Abstract Background and aims: Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C). The magnitude of atherosclerotic cardiovascular disease (ASCVD) risk in FH patients is highly variable, and this can result from genetic factors. The aim of our study was to characterize whether polymorphisms in VEGFR2 and OPG genes could influence the expression of ASCVD in FH patients. Methods: We studied 318 FH patients from the SAFEHEART registry, without clinical diagnosis of ASCVD. A coronary tomographic angiography (CTA) was performed to determine and evaluate the presence of coronary stenosis and coronary artery calcium, as measured by coronary calcium score (CCS). Genotyping of OPG rs2073618 and VEGFR2 rs2071559 polymorphisms was performed using TaqMan 5´-exonuclease allelic discrimination assays. Results: Homozygous GG genotype and G allele of VEGFR2 rs2071559 polymorphism were associated with decreased risk of developing coronary artery stenosis. In the analysis of the OPG rs2073618 and VEGFR2 rs2071559 polymorphisms, according to the presence of coronary artery calcium, we found significant differences in both polymorphisms. Homozygous GG genotype and G allele of VEGFR2 rs2071559 polymorphism were associated with decreased risk of accumulation of coronary artery calcium measured by CCS in CTA. Moreover, being a carrier of the GG genotype and G allele of the OPG rs2073618 polymorphism increased the risk of the presence of coronary artery calcium measured by CCS in CTA. Conclusions: Polymorphisms in VEGFR2 and OPG genes modify the risk of ASCVD in FH patients.
Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015 Dec 1;132(22):2167–92.
Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet. 1969 Dec 27;2(7635):1380–2.
Hutter CM, Austin MA, Humphries SE. Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview. Am J Epidemiol. 2004 Sep 1;160(5):430–5.
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013 Dec;34(45):3478–3490a.
Jansen ACM, van Wissen S, Defesche JC, Kastelein JJP. Phenotypic variability in familial hypercholesterolaemia: an update. Curr Opin Lipidol. 2002 Apr;13(2):165–71.
Alonso R, Andres E, Mata N, Fuentes-Jiménez F, Badimón L, López-Miranda J, et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014 May 20;63(19):1982–9.
Pimstone SN, Sun XM, du Souich C, Frohlich JJ, Hayden MR, Soutar AK. Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):309–15.
Pérez de Isla L, Alonso R, Mata N, Saltijeral A, Muñiz O, Rubio-Marin P, et al. Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study). Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):2004–10.
Pérez de Isla L, Alonso R, Muñiz-Grijalvo O, Díaz-Díaz JL, Zambón D, Miramontes JP, et al. Coronary computed tomographic angiography findings and their therapeutic implications in asymptomatic patients with familial hypercholesterolemia. Lessons from the SAFEHEART study. J Clin Lipidol. 2018 Apr 17;
Mata N, Alonso R, Badimón L, Padró T, Fuentes F, Muñiz O, et al. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids Health Dis. 2011 Jun 10;10:94.
Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005 Sep 20;112(12):1813–24.
Ylä-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol. 2007 Mar 13;49(10):1015–26.
Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998 Nov 13;273(46):30336–43.
Howell WM, Ali S, Rose-Zerilli MJ, Ye S. VEGF polymorphisms and severity of atherosclerosis. J Med Genet. 2005 Jun;42(6):485–90.
Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, et al. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007 Aug 21;50(8):760–7.
Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, et al. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation. 2002 Sep 3;106(10):1192–4.
Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004 May 11;109(18):2175–80.
Rhee E-J, Lee W-Y, Kim S-Y, Kim B-J, Sung K-C, Kim B-S, et al. Relationship of serum osteoprotegerin levels with coronary artery disease severity, left ventricular hypertrophy and C-reactive protein. Clin Sci. 2005 Mar;108(3):237–43.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997 Apr 18;89(2):309–19.
Hofbauer LC, Schoppet M. Osteoprotegerin: a link between osteoporosis and arterial calcification? Lancet. 2001 Jul 28;358(9278):257–9.
Shimamura M, Nakagami H, Osako MK, Kurinami H, Koriyama H, Zhengda P, et al. OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice. Proc Natl Acad Sci USA. 2014 Jun 3;111(22):8191–6.
Pérez de Isla L, Alonso R, Mata N, Fernández-Pérez C, Muñiz O, Díaz-Díaz JL, et al. Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation. 2017 May 30;135(22):2133–44.
Schleinitz D, Distefano JK, Kovacs P. Targeted SNP genotyping using the TaqMan® assay. Methods Mol Biol. 2011;700:77–87.
Zhang W, Sun K, Zhen Y, Wang D, Wang Y, Chen J, et al. VEGF receptor-2 variants are associated with susceptibility to stroke and recurrence. Stroke. 2009 Aug;40(8):2720–6.
Chung CP, Solus JF, Oeser A, Li C, Raggi P, Smith JR, et al. A variant in the osteoprotegerin gene is associated with coronary atherosclerosis in patients with rheumatoid arthritis: results from a candidate gene study. Int J Mol Sci. 2015 Feb 11;16(2):3885–94.
Taher M, Nakao S, Zandi S, Melhorn MI, Hayes KC, Hafezi-Moghadam A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2. FASEB J. 2016;30(7):2490–9.
Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001 Apr;7(4):425–9.
Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2054–61.
Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001 Dec;142(12):5050–5.
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998 May 1;12(9):1260–8.
Adamczyk T, Mizia-Stec K, Mizia M, Haberka M, Chmiel A, Chudek J, et al. Biomarkers of calcification and atherosclerosis in patients with degenerative aortic stenosis in relation to concomitant coronary artery disease. Pol Arch Med Wewn. 2012;122(1–2):14–21.
Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B, Hofbauer LC. Increased osteoprotegerin serum levels in men with coronary artery disease. J Clin Endocrinol Metab. 2003 Mar;88(3):1024–8.