IL6–174G>C allele predisposes to enhanced inflammatory response suggests that examination of the entire haplotype may illuminate in vivo function, and also that IL6–174G>C may be in strong linkage disequilibrium with a functional polymorphism elsewhere in the gene. Although only 1 of the 2 IL6 promoter polymorphisms examined showed association with ICH presentation, follow-up evaluation of the full IL6 haplotype in a larger BAVM cohort is needed.

The suggestive but not significant association of hemorrhagic BAVM presentation with the GG genotype of the TNF–308G>A promoter variant may further implicate inflammatory pathways in BAVM hemorrhage etiology. The TNF–308A allele has been associated with higher promoter activity in vitro,²⁵ and with greater left ventricular mass index in hypertrophic cardiomyopathy.²⁶ In our study, TNF–308A carriers presented less often with hemorrhage, suggesting that the higher-expression A allele is protective, and that polymorphisms in more than one inflammatory cytokine gene may produce clinically relevant changes in vascular behavior.

Although we detected no association of hemorrhagic BAVM presentation with polymorphisms in genes implicated in angiogenesis, this survey was not exhaustive; evaluation of additional polymorphisms in angiogenesis-related genes remains an active area of investigation. Furthermore, a much larger study cohort would be required to achieve the power to detect significant associations with very rare variants.

The association between genetic polymorphisms and BAVM hemorrhage raises the possibility that, in the future, once genetic association results are confirmed by functional studies, genotyping could individualize assessment of a patient’s BAVM rupture risk. In conjunction with natural history data, genetic information may eventually facilitate evaluation of the relative risks of conservative management versus surgical or radiosurgical intervention.

	Acknowledgments

 
The following members of the UCSF BAVM Study Project assisted with data collection or analysis: N. J. Quinnine, RN; R.T. Higashida, MD; C. F. Dowd, MD; V. V. Halbach, MD; Manju Chopra, MD; Thomas Chaly, BS; S. C. Johnston, MD, PhD; Yongmei Chen, PhD; and G. Y. Yang, MD, PhD. The authors thank Carroll Schreibman, Broderick Belenson, and the UCSF Brain Arteriovenous Malformation Study Project (http://avm.ucsf.edu), and Henry Matallana and the UCSF DNA Bank. Supported in part by PHS grants RO1 NS34949, K24 NS02091, and P01 NS44155 (W.L.Y.).

Received April 19, 2004; revision received May 27, 2004; accepted June 16, 2004.

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This Article Abstract Full Text (PDF) All Versions of this Article: 35/10/2294    most recent 01.STR.0000141932.44613.b1v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pawlikowska, L. Search for Related Content PubMed PubMed Citation Articles by Pawlikowska, L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Substance via MeSH Medline Plus Health Information Arteriovenous Malformations Related Collections Other Vascular biology Angiogenesis Acute Cerebral Hemorrhage Genetics of Stroke