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GCKR and GCK polymorphisms are associated with increased risk of end-stage kidney disease in Chinese patients with type 2 diabetes: The Hong Kong Diabetes Register (1995–2019)

  • Author Footnotes
    1 Equal contribution.
    Ke Wang
    Footnotes
    1 Equal contribution.
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Author Footnotes
    1 Equal contribution.
    Mai Shi
    Footnotes
    1 Equal contribution.
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
    Search for articles by this author
  • Aimin Yang
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Baoqi Fan
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Claudia H.T. Tam
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Eric Lau
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Andrea O.Y. Luk
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Alice P.S. Kong
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Ronald C.W. Ma
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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  • Author Footnotes
    2 Co-Corresponding authors at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (J.C.N. Chan). Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (E. Chow).
    Juliana C.N. Chan
    Footnotes
    2 Co-Corresponding authors at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (J.C.N. Chan). Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (E. Chow).
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
    Search for articles by this author
  • Author Footnotes
    2 Co-Corresponding authors at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (J.C.N. Chan). Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (E. Chow).
    Elaine Chow
    Correspondence
    Corresponding author.
    Footnotes
    2 Co-Corresponding authors at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (J.C.N. Chan). Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (E. Chow).
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

    Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution.
    2 Co-Corresponding authors at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (J.C.N. Chan). Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (E. Chow).
Published:October 12, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110118

      Abstract

      Aims

      Glucokinase (GCK) and glucokinase regulatory protein (GKRP) regulate glucose and lipid metabolism. We investigated the associations of GCKR and GCK polymorphisms with kidney outcomes.

      Methods

      Analyses were performed in a prospective cohort who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017. The associations of GCKR rs1260326 and GCK rs1799884 polymorphisms with incident end-stage kidney disease (ESKD), albuminuria and rapid eGFR decline were analysed by Cox regression or logistic regression with adjustment.

      Results

      6072 patients (baseline mean age 57.4 years; median diabetes duration 6.0 years; 54.5 % female) were included, with a median follow-up of 15.5 years. The GCKR rs1260326 [HR (95 %CI) 1.23 (1.05–1.44) for CT; HR 1.23 (1.02–1.48) for TT] and GCK rs1799884 T alleles [HR 1.73 (1.24–2.40) for TT] were independently associated with increased risk of ESKD versus their respective CC genotypes. GCKR rs1260326 T allele was also associated with albuminuria [OR 1.18 (1.05–1.33) for CT; OR 1.34 (1.16–1.55) for TT] and rapid eGFR decline.

      Conclusions

      In Chinese patients with type 2 diabetes, T allele carriers of GCKR rs1260326 and GCK rs1799884 were at high risk for ESKD. These genetic markers may be used to identify high risk patients for early intensive management for renoprotection.

      Keywords

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      References

        • Jha V.
        • Garcia-Garcia G.
        • Iseki K.
        • et al.
        Chronic kidney disease: global dimension and perspectives.
        Lancet (London, England). 2013; 382: 260-272https://doi.org/10.1016/s0140-6736(13)60687-x
        • Matsushita K.
        • van der Velde M.
        • Astor B.C.
        • et al.
        Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
        Lancet (London, England). 2010; 375: 2073-2081https://doi.org/10.1016/s0140-6736(10)60674-5
      1. Ghaderian SB, Hayati F, Shayanpour S, Beladi Mousavi SS. Diabetes and end-stage renal disease; a review article on new concepts. J Renal Inj Prevent 2015; 4(2): 28–33. doi:10.12861/jrip.2015.07.

        • Chen T.K.
        • Knicely D.H.
        • Grams M.E.
        Chronic kidney disease diagnosis and management: a review.
        JAMA. 2019; 322: 1294-1304https://doi.org/10.1001/jama.2019.14745
        • Ma R.C.
        • Cooper M.E.
        Genetics of diabetic kidney disease-from the worst of nightmares to the light of dawn?.
        J Am Soc Nephrol: JASN. 2017; 28: 389-393https://doi.org/10.1681/asn.2016091028
        • de Boer I.H.
        • Caramori M.L.
        • Chan J.C.N.
        • et al.
        Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
        Kidney Int. 2020; 98: 839-848https://doi.org/10.1016/j.kint.2020.06.024
        • Matschinsky F.M.
        • Wilson D.F.
        The central role of Glucokinase in glucose homeostasis: a perspective 50 years after demonstrating the presence of the enzyme in islets of Langerhans.
        Front Physiol. 2019; 10: 148https://doi.org/10.3389/fphys.2019.00148
        • Van Schaftingen E.
        Short-term regulation of glucokinase.
        Diabetologia. 1994; 37: S43-S47https://doi.org/10.1007/bf00400825
        • Zhu D.
        • Li X.
        • Ma J.
        • et al.
        Dorzagliatin in drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.
        Nat Med. 2022; https://doi.org/10.1038/s41591-022-01802-6
        • Yang W.
        • Zhu D.
        • Gan S.
        • et al.
        Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.
        Nat Med. 2022; 28: 974-981https://doi.org/10.1038/s41591-022-01803-5
        • Vella A.
        • Freeman J.L.R.
        • Dunn I.
        • Keller K.
        • Buse J.B.
        • Valcarce C.
        Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator.
        Sci Transl Med. 2019; 11https://doi.org/10.1126/scitranslmed.aau3441
        • Tam C.H.
        • Ma R.C.
        • So W.Y.
        • et al.
        Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents.
        Diabetes. 2009; 58: 765-769https://doi.org/10.2337/db08-1277
        • Scott R.A.
        • Lagou V.
        • Welch R.P.
        • et al.
        Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
        Nat Genet. 2012; 44: 991-1005https://doi.org/10.1038/ng.2385
        • Tam C.H.
        • Ho J.S.
        • Wang Y.
        • et al.
        Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects.
        PLoS ONE. 2010; 5: e11428
        • Raimondo A.
        • Rees M.G.
        • Gloyn A.L.
        Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism.
        Curr Opin Lipidol. 2015; 26: 88-95https://doi.org/10.1097/mol.0000000000000155
        • Kottgen A.
        • Pattaro C.
        • Boger C.A.
        • et al.
        New loci associated with kidney function and chronic kidney disease.
        Nat Genet. 2010; 42: 376-384https://doi.org/10.1038/ng.568
        • Boger C.A.
        • Gorski M.
        • Li M.
        • et al.
        Association of eGFR-related loci identified by GWAS with incident CKD and ESRD.
        PLoS Genet. 2011; 7: e1002292
        • Hishida A.
        • Takashima N.
        • Turin T.C.
        • et al.
        GCK, GCKR polymorphisms and risk of chronic kidney disease in Japanese individuals: data from the J-MICC study.
        J Nephrol. 2014; 27: 143-149https://doi.org/10.1007/s40620-013-0025-0
        • Ellis J.W.
        • Chen M.H.
        • Foster M.C.
        • et al.
        Validated SNPs for eGFR and their associations with albuminuria.
        Hum Mol Genet. 2012; 21: 3293-3298https://doi.org/10.1093/hmg/dds138
        • Chan J.C.N.
        • Lim L.L.
        • Luk A.O.Y.
        • et al.
        From Hong Kong diabetes register to JADE program to RAMP-DM for data-driven actions.
        Diabetes Care. 2019; 42: 2022-2031https://doi.org/10.2337/dci19-0003
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Int Med. 2009; 150: 604-612https://doi.org/10.7326/0003-4819-150-9-200905050-00006
        • Yang A.
        • Shi M.
        • Wu H.
        • et al.
        Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study.
        Diabetologia. 2021; 64: 1760-1765https://doi.org/10.1007/s00125-021-05452-0
        • Köchl S.
        • Niederstätter H.
        • Parson W.
        DNA extraction and quantitation of forensic samples using the phenol-chloroform method and real-time PCR.
        Meth Mole Biol (Clifton, NJ). 2005; 297: 13-30https://doi.org/10.1385/1-59259-867-6:013
        • Navaneethan S.D.
        • Zoungas S.
        • Caramori M.L.
        • et al.
        Diabetes management in chronic kidney disease: synopsis of the 2020 KDIGO clinical practice guideline.
        Ann Int Med. 2021; 174: 385-394https://doi.org/10.7326/m20-5938
        • Gorski M.
        • Jung B.
        • Li Y.
        • et al.
        Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
        Kidney Int. 2021; 99: 926-939https://doi.org/10.1016/j.kint.2020.09.030
        • Stensrud M.J.
        • Hernán M.A.
        Why test for proportional hazards?.
        JAMA. 2020; 323: 1401-1402https://doi.org/10.1001/jama.2020.1267
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509https://doi.org/10.1080/01621459.1999.10474144
        • Chiu K.C.
        • Chuang L.M.
        • Yoon C.
        • Saad M.F.
        Hepatic glucokinase promoter polymorphism is associated with hepatic insulin resistance in Asian Indians.
        BMC Genet. 2000; 1: 2https://doi.org/10.1186/1471-2156-1-2
        • Yamada Y.
        • Ando F.
        • Shimokata H.
        Association of polymorphisms of SORBS1, GCK and WISP1 with hypertension in community-dwelling Japanese individuals.
        Hypertens Res: Offi J Japan Soc Hypertens. 2009; 32: 325-331https://doi.org/10.1038/hr.2009.23
        • Fan R.
        • Wang W.J.
        • Zhong Q.L.
        • et al.
        Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension.
        Mol Med Rep. 2015; 12: 2390-2394https://doi.org/10.3892/mmr.2015.3631
        • Rees M.G.
        • Wincovitch S.
        • Schultz J.
        • et al.
        Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk.
        Diabetologia. 2012; 55: 114-122https://doi.org/10.1007/s00125-011-2348-5
        • Orho-Melander M.
        • Melander O.
        • Guiducci C.
        • et al.
        Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
        Diabetes. 2008; 57: 3112-3121https://doi.org/10.2337/db08-0516
        • Wang Y.-X.
        • Wang A.-P.
        • Ye Y.-N.
        • et al.
        Elevated triglycerides rather than other lipid parameters are associated with increased urinary albumin to creatinine ratio in the general population of China: a report from the REACTION study.
        Cardiovasc Diabetol. 2019; 18: 57https://doi.org/10.1186/s12933-019-0863-8
        • Kolz M.
        • Johnson T.
        • Sanna S.
        • et al.
        Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
        PLoS Genet. 2009; 5: e1000504
        • Speliotes E.K.
        • Yerges-Armstrong L.M.
        • Wu J.
        • et al.
        Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
        PLoS Genet. 2011; 7: e1001324
        • Chasman D.I.
        • Paré G.
        • Mora S.
        • et al.
        Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis.
        PLoS Genet. 2009; 5: e1000730
        • Thomas G.
        • Sehgal A.R.
        • Kashyap S.R.
        • Srinivas T.R.
        • Kirwan J.P.
        • Navaneethan S.D.
        Metabolic syndrome and kidney disease: a systematic review and meta-analysis.
        Clin J Am Soc Nephrol: CJASN. 2011; 6: 2364-2373https://doi.org/10.2215/cjn.02180311
        • Luk A.O.
        • So W.Y.
        • Ma R.C.
        • et al.
        Metabolic syndrome predicts new onset of chronic kidney disease in 5,829 patients with type 2 diabetes: a 5-year prospective analysis of the Hong Kong Diabetes Registry.
        Diabetes Care. 2008; 31: 2357-2361https://doi.org/10.2337/dc08-0971
        • Ahlqvist E.
        • Storm P.
        • Käräjämäki A.
        • et al.
        Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables.
        Lancet Diab Endocrinol. 2018; 6: 361-369https://doi.org/10.1016/S2213-8587(18)30051-2
        • März W.
        • Nauck M.
        • Hoffmann M.M.
        • et al.
        G(-30)A polymorphism in the pancreatic promoter of the glucokinase gene associated with angiographic coronary artery disease and type 2 diabetes mellitus.
        Circulation. 2004; 109: 2844-2849https://doi.org/10.1161/01.Cir.0000129306.44085.C4
        • Simons P.
        • Simons N.
        • Stehouwer C.D.A.
        • Schalkwijk C.G.
        • Schaper N.C.
        • Brouwers M.
        Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: a systematic review and meta-analysis.
        PLoS ONE. 2018; 13: e0206174
        • Okada Y.
        • Sim X.
        • Go M.J.
        • et al.
        Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.
        Nat Genet. 2012; 44: 904-909https://doi.org/10.1038/ng.2352
      2. Di Costanzo A, Pacifico L, D'Erasmo L, et al. Nonalcoholic Fatty Liver Disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children. Int J Mole Sci 2019; 20(18). doi:10.3390/ijms20184444.

        • Melsom T.
        • Stefansson V.
        • Schei J.
        • et al.
        Association of increasing GFR with change in albuminuria in the general population.
        Clin J Am Soc Nephrol: CJASN. 2016; 11: 2186-2194https://doi.org/10.2215/cjn.04940516
        • Sirugo G.
        • Williams S.M.
        • Tishkoff S.A.
        The missing diversity in human genetic studies.
        Cell. 2019; 177: 26-31https://doi.org/10.1016/j.cell.2019.02.048
      3. Matschinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996; 45(2): 223–241. doi:10.2337/diab.45.2.223.

        • Taal M.W.
        • Brenner B.M.
        Predicting initiation and progression of chronic kidney disease: developing renal risk scores.
        Kidney Int. 2006; 70: 1694-1705https://doi.org/10.1038/sj.ki.5001794
        • Chen H.
        • Wang J.
        • Li Z.
        • et al.
        Consumption of sugar-sweetened beverages has a dose-dependent effect on the risk of non-alcoholic fatty liver disease: an updated systematic review and dose-response meta-analysis.
        Int J Environ Res Public Health. 2019; 16https://doi.org/10.3390/ijerph16122192
        • Tam C.H.
        • Wang Y.
        • Lee H.M.
        • et al.
        Early gene-diet interaction between glucokinase regulatory protein (GCKR) polymorphism, vegetable and fish intakes in modulating triglyceride levels in healthy adolescents.
        Nutr Metab Cardiovasc Diseases : NMCD. 2015; 25: 951-958https://doi.org/10.1016/j.numecd.2015.06.011
        • Evans D.M.
        • Davey Smith G.
        Mendelian randomization: new applications in the coming age of hypothesis-free causality.
        Annu Rev Genomics Hum Genet. 2015; 16: 327-350https://doi.org/10.1146/annurev-genom-090314-050016
        • Futamura M.
        • Hosaka H.
        • Kadotani A.
        • et al.
        An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism.
        J Biol Chem. 2006; 281: 37668-37674https://doi.org/10.1074/jbc.M605186200