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. Author manuscript; available in PMC: 2016 Jun 1.
Published in final edited form as: Am J Med Genet A. 2015 Apr 2;167(6):1262–1267. doi: 10.1002/ajmg.a.36936

The ACVRL1 c.314-35A>G Polymorphism is Associated with Organ Vascular Malformations in Hereditary Hemorrhagic Telangiectasia Patients with ENG Mutations, but not in Patients with ACVRL1 Mutations

Ludmila Pawlikowska 1,2, Jeffrey Nelson 1, Diana E Guo 1, Charles E McCulloch 3, Michael T Lawton 4, William L Young 1,4,5,†, Helen Kim 1,2,3, Marie E Faughnan 6,7,*; the Brain Vascular Malformation Consortium HHT Investigator Group‡
PMCID: PMC4449292  NIHMSID: NIHMS683606  PMID: 25847705

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse phenotypes related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a potential role for genetic modifier effects. We hypothesized that the common polymorphisms ACVRL1 c.314-35A>G and ENG c.207G>A, previously associated with sporadic brain AVM, are also associated with organ VM in HHT. We genotyped ACVRL1 c.314-35A>G and ENG c.207G>A in 716 patients with HHT recruited by the Brain Vascular Malformation Consortium and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR=1.48, p=0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR=2.66, p=0.022), but not ACVRL1 (OR=0.79, p=0.52) mutations. ACVRL1 c.314-35A>G was also significantly associated with pulmonary AVM and liver VM among ENG mutation carriers. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM.

Keywords: hereditary hemorrhagic telangiectasia, vascular malformation, arteriovenous malformation, phenotype, genetic modifier

INTRODUCTION

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant Mendelian disorder caused by mutations in several genes encoding proteins in the TGFβ/BMP9 signaling pathway [McDonald et al., 2011]. Approximately 85% of patients with HHT have a mutation in ENG [McAllister et al., 1994] or ACVRL1 [Johnson et al., 1996] and 3% have a mutation in SMAD4 [Gallione et al., 2004]. BMPR2 [Rigelsky et al., 2008] and BMP9 [Wooderchak-Donahue et al., 2013] mutations have been reported in syndromes with phenotypic overlap. Patients with HHT have skin and mucosal telangiectases and vascular malformations (VM), including arteriovenous malformations (AVM), in visceral organs including brain, liver and lung, which can lead to chronic bleeding, anemia, life-threatening hemorrhage, stroke and heart failure[Faughnan et al., 2011; McDonald et al., 2011]. Pulmonary AVM and brain VM are more common in patients with ENG mutations, while liver VM are more common in patients with ACVRL1 mutations [Bayrak-Toydemir et al., 2006; Letteboer et al., 2006]. The considerable clinical heterogeneity of HHT phenotypes, even among patients with the same mutated HHT gene and within families, suggests a possible role for genetic modifier effects.

Two common polymorphisms in HHT genes, ACVRL1 c.314-35A>G (ACVRL1 IVS3-35A>G) and ENG c.207G>A, have been reported to be associated with sporadic brain AVM [Pawlikowska et al., 2005]; the ACVRL1 c.314-35A>G association has been replicated in 2 independent cohorts [Simon et al., 2006]. ENG c.207G>A was also associated with surgical outcomes in sporadic brain AVM [Shen et al., 2014]. We hypothesized that these polymorphisms are also associated with organ VM in HHT and tested this hypothesis in an HHT cohort recruited by the Brain Vascular Malformation Consortium (BVMC) [Akers et al., 2013].

METHODS

Cohort Recruitment

Patients with a confirmed clinical HHT diagnosis by the Curaçao criteria [Faughnan et al., 2011] were enrolled by the BVMC HHT Project as previously described (http://rarediseasesnetwork.epi.usf.edu/BVMC) [Akers et al., 2013]. We analyzed 716 patients enrolled at 11 sites between June 2010 and December 2013. All patients provided written informed consent, including for genetic studies. The study protocol was approved by each institutional review board. Data collected included age, sex, family relationships, genetic testing results (mutated gene: ACVRL1, ENG, SMAD4, unknown), clinical presentation and symptoms. Patients were screened for organ VM and other clinical features according to standard clinical practice and International HHT Guidelines [Faughnan et al., 2011], including: comprehensive history, physical, routine blood tests, screening for pulmonary AVM by contrast echocardiography, brain VM screening by magnetic resonance imaging, clinical screening for liver VM (chronic right upper quadrant pain, portal hypertension, high-output heart failure, liver bruit on examination, abnormal liver function tests) and clinical screening for recurrent spontaneous epistaxis and HHT-related gastrointestinal bleeding. If screening was positive for pulmonary AVM or brain VM, patients underwent further diagnostic imaging and treatment, where appropriate. If clinical assessment was suggestive of symptomatic liver VM, diagnostic imaging was recommended and therapy where appropriate. The BVMC HHT cohort targets 25% brain VM-positive patients; other cohort characteristics are similar to other cohorts [Letteboer et al., 2006; Nishida et al., 2012]. The majority of the cohort is Caucasian (96%) reflecting patient populations at participating centers.

Patients provided blood or saliva (Oragene, DNA Genotek, Ontario, Canada) samples, which were sent for DNA extraction and banking to the NINDS Repository at Coriell Institute (http://ccr.coriell.org/Sections/Collections/NINDS), or to the University of California, San Francisco (UCSF) (saliva).

Genotyping

Genotyping was performed by staff blinded to clinical phenotype. ACVRL1 c.314-35A>G (formerly ACVRL1 IVS3-35A>G, rs2071219) and ENG c.207G>A (rs11545664) were genotyped using Taqman™ assays (C__15868502_10 and C__25592400_10, Applied Biosystems, Foster City, CA). Both SNPs had genotype call rates >98% and were in Hardy Weinberg equilibrium among Caucasians (p>0.05).

Statistical Analysis

Phenotype frequencies were compared by Fisher’s exact test. Genotypes were collapsed for analysis into risk genotype carriers (ACVRL1 c.314-35A>G: AA+AG, ENG c.207G>A: GG) vs. non-carriers [Pawlikowska et al., 2005]. Phenotypes evaluated included pulmonary AVM, liver VM, brain VM and the composite phenotype “any organ VM”, defined as presence of any organ VM or AVM. Association of genotype with phenotype was evaluated by logistic regression analyses adjusted for age, gender and clustering within known families and further stratified by HHT mutation status (ACVRL1 or ENG) for the two most frequently mutated genes. Since liver VM analysis restricted to ENG subjects produced an infinite estimated odds ratio (OR) for ACVRL1 c.314-35A>G, we calculated a one-sided 95% confidence interval (CI) based on the profile likelihood and derived a p-value from the likelihood ratio test comparing models with and without the polymorphism. To ensure familial clustering could be disregarded for this specific analysis, we tested the effect of family with a mixed-effects logistic regression model. The statistical significance threshold was set at p=0.025 after Bonferroni correction for 2 polymorphisms. We also evaluated associations using a co-dominant genetic model testing each genotype compared to the lowest-risk genotype [Pawlikowska et al., 2005], and restricted to Caucasians.

RESULTS

Of 716 patients with HHT studied, 93.7% were Caucasian and 59% were female; 71% had at least one VM of any type, 50% had pulmonary AVM, 20% had liver VM and 20% had brain VM (Table I). Known family relationships were recorded for 177 patients (2–4 patients per family, except for 1 family of 17 distant relatives). Among the 436 (61%) patients with mutation data, 48% had ENG mutations, 43% had ACVRL1 mutations and 4% had SMAD4 mutations (Table I). As reported for other cohorts [Bayrak-Toydemir et al., 2006; Letteboer et al., 2006], patients with ENG mutations were more likely to have any organ VM, brain VM and pulmonary AVM (all p<0.0001), while patients with ACVRL1 mutations were more likely to have liver VM (p<0.0001) and anemia (p=0.003) (Table I). Compared to patients without genetic testing results, patients with ACVRL1 or ENG mutations were more likely to have any organ VM (p=0.002), pulmonary AVM (p<0.0001) and anemia (p=0.001), likely due to more extensive clinical evaluation of patients from multiplex families.

TABLE I.

Demographic and Clinical Characteristics of HHT Subjects

Characteristic All Subjects ACVRL1 ENG P*
Female sex 425 / 716 (59%) 107/189 (57%) 127/211 (60%) 0.48
Age at baseline (y) 46.1 ± 19.1 45.2 ± 21.3 43.1 ± 18.8 0.30
Caucasian 671 / 700 (96%) 180/184 (98%) 201/208 (97%) 0.52
HHT mutation
 ACVRL1 189 / 436 (43%) 189/189 (100%) -
 ENG 211 / 436 (48%) - 211/211 (100%)
 SMAD4 16 / 436 (4%) - -
 All negative 20 / 436 (5%) - -
VM 490 / 689 (71%) 90/181 (50%) 172/209 (82%) <0.001
 Brain VM 140 / 716 (20%) 21/189 (11%) 66/211 (31%) <0.001
 Pulmonary AVM 346 / 690 (50%) 34/183 (19%) 140/208 (67%) <0.001
 Liver VM 138/ 677 (20%) 47/182 (26%) 21/203 (10%) <0.001
Epistaxis 678 / 700 (97%) 177/187 (95%) 201/208 (97%) 0.46
GI Bleeding 115 / 682 (17%) 22/183 (12%) 34/205 (17%) 0.25
Anemia 331 / 675 (49%) 92/180 (51%) 74/206 (36%) 0.003
ACVRL1 c.314-35A>G genotype 0.68
 GG 141 / 716 (20%) 37/189 (20%) 46/211 (22%)
 AG 337 / 716 (47%) 82/189 (43%) 97/211 (46%)
 AA 238 / 716 (33%) 69/189 (37%) 68/211 (32%)
ENG c.207G>A genotype 0.27
 AA 9 / 716 (2%) 6/189 (3%) 3/211 (1%)
 AG 121 / 716 (17%) 34/189 (18%) 30/211 (14%)
 GG 581 / 716 (81%) 149/189 (79%) 178/211 (84%)
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Values are the number observed over the total number of non-missing (and the percent) or mean ± standard deviation.

*

P-values are from comparison of subjects with known ACVRL1 and ENG mutations with Fisher’s exact test or a two-sample t-test. HHT, hereditary hemorrhagic telangiectasia; VM, any HHT organ vascular malformation including: brain VM, pulmonary arteriovenous malformation (AVM) or liver VM; GI, gastro-intestinal.

Among 689 patients with HHT with VM data, neither polymorphism was significantly associated with organ VM, although ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR=1.48, 95%CI=0.90–2.22, p=0.062) and liver VM (OR=1.46, 95%CI=0.85–2.50, p=0.17) (Table II).

TABLE II.

Association of ACVRL1 c.314-35A>G and ENG c.207G>A with VM Phenotypes in Patients with HHT

Outcome SNP All Subjects Subjects with ACVRL1 Mutation Subjects with ENG Mutation
n OR 95% CI p n OR 95% CI p n OR 95% CI p
VM ACVRL1 c.314-35A>G 689 1.34 (0.87, 2.07) 0.178 181 0.79 (0.38, 1.63) 0.520 209 2.66 (1.15, 6.13) 0.022
ENG c.207G>A 689 1.10 (0.70, 1.72) 0.682 181 1.29 (0.57, 2.93) 0.537 209 0.41 (0.12, 1.40) 0.155
Brain VM ACVRL1 c.314-35A>G 716 1.11 (0.68, 1.80) 0.675 189 1.03 (0.33, 3.16) 0.960 211 0.74 (0.36, 1.52) 0.411
ENG c.207G>A 716 1.19 (0.73, 1.93) 0.482 189 3.09 (0.63, 15.1) 0.163 211 0.62 (0.29, 1.32) 0.215
Pulmonary AVM ACVRL1 c.314-35A>G 690 1.48 (0.90, 2.22) 0.062 183 0.57 (0.25, 1.33) 0.192 208 2.45 (1.18, 5.06) 0.016
ENG c.207G>A 690 1.29 (0.86, 1.93) 0.220 183 0.91 (0.36, 2.27) 0.835 208 1.80 (0.86, 3.77) 0.122
Liver VM ACVRL1 c.314-35A>G 677 1.46 (0.85, 2.50) 0.170 182 1.57 (0.65, 3.81) 0.320 203 n/a* (3.10, ∞)* 0.001*
ENG c.207G>A 677 1.05 (0.62, 1.79) 0.856 182 1.17 (0.44, 3.10) 0.758 203 0.55 (0.16, 1.85) 0.332
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Results from multivariable logistic regression analysis for carriers of the risk genotypes adjusted for age, sex and family clustering (except*, see below) are shown. P values meeting the statistical significance threshold (0.025) are in bold.

*

The odds ratio (OR) cannot be determined, because 100% (21/21) of liver VM-positive patients carry the A risk allele, compared to 75% of liver VM-negative patients. We show a one-sided 95% confidence interval (CI) based on the profile likelihood and a p-value from the likelihood ratio test comparing models with and without the polymorphism. A mixed-effects logistic regression model found no estimated family effect; hence, the model was not adjusted for familial clustering. VM, any HHT organ vascular malformation including: brain VM, pulmonary arteriovenous malformation (AVM), liver VM; SNP, single nucleotide polymorphism.

When stratifying by HHT mutation, ACVRL1 c.314-35A>G was significantly associated with organ VM among the 211 ENG mutation carriers (overall: OR=2.66, 95%CI=1.15–6.13, p=0.022; Caucasians: OR=2.83, 95%CI=1.18–6.76, p=0.020), but not among the 189 ACVRL1 mutation carriers (OR=0.79, CI=0.38–1.63, p=0.52). In ENG mutation carriers, ACVRL1 c.314-35A>G was also significantly associated with pulmonary AVM (OR=2.45, p=0.016) and liver VM (p=0.001, all 21 liver VM-positive patients carried the A risk allele), but not with brain VM (Table II). When restricted to Caucasians, all significant associations were consistent (data not shown).

There were no statistically significant associations between ENG c.207G>A and VM of any type. However, among ACVRL1 mutation carriers only, the effect direction was consistent with association of ENG c.207G>A with VM overall (OR=1.29, p=0.5) and with brain VM (OR=3.09, p=0.16) (Table II). Again, no associations with ENG c.207G>A were observed among ENG mutation carriers.

DISCUSSION

We report here the first evidence that common polymorphisms in HHT genes other than the mutated gene are associated with differences in HHT phenotype severity, and specifically presence of organ VM. In a well-characterized cohort of patients with HHT, the common polymorphism ACVRL1 c.314-35A>G, previously reported as associated with sporadic brain AVM [Pawlikowska et al., 2005; Simon et al., 2006] was also associated with pulmonary AVM, liver VM and overall, with presence of any organ VM in patients with ENG mutations, but not in patients with ACVRL1 mutations. Conversely, there was also a pattern, although not statistically significant, for association of the ENG c.207G>A with any VM and brain VM in patients with ACVRL1, but not ENG mutations. These findings suggest that common genetic variation in HHT genes other than the mutated gene may modify HHT phenotype severity.

Common polymorphisms acting as genetic modifiers have been reported in other Mendelian diseases, such as cystic fibrosis [Wright et al., 2011] and there are other reports of phenotype-modifying polymorphisms near the gene that when mutated causes disease: a common polymorphism in KCNQ1, rs2074238, is associated with symptomatic status in patients with long-QT syndrome, who are heterozygous for KCNQ1 or KCNH2 (disease causative) mutations [Duchatelet et al., 2013]; and 2) a common polymorphism in TERT is associated with survival and with disease recurrence in bladder cancer caused by somatic mutations in the TERT promoter [Rachakonda et al., 2013]. In patients with HHT, common variants in PTPN14 and ADAM17, genes in loci originally mapped as phenotype modifiers in TGFβ knockout mice, have been reported to be associated with pulmonary VM [Benzinou et al., 2012; Kawasaki et al., 2014]. These associations have not yet been replicated in independent cohorts.

The association with the common polymorphism ACVRL1 c.314-35A>G was originally reported for sporadic brain AVM in two independent cohorts [Pawlikowska et al., 2005; Simon et al., 2006] and for dural arteriovenous fistulae in one cohort [Simon et al., 2006]. Extension of these associations to organ VMs in HHT suggests common mechanisms of VM development in different organs (brain, lung, liver) in both sporadic and HHT disease.

The functional effects of ACVRL1 c.314-35A>G are unknown. It is located 35 base-pairs from an intron-exon junction and is hypothesized to affect splicing [Pawlikowska et al., 2005]. As with sporadic brain AVM disease, the observed HHT VM association is with the major A allele carried by the majority of patients (GG genotype carriers have fewer VMs). ENG c.207A>G is a synonymous exonic variant, however it is also a cis eQTL linked to ENG mRNA expression in monocytes [Zeller et al., 2010]. Thus both polymorphisms could result in reduced expression or expression of an abnormal protein, further impairing TGFβ/BMP9 pathway signaling.

We acknowledge several limitations of our study. The genetic association results require replication in an independent HHT cohort and functional studies to determine their molecular mechanism. Family relationships (known and cryptic) within the cohort are a confounder; however, the statistical adjustment we used for known relatedness is conservative, and cryptic relationships should be rare. The findings are currently limited to Caucasians, as there are not enough patients of other ethnicities in the BVMC cohort to evaluate the effect in non-Caucasians. The ENG c.207A>G associations did not reach statistical significance and require a larger cohort to confirm or rule out. Unlike for sporadic brain AVM, we found no strong evidence for ACVRL1 c.314-35A>G association with brain VM in HHT, however the number of brain VM-positive patients is small resulting in low statistical power. The prevalence of brain VM in the BVMC cohort is targeted by design (25% planned, 20% observed), but similar (top end of the reported range) to frequencies observed in other HHT cohorts [Letteboer et al., 2006; Nishida et al., 2012]. Screening for liver VM was based on clinical assessment, and therefore the liver VM-positive group includes patients with more severe, clinically evident liver VM, consistent with the overall focus on organ VM involvement as a marker of more severe HHT disease. The strengths of our study include the large size of the HHT cohort and the comprehensive phenotype information collected.

In conclusion, we report for the first time that common polymorphisms in HHT genes other than the mutated gene may modify the HHT phenotype, and that genetic associations previously reported in sporadic brain AVM extend to the Mendelian form of the disease. Our results suggest a multiple-hit mechanism, where diverse genetic hits to multiple HHT genes may predispose to the most severe phenotypic manifestations. The findings provide insights into potential mechanisms underlying the marked clinical heterogeneity of HHT, where some patients suffer from severe VM organ involvement with devastating complications, while others have only skin telangiectases. A better understanding of which patients with HHT are at highest risk of complications would aid in clinical management, risk stratification and therapy development.

Acknowledgments

We gratefully acknowledge all study participants and the staff at the participating clinical centers. This study and the BVMC were supported by National Institutes of Health (NIH) grant U54 NS065705. The BVMC is a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS). MEF was also supported by the Nelson Arthur Hyland Foundation and Li Ka Shing Knowledge Institute. BVMC HHT cohort DNA samples are available to researchers via the NINDS Repository at Coriell Institute: http://ccr.coriell.org/Sections/Collections/NINDS.

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