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Mediation analysis reveals a sex-dependent association between ABO gene variants and TG/HDL-C ratio that is suppressed by sE-selectin level

  • Ming-Sheng Teng
    Affiliations
    Graduate Institute of Medical Sciences, Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Department of Research, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan
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  • Lung-An Hsu
    Affiliations
    The First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Semon Wu
    Affiliations
    Department of Research, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan

    Department of Life Science (S.W.), Chinese Culture University, Taipei, Taiwan
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  • Hsin-Hua Chou
    Affiliations
    The Division of Cardiology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan
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  • Chi-Jen Chang
    Affiliations
    The First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Yu-Zen Sun
    Affiliations
    Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan
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  • Shu-Hui Juan
    Correspondence
    Corresponding author. Department of Physiology, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Tel.: +886 2 27361661x3178.
    Affiliations
    Graduate Institute of Medical Sciences, Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Yu-Lin Ko
    Correspondence
    Corresponding author. The Division of Cardiology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, 289 Jianguo Road, Xindian City, Taipei 231, Taiwan. Tel.: +886 2 6628 9779x5709; fax: +886 2 6628 9009.
    Affiliations
    The Division of Cardiology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan

    School of Medicine, Tzu Chi University, Hualien, Taiwan
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      Highlights

      • ABO blood group genotypes independently affect sE-selectin level in Taiwanese.
      • Significantly higher TG/HDL-C ratio was noted in individuals with blood group A.
      • Mediation analysis revealed a suppression effect of sE-selectin level.
      • Association of ABO locus variants with TG/HDL-C ratio is suppressed by sE-selectin.
      • The suppression effect of sE-selectin level was also observed in Taiwanese males.

      Abstract

      Objective

      Previous investigations have revealed an association between the ABO locus/blood group and total cholesterol and inflammatory biomarker levels. We aimed to test the statistical association of ABO locus variants with lipid profiles and levels of thirteen inflammatory markers in a Taiwanese population.

      Methods and results

      A sample population of 617 Taiwanese subjects was enrolled. Five ABO gene region polymorphisms were selected and genotyped. After adjusting for clinical covariates and inflammatory marker levels, the genetic-inferred ABO blood group genotypes were associated with sE-selectin level (P = 3.5 × 10−36). Significantly higher total and low-density lipoprotein cholesterol (LDL-C) levels were noted in individuals with blood group A (P = 7.2 × 10−4 and P = 7.3 × 10−4, respectively). Interestingly, after adjusting for sE-selectin level, significantly lower high-density lipoprotein cholesterol (HDL-C) level as well as higher triglyceride (TG) level and ratio of triglyceride to HDL-C (TG/HDL-C ratio) were noted in individuals with blood group A comparing to non-A individuals (P = 0.009, P = 0.004 and P = 0.001, respectively); these associations were also observed in the group A male subjects (P = 0.027, P = 0.001, and P = 0.002, respectively). Mediation analysis further revealed a suppression effect of sE-selectin level on the association between genetic-inferred ABO blood group genotypes and TG/HDL-C ratio in total participants (P = 1.18 × 10−6) and in males (P = 5.99 × 10−5).

      Conclusion

      Genetic variants at the ABO locus independently affect sE-selectin level in Taiwanese subjects, while the association of ABO locus variants with TG/HDL-C ratio is suppressed by sE-selectin level in Taiwanese males. These results provided further evidence for the mechanism in the association of ABO blood groups with atherosclerotic cardiovascular diseases.

      Keywords

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      References

        • Yamamoto F.
        • Clausen H.
        • White T.
        • Marken J.
        • Hakomori S.
        Molecular genetic basis of the histo-blood group ABO system.
        Nature. 1990; 345: 229-233
        • Eastlund T.
        The histo-blood group ABO system and tissue transplantation.
        Transfusion. 1998; 38: 975-988
        • Wu O.
        • Bayoumi N.
        • Vickers M.A.
        • Clark P.
        ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.
        J Thromb Haemost. 2008; 6: 62-69
        • Trégouët D.A.
        • Heath S.
        • Saut N.
        • et al.
        Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach.
        Blood. 2009; 113: 5298-5303
        • Schunkert H.
        • König I.R.
        • Kathiresan S.
        • et al.
        Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
        Nat Genet. 2011; 43: 333-338
        • Blann A.D.
        • Daly R.J.
        • Amiral J.
        The influence of age, gender and ABO blood group on soluble endothelial cell markers and adhesion molecules.
        Br J Haematol. 1996; 92: 498-500
        • O'Donnell J.
        • Laffan M.A.
        The relationship between ABO histo-blood group, factor VIII and von Willebrand factor.
        Transfus Med. 2001; 11: 343-351
        • Jenkins P.V.
        • O'Donnell J.S.
        ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?.
        Transfusion. 2006; 46: 1836-1844
        • Paterson A.D.
        • Lopes-Virella M.F.
        • Waggott D.
        • et al.
        Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1958-1967
        • Qi L.
        • Cornelis M.C.
        • Kraft P.
        • et al.
        Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes.
        Hum Mol Genet. 2010; 19: 1856-1862
        • Barbalic M.
        • Dupuis J.
        • Dehghan A.
        • et al.
        Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels.
        Hum Mol Genet. 2010; 19: 1863-1872
        • Gillum R.F.
        Blood groups, serum cholesterol, serum uric acid, blood pressure, and obesity in adolescents.
        J Natl Med Assoc. 1991; 83: 682-688
        • Wu S.
        • Hsu L.A.
        • Cheng C.F.
        • et al.
        Effect of obesity on the association between ATF3 gene haplotypes and C-reactive protein level in Taiwanese.
        Clin Chim Acta. 2011; 412: 1026-1031
        • Souto J.C.
        • Almasy L.
        • Muñiz-Diaz E.
        • et al.
        Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII, and activated partial thromboplastin time.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2024-2028
        • O'Donnell J.S.
        • McKinnon T.A.
        • Crawley J.T.
        • Lane D.A.
        • Laffan M.A.
        Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis.
        Blood. 2005; 106: 1988-1991
        • Mohlke K.L.
        • Purkayastha A.A.
        • Westrick R.J.
        • et al.
        Mvwf, a dominant modifier of murine von Willebrand facto results from altered lineage-specific expression of a glycosyltransferase.
        Cell. 1999; 96: 111-120
        • Martinez M.
        • Joffraud M.
        • Giraud S.
        • et al.
        Regulation of PSGL-1 interactions with L-selectin, P-selectin, and E-selectin: role of human fucosyltransferase-IV and -VII.
        J Biol Chem. 2005; 280: 5378-5390
        • Martín M.J.
        • Feizi T.
        • Leteux C.
        • Pavlovic D.
        • Piskarev V.E.
        • Chai W.
        An investigation of the interactions of E-selectin with fuco-oligosaccharides of the blood group family.
        Glycobiology. 2002; 12: 829-835
        • Kingsley D.M.
        • Kozarsky K.F.
        • Hobbie L.
        • Krieger M.
        Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-Gal/UDP-GalNAc 4-epimerase deficient mutant.
        Cell. 1986; 44: 749-759
        • Magrané J.
        • Casaroli-Marano R.P.
        • Reina M.
        • Gåfvels M.
        • Vilaró S.
        The role of O-linked sugars in determining the very low density lipoprotein receptor stability or release from the cell.
        FEBS Lett. 1999; 451: 56-62
        • Schjoldager K.T.
        • Vester-Christensen M.B.
        • Bennett E.P.
        • et al.
        O-glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3: possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids.
        J Biol Chem. 2010; 285: 36293-36303
        • Kathiresan S.
        • Melander O.
        • Guiducci C.
        • et al.
        Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.
        Nat Genet. 2008; 40: 189-197
        • Garrison R.J.
        • Havlik R.J.
        • Harris R.B.
        • Feinleib M.
        • Kannel W.B.
        • Padgett S.J.
        ABO blood group and cardiovascular disease: the Framingham study.
        Atherosclerosis. 1976; 25: 311-318
        • Platt D.
        • Muhlberg W.
        • Kiehl L.
        • Schmitt-Ruth R.
        ABO blood group system, age, sex, risk factors and cardiac infarction.
        Arch Gerontol Geriatr. 1985; 4: 241-249
        • Whincup P.H.
        • Cook D.G.
        • Phillips A.N.
        • Shaper A.G.
        ABO blood group and ischaemic heart disease in British men.
        Brit Med J. 1980; 300: 1679-1682
        • Paré G.
        • Chasman D.I.
        • Kellogg M.
        • et al.
        Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6578 women.
        PLoS Genet. 2008; 4: e1000118
        • MacKinnon D.
        • Krull J.L.
        • Lockwood C.M.
        Equivalence of the mediation, confounding and suppression effect.
        Prev Sci. 2000; 1: 173-181
        • Aiello A.E.
        • Nguyen H.O.
        • Haan M.N.
        C-reactive protein mediates the effect of apolipoprotein E on cytomegalovirus infection.
        J Infect Dis. 2008; 197: 34-41
        • Connelly P.W.
        • Petrasovits A.
        • Stachenko S.
        • et al.
        Prevalence of high plasma triglyceride combined with low HDL-C levels and its association with smoking, hypertension, obesity, diabetes, sedentariness and LDL-C levels in the Canadian population.
        Can J Cardiol. 1999; 15: 428-433
        • Cordero A.
        • Andres E.
        • Ordoñez B.
        • et al.
        Usefulness of triglycerides-to-high density lipoprotein cholesterol ratio for predicting the first coronary event in men.
        Am J Cardiol. 2009; 104: 1393-1397
        • Maggio A.B.
        • Farpour-Lambert N.J.
        • Montecucco F.
        • et al.
        Elevated E-selectin and diastolic blood pressure in diabetic children.
        Eur J Clin Invest. 2012; 42: 303-309
        • Alina S.
        • Barbara R.
        • Krzysztof G.
        • et al.
        Elevation of sE-selectin levels from 2–24 months following gestational diabetes is associated with early cardiometabolic risk in non-diabetic women.
        J Diabetes Metab. 2011; 2011: 138
        • Khampanon K.
        • Chanprakop T.
        • Sriwanitchrak P.
        • Setthakarn M.
        • Oota S.
        • Nathalang O.
        The characteristics of ABO antibodies in group O Thai blood donors.
        J Clin Lab Anal. 2012; 26: 223-226
        • Hirschhorn J.N.
        • Lohmueller K.
        • Byrne E.
        • Hirschhorn K.
        A comprehensive review of genetic association studies.
        Genet Med. 2002; 4: 45-61
        • Zhu F.
        • Tao S.
        • Xu X.
        • et al.
        Distribution of ABO blood group allele and identification of three novel alleles in the Chinese Han population.
        Vox Sang. 2010; 98: 554-559

      Linked Article

      • ABO gene variants and increased risk of atherosclerosis
        AtherosclerosisVol. 228Issue 2
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          Variations at the ABO locus have been associated to circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, soluble E-selectin and to other markers known to participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Soluble levels of these molecules have been shown to be associated to adverse cardiovascular events because of direct consequences on plaque stability and thrombogenesis [1].
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