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G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation

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Abstract

Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic central nervous system angiogenesis; thus, we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ 2 analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of three GPR124 SNPs adjacent to exon 2 and localized to a 16-kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P = 0.001; rs7823249 T, P = 0.014; rs12676965 C, P = 0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P = 0.033). Haplotype analysis revealed a significant overall association (χ 2 = 12.55, 4 degrees of freedom, P = 0.014); two haplotypes (ATCC, P = 0.006 and GGCT, P = 0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2; however, genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel insertion/deletion polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.

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Abbreviations

BAVM:

Brain arteriovenous malformation

CI:

Confidence interval

CNS:

Central nervous system

df :

Degrees of freedom

ENG:

Endoglin

GPCR:

G protein-coupled receptor

GPR124:

G protein-coupled receptor 124

HHT:

Hereditary hemorrhagic telangiectasia

HWE:

Hardy–Weinberg equilibrium

ICH:

Intracranial hemorrhage

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

OR:

Odds ratio

PCR:

Polymerase chain reaction

SNP:

Single nucleotide polymorphism

STA:

Superficial temporal artery

TEM5:

Tumor endothelial marker 5

TGF-β:

Transforming growth factor beta

VEGF:

Vascular endothelial growth factor

References

  1. Choi JH, Mohr JP. Brain arteriovenous malformations in adults. Lancet Neurol. 2005;4(5):299–308.

    Article  PubMed  Google Scholar 

  2. Fleetwood IG, Steinberg GK. Arteriovenous malformations. Lancet. 2002;359(9309):863–73.

    Article  PubMed  Google Scholar 

  3. Rost NS, Greenberg SM, Rosand J. The genetic architecture of intracerebral hemorrhage. Stroke. 2008;39(7):2166–73.

    Article  PubMed  Google Scholar 

  4. Kim H, Marchuk DA, Pawlikowska L, Chen Y, Su H, Yang GY, et al. Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations. Acta Neurochir Suppl. 2008;105:199–206.

    Article  PubMed  CAS  Google Scholar 

  5. Weinsheimer S, Kim H, Pawlikowska L, Chen Y, Lawton MT, Sidney S, et al. EPHB4 gene polymorphisms and risk of intracranial hemorrhage in patients with brain arteriovenous malformations. Circ Cardiovasc Genet. 2009;2(5):476–82.

    Article  PubMed  CAS  Google Scholar 

  6. Kim H, Hysi PG, Pawlikowska L, Poon A, Burchard EG, Zaroff JG, et al. Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis. 2009;27(2):176–82.

    Article  PubMed  CAS  Google Scholar 

  7. Stapleton CJ, Armstrong DL, Zidovetzki R, Liu CY, Giannotta SL, Hofman FM. Thrombospondin-1 modulates the angiogenic phenotype of human cerebral arteriovenous malformation endothelial cells. Neurosurgery. 2011;68(5):1342–53.

    PubMed  Google Scholar 

  8. Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, et al. VEGF induces more severe cerebrovascular dysplasia in Endoglin+/− than in Alk1+/− mice. Transl Stroke Res. 2010;1(3):197–201.

    Article  PubMed  CAS  Google Scholar 

  9. Walker EJ, Su H, Shen F, Choi EJ, Oh SP, Chen G, et al. Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol. 2011;69(6):954–62.

    Article  PubMed  CAS  Google Scholar 

  10. Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl. 2011;111:83–92.

    Article  PubMed  Google Scholar 

  11. Mikhak B, Weinsheimer S, Pawlikowska L, Poon A, Kwok PY, Lawton MT, et al. Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovasc Dis. 2011;31(4):338–45.

    Article  PubMed  CAS  Google Scholar 

  12. Chen Y, Pawlikowska L, Yao JS, Shen F, Zhai W, Achrol AS, et al. Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol. 2006;59(1):72–80.

    Article  PubMed  CAS  Google Scholar 

  13. Fontanella M, Rubino E, Crobeddu E, Gallone S, Gentile S, Garbossa D, et al. Brain arteriovenous malformations are associated with interleukin-1 cluster gene polymorphisms. Neurosurgery. 2012;70(1):12–7.

    Article  PubMed  Google Scholar 

  14. ZhuGe Q, Zhong M, Zheng W, Yang GY, Mao X, Xie L, et al. Notch1 signaling is activated in brain arteriovenous malformation in humans. Brain. 2009;132(Pt 12):3231–41.

    Article  PubMed  Google Scholar 

  15. Chen Y, Xu B, Arderiu G, Hashimoto T, Young WL, Boudreau NJ, et al. Retroviral delivery of homeobox d3 gene induces cerebral angiogenesis in mice. J Cereb Blood Flow Metab. 2004;24(11):1280–7.

    Article  PubMed  CAS  Google Scholar 

  16. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55–60.

    Article  PubMed  CAS  Google Scholar 

  17. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87(7):1161–9.

    Article  PubMed  CAS  Google Scholar 

  18. Hashimoto T, Wu Y, Lawton MT, Yang GY, Barbaro NM, Young WL. Co-expression of angiogenic factors in brain arteriovenous malformations. Neurosurgery. 2005;56(5):1058–65.

    PubMed  Google Scholar 

  19. Sandalcioglu IE, Wende D, Eggert A, Muller D, Roggenbuck U, Gasser T, et al. Vascular endothelial growth factor plasma levels are significantly elevated in patients with cerebral arteriovenous malformations. Cerebrovasc Dis. 2006;21(3):154–8.

    Article  PubMed  CAS  Google Scholar 

  20. Sandalcioglu IE, Asgari S, Wende D, van de Nes JA, Dumitru CA, Zhu Y, et al. Proliferation activity is significantly elevated in partially embolized cerebral arteriovenous malformations. Cerebrovasc Dis. 2010;30(4):396–401.

    Article  PubMed  Google Scholar 

  21. Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J, Ferretti M, et al. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis. 2010;13(3):259–67.

    Article  PubMed  CAS  Google Scholar 

  22. Kuhnert F, Mancuso MR, Shamloo A, Wang HT, Choksi V, Florek M, et al. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science. 2010;330(6006):985–9.

    Article  PubMed  CAS  Google Scholar 

  23. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, et al. Genes expressed in human tumor endothelium. Science. 2000;289(5482):1197–202.

    Article  PubMed  CAS  Google Scholar 

  24. Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, St Croix B. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res. 2001;61(18):6649–55.

    PubMed  CAS  Google Scholar 

  25. Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR, Dominguez MG, et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc Natl Acad Sci U S A. 2011;108(7):2807–12.

    Article  PubMed  CAS  Google Scholar 

  26. Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J, Yang MY, et al. GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood–brain barrier. Proc Natl Acad Sci U S A. 2011;108(14):5759–64.

    Article  PubMed  CAS  Google Scholar 

  27. Kim H, Sidney S, McCulloch CE, Poon KY, Singh V, Johnston SC, et al. Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke. 2007;38(9):2430–7.

    Article  PubMed  Google Scholar 

  28. Halim AX, Singh V, Johnston SC, Higashida RT, Dowd CF, Halbach VV, et al. Characteristics of brain arteriovenous malformations with coexisting aneurysms: a comparison of two referral centers. Stroke. 2002;33(3):675–9.

    Article  PubMed  Google Scholar 

  29. Achrol AS, Pawlikowska L, McCulloch CE, Poon KY, Ha C, Zaroff JG, et al. Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations. Stroke. 2006;37(1):231–4.

    Article  PubMed  CAS  Google Scholar 

  30. Atkinson RP, Awad IA, Batjer HH, Dowd CF, Furlan A, Giannotta SL, et al. Reporting terminology for brain arteriovenous malformation clinical and radiographic features for use in clinical trials. Stroke. 2001;32(6):1430–42.

    Article  PubMed  CAS  Google Scholar 

  31. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83(2):273–80.

    Article  PubMed  CAS  Google Scholar 

  32. de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D. Efficiency and power in genetic association studies. Nat Genet. 2005;37(11):1217–23.

    Article  PubMed  Google Scholar 

  33. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.

    Article  PubMed  CAS  Google Scholar 

  34. Hsu TM, Kwok PY. Homogeneous primer extension assay with fluorescence polarization detection. Methods Mol Biol. 2003;212:177–87.

    PubMed  CAS  Google Scholar 

  35. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.

    Article  PubMed  CAS  Google Scholar 

  36. Cavalli-Sforza LL, Bodmer WF. The genetics of human populations. Mineola: Dover; 1999.

    Google Scholar 

  37. Lunetta KL. Genetic association studies. Circulation. 2008;118(1):96–101.

    Article  PubMed  Google Scholar 

  38. Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S, editors. Bioinformatics methods and protocols: methods in molecular biology. Totowa: Humana; 2000. p. 365–86.

    Google Scholar 

  39. Orom UA, Shiekhattar R. Noncoding RNAs and enhancers: complications of a long-distance relationship. Trends Genet. 2011;27(10):433–9.

    Article  PubMed  CAS  Google Scholar 

  40. Vallon M, Essler M. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin alpha(v)beta3 to glycosaminoglycans. J Biol Chem. 2006;281(45):34179–88.

    Article  PubMed  CAS  Google Scholar 

  41. Vallon M, Rohde F, Janssen KP, Essler M. Tumor endothelial marker 5 expression in endothelial cells during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of cell proliferation. Exp Cell Res. 2010;316(3):412–21.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank the patients who participated in this study and members of the Brain AVM Project for the assistance with patient recruitment, technical support, and data management. This study was supported by National Institutes of Health grants: K23 NS058357 (HK), R01 NS034949 (WLY), P01 NS044155 (WLY), R01 NS064517 (CJK), R01 NS052830 (CJK), and T32 GM008440 (SW); American Heart Association Western States Affiliate Post-doctoral Fellowship 10POST3640020 (SW) and Pre-doctoral Fellowship (MRM); Sarnoff Foundation Research Fellowship (ADB); and Medical Scientist Training Program at Stanford University (MRM). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94110, USA

    Shantel Weinsheimer, Ludmila Pawlikowska, William L. Young & Helen Kim

  2. Department of Medicine, Harvard Medical School, and Cardiology Division, Massachusetts General Hospital, Boston, MA, USA

    Ari D. Brettman

  3. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    Ludmila Pawlikowska

  4. Department of Medicine, Hematology Division, Stanford University, Stanford, CA, USA

    D. Christine Wu, Michael R. Mancuso, Frank Kuhnert & Calvin Kuo

  5. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    Michael T. Lawton & William L. Young

  6. Division of Research, Kaiser Permanente Medical Care Program of Northern California (KPNC), Oakland, CA, USA

    Stephen Sidney & Jonathan G. Zaroff

  7. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

    Charles E. McCulloch & Helen Kim

  8. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    William L. Young

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  1. Shantel Weinsheimer
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  2. Ari D. Brettman
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  12. Calvin Kuo
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  13. Helen Kim
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Correspondence to Helen Kim.

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Weinsheimer, S., Brettman, A.D., Pawlikowska, L. et al. G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation. Transl. Stroke Res. 3, 418–427 (2012). https://doi.org/10.1007/s12975-012-0202-9

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