Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism

Abrar Ahmad; Kristina Sundquist; Bengt Zöller; Björn Dahlbäck; Peter J. Svensson; Jan Sundquist; Ashfaque A. Memon

doi:10.1160/TH16-03-0178

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(03): 432-441
DOI: 10.1160/TH16-03-0178

Coagulation and Fibrinolysis

Schattauer GmbH

Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism

Abrar Ahmad

¹Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Skåne University Hospital, Malmö, Sweden

,

Kristina Sundquist

¹Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Skåne University Hospital, Malmö, Sweden

,

Bengt Zöller

¹Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Skåne University Hospital, Malmö, Sweden

,

Björn Dahlbäck

²Department of Translational Medicine, Skåne University Hospital, Lund University, Sweden

,

Peter J. Svensson

³Department of Coagulation Disorders, Skåne University Hospital, Lund University, Sweden

,

Jan Sundquist

¹Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Skåne University Hospital, Malmö, Sweden

,

Ashfaque A. Memon

¹Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Skåne University Hospital, Malmö, Sweden

› Author Affiliations

Abstract

Summary

Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger’s sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03–2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Apolipoprotein M - recurrent VTE - multivariate analysis

Full Text

References

References
1 Oger E.. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000; 83: 657-660.
2 Heit JA, Mohr DN, Silverstein MD. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160: 761-768.
3 Tapson VF.. Acute pulmonary embolism. N Engl J Med 2008; 358: 1037-1052.
4 Naess IA, Christiansen SC, Romundstad P. et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5: 692-699.
5 Mason C.. Venous thromboembolism: a chronic illness. J Cardiovasc Nursing 2009; 24 (Suppl. 06) S4-7.
6 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
7 Eischer L, Eichinger S, Kyrle PA.. Age at first venous thromboembolism and risk of recurrence: a prospective cohort study. Medicine 2009; 88: 366-370.
8 Kyrle PA, Eichinger S.. Deep vein thrombosis. Lancet 2005; 365: 1163-1174.
9 Carrier M, Le Gal G, Wells PS. et al. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152: 578-589.
10 Kyrle PA, Rosendaal FR, Eichinger S.. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376: 2032-2039.
11 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67: 1452-1459.
12 Larsen TB, Sorensen HT, Skytthe A. et al. Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins. Epidemiology 2003; 14: 328-332.
13 Heit JA, Phelps MA, Ward SA. et al. Familial segregation of venous thromboembolism. J Thromb Haemost 2004; 2: 731-736.
14 Sundquist K, Sundquist J, Svensson PJ. et al. Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study. J Thromb Haemost 2015; 13: 2180-2186.
15 Memon AA, Sundquist J, Zoller B. et al. Apolipoprotein M and the risk of unprovoked recurrent venous thromboembolism. Thromb Res 2014; 133: 322-326.
16 Sveinsdottir SV, Saemundsson Y, Isma N. et al. Evaluation of recurrent venous thromboembolism in patients with Factor V Leiden mutation in heterozygous form. Thromb Res 2012; 130: 467-471.
17 Ho WK, Hankey GJ, Quinlan DJ. et al. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166: 729-736.
18 Tsai AW, Cushman M, Rosamond WD. et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636-642.
19 Miller NE.. HDL metabolism and its role in lipid transport. Eur Heart J 1990; 11 (Suppl H) 1-3.
20 Deguchi H, Pecheniuk NM, Elias DJ. et al. High-density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation 2005; 112: 893-899.
21 Eichinger S, Pecheniuk NM, Hron G. et al. High-density lipoprotein and the risk of recurrent venous thromboembolism. Circulation 2007; 115: 1609-1614.
22 Chamberlain AM, Folsom AR, Heckbert SR. et al. High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE). Blood 2008; 112: 2675-2680.
23 Xu N, Dahlback B.. A novel human apolipoprotein (apoM). J Biol Chem 1999; 274: 31286-31290.
24 Dahlback B, Nielsen LB.. Apolipoprotein M--a novel player in high-density lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol 2006; 17: 291-295.
25 Wolfrum C, Poy MN, Stoffel M.. Apolipoprotein M is required for prebeta-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis. Nat Med 2005; 11: 418-422.
26 Christoffersen C, Jauhiainen M, Moser M. et al. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipopro-tein receptor knock-out mice. J Biol Chem 2008; 283: 1839-1847.
27 Borup A, Christensen PM, Nielsen LB. et al. Apolipoprotein M in lipid metabolism and cardiometabolic diseases. Curr Opin Lipidol 2015; 26: 48-55.
28 Niu N, Zhu X, Liu Y. et al. Single nucleotide polymorphisms in the proximal promoter region of apolipoprotein M gene (apoM) confer the susceptibility to development of type 2 diabetes in Han Chinese. Diabetes Metab Res Rev 2007; 23: 21-25.
29 Jiao GQ, Yuan ZX, Xue YS. et al. A prospective evaluation of apolipoprotein M gene T-778C polymorphism in relation to coronary artery disease in Han Chinese. Clin Biochem 2007; 40: 1108-1112.
30 Xu WW, Zhang Y, Tang YB. et al. A genetic variant of apolipoprotein M increases susceptibility to coronary artery disease in a Chinese population. Clin Exp Pharmacol Physiol 2008; 35: 546-551.
31 Isma N, Svensson PJ, Gottsater A. et al. Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmo Thrombophilia Study (MATS). Thromb Res 2009; 124: 663-666.
32 Ahmad A, Sundquist K, Zoller B. et al. Thrombomodulin gene c.1418C>T polymorphism and risk of recurrent venous thromboembolism. J Thromb Thrombol. 2016 Epub ahead of print.
33 Ye J, Coulouris G, Zaretskaya I. et al. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinform 2012; 13: 134.
34 Sanger F, Nicklen S, Coulson AR.. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 1977; 74: 5463-5467.
35 Francis Jr. RB, Seyfert U.. Rapid amidolytic assay of protein C in whole plasma using an activator from the venom of Agkistrodon contortrix. Am J Clin Pathol 1987; 87: 619-625.
36 Giri TK, Hillarp A, Hardig Y. et al. A new direct, fast and quantitative enzyme-linked ligandsorbent assay for measurement of free protein S antigen. Thromb Haemost 1998; 79: 767-772.
37 Odegard OR, Lie M, Abildgaard U.. Heparin cofactor activity measured with an amidolytic method. Thromb Res 1975; 6: 287-294.
38 Huang Y, Liu Y, Jiang L. et al. Apolipoprotein m (APOM) levels and APOM rs805297 G/T polymorphism are associated with increased risk of rheumatoid arthritis. Joint Bone Spine 2014; 81: 32-36.
39 Zhao D, He Z, Qin X. et al. Association of apolipoprotein M gene polymorphisms with ischemic stroke in a Han Chinese population. J Mol Neuroscience 2011; 43: 370-375.
40 Cao B, Ye YZ, Rui J. et al. A single-nucleotide polymorphism in the proximal promoter region of the apolipoprotein M gene is associated with dyslipidaemia but not increased coronary artery diseases in Chinese populations. Lipids Health Dis 2013; 12: 184.
41 Zheng L, Luo G, Zhang J. et al. Decreased activities of apolipoprotein m promoter are associated with the susceptibility to coronary artery diseases. Intern J Med Sci 2014; 11: 365-372.
42 Hu HJ, Jin EH, Yim SH. et al. Common variants at the promoter region of the APOM confer a risk of rheumatoid arthritis. Exp Mol Med 2011; 43: 613-621.
43 Luo G, Zhang X, Nilsson-Ehle P. et al. Apolipoprotein M. Lipids Health Dis 2004; 3: 21.
44 Carthew RW, Sontheimer EJ.. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009; 136: 642-655.
45 Chen K, Rajewsky N.. The evolution of gene regulation by transcription factors and microRNAs. Nature Rev Genetics 2007; 8: 93-103.
46 Smith Jr. JA. The risk of recurrent venous thromboembolism in men and women. J Urol 2005; 173: 886-887.
47 Sherry ST, Ward MH, Kholodov M. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29: 308-311.
48 Wu X, Niu N, Brismar K. et al. Apolipoprotein M promoter polymorphisms alter promoter activity and confer the susceptibility to the development of type 1 diabetes. Clin Biochem 2009; 42: 17-21.
49 Kabbara A, Payet N, Cottel D. et al. Exclusion of CYP46 and APOM as candidate genes for Alzheimer's disease in a French population. Neurosci Lett 2004; 363: 139-143.
50 Xie HG, Stein CM, Kim RB. et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacogen 1999; 9: 511-516.

Supplementary Material

Online Supplementary Material (PDF)