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Positive association between serum resistin and smoking was strongest in homozygotes of the G-A haplotype at c.-420 C>G and c.-358 G>A in RETN promoter: the Toon Genome Study

Journal of Human Genetics volume 68, pages 745–750 (2023)Cite this article

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Abstract

Resistin is mainly expressed in human monocytes/macrophages and is associated with insulin resistance, inflammation, and atherosclerosis. Serum resistin is strongly correlated with the G-A haplotype defined by single nucleotide polymorphisms (SNPs) c.-420 C>G (SNP-420) (rs1862513) and c.-358 G>A (SNP-358) (rs3219175) in the promoter region of the human resistin gene (RETN). Smoking is also associated with insulin resistance. We investigated the association between smoking and serum resistin and the effect of the G-A haplotype on this association. Participants were recruited under the Toon Genome Study (an observational epidemiology research in the Japanese population). Of these, 1975 subjects genotyped for both SNP-420 and SNP-358 were analyzed for serum resistin by grouping them based on smoking status and G-A haplotype status. RETN mRNA, isolated from whole blood cells, was evaluated in smokers (n = 7) and age-, sex-, and BMI-matched non-smokers (n = 7) with the G-A haplotype homozygotes. Serum resistin tended to be higher in current smokers who smoked more cigarettes per day (P for trend < 0.0001). The positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes, followed by heterozygotes and non-carriers (interaction P < 0.0001). This positive association was stronger in the G-A homozygotes than the C-G homozygotes (interaction P < 0.0001). RETN mRNA was 1.40-fold higher in smokers than non-smokers with the G-A homozygotes (P = 0.022). Therefore, the positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes defined by RETN SNP-420 and SNP-358.

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References

  1. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–12.

    Article  CAS  PubMed  Google Scholar 

  2. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, et al. Resistin is expressed in human macrophages and directly regulated by PPARγ activators. Biochem Biophys Res Commun. 2003;300:472–6.

    Article  CAS  PubMed  Google Scholar 

  3. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 2003;309:286–90.

    Article  CAS  PubMed  Google Scholar 

  4. Qatanani M, Szwergold NR, Greaves DR, Ahima RS, Lazar MA. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest. 2009;119:531–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Osawa H, Tabara Y, Kawamoto R, Ohashi J, Ochi M, Onuma H, et al. Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population. Diabetes Care. 2007;30:1501–6.

    Article  CAS  PubMed  Google Scholar 

  6. de León AC, González DA, Hernández AG, Sánchez JJA, Díaz BB, Coello SD, et al. The association of resistin with coronary disease in the general population. J Atheroscler Thromb. 2014;21:273–81.

    Article  Google Scholar 

  7. Prugger C, Luc G, Haas B, Morange P-E, Ferrieres J, Amouyel P, et al. Multiple biomarkers for the prediction of ischemic stroke: the PRIME study. Arterioscler Thromb Vasc Biol. 2013;33:659–66.

    Article  CAS  PubMed  Google Scholar 

  8. Jamaluddin MS, Yan S, Lü J, Liang Z, Yao Q, Chen C. Resistin increases monolayer permeability of human coronary artery endothelial cells. PLoS One. 2013;8:e84576.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Osawa H, Yamada K, Onuma H, Murakami A, Ochi M, Kawata H, et al. The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet. 2004;75:678–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kawamura R, Tabara Y, Tsukada A, Igase M, Ohashi J, Yamada R, et al. Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population. Physiol Genomics. 2016;48:874–81.

    Article  CAS  PubMed  Google Scholar 

  11. Onuma H, Tabara Y, Kawamura R, Tanaka T, Ohashi J, Nishida W, et al. A at single nucleotide polymorphism-358 is required for G at -420 to confer the highest plasma resistin in the general Japanese population. PLoS One. 2010;5:e9718.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Targher G, Alberiche M, Zenere MB, Bonadonna RC, Muggeo M, Bonora E. Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:3619–24.

    CAS  PubMed  Google Scholar 

  13. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007;298:2654–64.

    Article  CAS  PubMed  Google Scholar 

  14. Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol. 2004;43:1731–7.

    Article  CAS  PubMed  Google Scholar 

  15. Kondo T, Osugi S, Shimokata K, Honjo H, Morita Y, Maeda K, et al. Smoking and smoking cessation in relation to all-cause mortality and cardiovascular events in 25,464 healthy male Japanese workers. Circ J. 2011;75:2885–92.

    Article  PubMed  Google Scholar 

  16. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477–82.

    Article  CAS  PubMed  Google Scholar 

  17. Tibuakuu M, Kamimura D, Kianoush S, DeFilippis AP, Rifai MA, Reynolds LM, et al. The association between cigarette smoking and inflammation: the Genetic Epidemiology Network of Arteriopathy (GENOA) study. PLoS One. 2017;12:e0184914.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Noumi Y, Kawamura R, Tabara Y, Maruyama K, Takata Y, Nishida W, et al. An inverse association between serum resistin levels and n-3 polyunsaturated fatty acids intake was strongest in the SNP-420 G/G genotype in the Japanese cohort: the Toon Genome Study. Clin Endocrinol (Oxf). 2018;88:51–57.

    Article  CAS  PubMed  Google Scholar 

  19. Khazen W, M’bika JP, Tomkiewicz C, Benelli C, Chany C, Achour A, et al. Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett. 2005;579:5631–4.

    Article  CAS  PubMed  Google Scholar 

  20. Nagaev I, Bokarewa M, Tarkowski A, Smith U. Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes. PLoS One. 2006;1:e31.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kawamura R, Doi Y, Osawa H, Ninomiya T, Hata J, Yonemoto K, et al. Circulating resistin is increased with decreasing renal function in a general Japanese population: the Hisayama Study. Nephrol Dial Transplant. 2010;25:3236–40.

    Article  CAS  PubMed  Google Scholar 

  22. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–9.

    Article  PubMed  Google Scholar 

  23. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M. Association between cigarette smoking, white blood cell count, and metabolic syndrome as defined by the Japanese criteria. Intern Med. 2007;46:1167–70.

    Article  PubMed  Google Scholar 

  24. King CC, Piper ME, Gepner AD, Fiore MC, Baker TB, Stein JH. Longitudinal impact of smoking and smoking cessation on inflammatory markers of cardiovascular disease risk. Arterioscler Thromb Vasc Biol. 2017;37:374–9.

    Article  CAS  PubMed  Google Scholar 

  25. Karimi K, Sarir H, Mortaz E, Smit JJ, Hosseini H, De Kimpe SJ, et al. Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Respir Res. 2006;7:66.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Furugen R, Hayashida H, Saito T. Porphyromonas gingivalis and Escherichia coli lipopolysaccharide causes resistin release from neutrophils. Oral Dis. 2013;19:479–83.

    Article  CAS  PubMed  Google Scholar 

  27. Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL. Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett. 2002;530:158–62.

    Article  CAS  PubMed  Google Scholar 

  28. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 2004;1:e45.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, et al. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation. 2003;108:736–40.

    Article  CAS  PubMed  Google Scholar 

  30. Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun. 2004;314:415–9.

    Article  CAS  PubMed  Google Scholar 

  31. Ito S, Gojoubori T, Tsunoda K, Yamaguchi Y, Asano M, Goke E, et al. Nicotine-induced expression of low-density lipoprotein receptor in oral epithelial cells. PLoS One. 2013;8:e82563.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mercer BA, Wallace AM, Brinckerhoff CE, D’Armiento JM. Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter. Am J Respir Cell Mol Biol. 2009;40:4–12.

    Article  CAS  PubMed  Google Scholar 

  33. Di YP, Zhao J, Harper R. Cigarette smoke induces MUC5AC protein expression through the activation of Sp1. J Biol Chem. 2012;287:27948–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics. 2005;21:2933–42.

    Article  CAS  PubMed  Google Scholar 

  35. Kumar D, Lee B, Puan KJ, Lee W, Luis BS, Yusof N, et al. Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFkB p50/p50 binding and C-methylation. Sci Rep. 2019;9:15245.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by JSPS KAKENHI, grants from Ehime University, and by support from Mr. Takeshi Ikeda. The authors wish to thank all the members in the department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine for critical discussions. We are also grateful to all the staff members associated with this study, especially Ms. Otaki, Ms. Kagawa, and Dr. Sano, for supporting the medical check-ups and technical assistance.

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Authors and Affiliations

  1. Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan

    Toshimi Hadate, Ryoichi Kawamura, Misaki Takakado, Yosuke Ikeda, Yasunori Takata & Haruhiko Osawa

  2. Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan

    Yasuharu Tabara

  3. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yasuharu Tabara

  4. Department of Bioscience, Graduate School of Agriculture, Ehime University, Ehime, Japan

    Koutatsu Maruyama

  5. Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan

    Jun Ohashi

  6. Department of Public Health and Epidemiology, Faculty of Medicine, Oita University, Oita, Japan

    Isao Saito

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  1. Toshimi Hadate
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Contributions

TH designed the experiments, researched and analyzed data, and wrote the manuscript. RK designed the experiments, researched data, contributed to discussion, reviewed and edited the manuscripts. YTab and JO conducted statistical analyses, contributed to discussion, and reviewed the manuscripts. KM, MT, YI, and IS contributed to discussion, and reviewed the manuscripts. YTak designed the experiments, researched data, contributed to discussion, and reviewed the manuscripts. HO designed the experiments, contributed to discussion, and reviewed and edited the manuscripts. HO is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Haruhiko Osawa.

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Hadate, T., Kawamura, R., Tabara, Y. et al. Positive association between serum resistin and smoking was strongest in homozygotes of the G-A haplotype at c.-420 C>G and c.-358 G>A in RETN promoter: the Toon Genome Study. J Hum Genet 68, 745–750 (2023). https://doi.org/10.1038/s10038-023-01176-8

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