Preliminary study of the urinary proteome in Li and Han ethnic individuals from Hainan

  • Fanshuang Zhang
  • Xundou Li
  • Yanying Ni
  • Guangliang ShanEmail author
  • Youhe GaoEmail author
Research Paper


Biomarkers indicate changes associated with disease. Blood is relatively stable due to the homeostatic mechanisms of the body; however, urine accumulates metabolites from changes in the body, making it a better source for early biomarker discovery. The Li ethnic group is a unique minority ethnic group that has only lived on Hainan Island for approximately 5,000 years. Studies have shown that various specific genetic variations are different between the Li and Han ethnic groups. However, whether the urinary proteome between these two ethnic groups is significantly different remains unknown. In this study, differential urinary proteins were identified in the Li and Han ethnic groups using liquid chromatography tandem mass spectrometry (LC-MS/MS). In total, 1,555 urinary proteins were identified. Twenty-five of the urinary proteins were statistically significantly different, 16 of which have been previously reported to be biomarkers of many diseases, and that these significantly different proteins were caused by ethnic differences rather than random differences. Ethnic group differences may be an influencing factor in urine proteome studies and should be considered when human urine samples are used for biomarker discovery.

proteomics urine biomarker Li ethnic group Han ethnic group 


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This work was supported by the National Key Research and Development Program of China (2018YFC0910202, 2016YFC1306300), Beijing Natural Science Foundation (7172076), the Key Basic Research Program of the Ministry of Science and Technology of China (2013FY114100), Beijing Cooperative Construction Project (110651103), Beijing Normal University (11100704), and Peking Union Medical College Hospital (2016-2.27).

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  1. Albert, C., Albert, A., Kube, J., Bellomo, R., Wettersten, N., Kuppe, H., Westphal, S., Haase, M., and Haase-Fielitz, A. (2018). Urinary biomarkers may provide prognostic information for subclinical acute kidney injury after cardiac surgery. J Thoracic Cardiovasc Surg 155, 2441–2452.e13.CrossRefGoogle Scholar
  2. An, M., and Gao, Y. (2015). Urinary biomarkers of brain diseases. Genom Proteom Bioinform 13, 345–354.CrossRefGoogle Scholar
  3. Arner, P., Henjes, F., Schwenk, J.M., Darmanis, S., Dahlman, I., Iresjö, B. M., Naredi, P., Agustsson, T., Lundholm, K., Nilsson, P., et al. (2015). Circulating carnosine dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer. PLoS ONE 10, e0123566.CrossRefGoogle Scholar
  4. Aslebagh, R., Channaveerappa, D., Arcaro, K.F., and Darie, C.C. (2018). Proteomics analysis of human breast milk to assess breast cancer risk. Electrophoresis 39, 653–665.CrossRefGoogle Scholar
  5. Azurmendi, L., Lapierre-Fetaud, V., Schneider, J., Montaner, J., Katan, M., and Sanchez, J.C. (2017). Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection: a pilot study. Clin Proteom 14, 27.CrossRefGoogle Scholar
  6. Bellei, E., Rossi, E., Lucchi, L., Uggeri, S., Albertazzi, A., Tomasi, A., and Iannone, A. (2008). Proteomic analysis of early urinary biomarkers of renal changes in type 2 diabetic patients. Prot Clin Appl 2, 478–491.CrossRefGoogle Scholar
  7. Beretov, J., Wasinger, V.C., Millar, E.K.A., Schwartz, P., Graham, P.H., and Li, Y. (2015). Proteomic analysis of urine to identify breast cancer biomarker candidates using a label-free LC-MS/MS approach. PLoS ONE 10, e0141876.CrossRefGoogle Scholar
  8. Bracht, T., Schweinsberg, V., Trippler, M., Kohl, M., Ahrens, M., Padden, J., Naboulsi, W., Barkovits, K., Megger, D.A., Eisenacher, M., et al. (2015). Analysis of disease-associated protein expression using quantitative proteomics—Fibulin-5 is expressed in association with hepatic fibrosis. J Proteome Res 14, 2278–2286.CrossRefGoogle Scholar
  9. Buanes, T.A. (2016). Updated therapeutic outcome for patients with periampullary and pancreatic cancer related to recent translational research. World J Gastroenterol 22, 10502–10511.CrossRefGoogle Scholar
  10. Capo-chichi, C.D., Aguida, B., Chabi, N.W., Cai, Q.K., Offrin, G., Agossou, V.K., Sanni, A., and Xu, X.X. (2016). Lamin A/C deficiency is an independent risk factor for cervical cancer. Cell Oncol 39, 59–68.CrossRefGoogle Scholar
  11. Chan, H.H., Rahim, Z.H.A., Jessie, K., Hashim, O.H., and Taiyeb-Ali, T.B. (2012). Salivary proteins associated with periodontitis in patients with type 2 diabetes mellitus. Int J Mol Sci 13, 4642–4654.CrossRefGoogle Scholar
  12. Chen, S.L., Lu, S.X., Liu, L.L., Wang, C.H., Yang, X., Zhang, Z.Y., Zhang, H.Z., and Yun, J.P. (2018). eEF1A1 overexpression enhances tumor progression and indicates poor prognosis in hepatocellular carcinoma. Transl Oncol 11, 125–131.CrossRefGoogle Scholar
  13. Chen, T., Guo, M., Gao, Y., Chen, F., Guo, J., Liu, T., Wu, D., and Jiang, X. (2014). A comparative study on the levels of serum cytokines and cortisol among post-traumatic stress disorder patients of Li and Han ethnicities in Hainan. Chin Med J 127, 2771–2774.Google Scholar
  14. Cho-Vega, J.H., Tsavachidis, S., Do, K.A., Nakagawa, J., Medeiros, L.J., and McDonnell, T.J. (2007). Dicarbonyl/L-xylulose reductase: a potential biomarker identified by laser-capture microdissection-micro serial analysis of gene expression of human prostate adenocarcinoma. Cancer Epidemiol Biomark Prevent 16, 2615–2622.CrossRefGoogle Scholar
  15. Chu, Y., Lai, Y. H., Lee, M. C., Yeh, Y. J., Wu, Y. K., Tsao, W., Huang, C. Y., and Wu, S. (2017). Calsyntenin-1, clusterin and neutrophil gelatinase-associated lipocalin are candidate serological biomarkers for lung adenocarcinoma. Oncotarget 8, 107964–107976.Google Scholar
  16. Ding, Y., He, P., He, N., Li, Q., Sun, J., Yao, J., Yi, S., Xu, H., Wu, D., Wang, X., et al. (2016). Genetic polymorphisms of pharmacogenomic VIP variants in Li nationality of southern China. Environ Toxicol Pharmacol 42, 237–242.CrossRefGoogle Scholar
  17. Ding, Y., Yang, D., Zhou, L., He, P., Yao, J., Xie, P., Lin, D., Sun, D., Sun, P., Li, Q., et al. (2015a). Cytochrome P450 2C9 (CYP2C9) polymorphisms in Chinese Li population. Int J Clin Exp Med 8, 21024–21033.Google Scholar
  18. Ding, Y., Yang, D., Zhou, L., Xu, J., Chen, Y., He, P., Yao, J., Chen, J., Niu, H., Sun, P., et al. (2015b). Variants in multiple genes polymorphism association analysis of COPD in the Chinese Li population. Int J Chron Obstruct Pulmon Dis 10, 1455–1463.CrossRefGoogle Scholar
  19. Eisenach, P.A., Soeth, E., Röder, C., Klöppel, G., Tepel, J., Kalthoff, H., and Sipos, B. (2013). Dipeptidase 1 (DPEP1) is a marker for the transition from low-grade to high-grade intraepithelial neoplasia and an adverse prognostic factor in colorectal cancer. Br J Cancer 109, 694–703.CrossRefGoogle Scholar
  20. Gajbhiye, A., Dabhi, R., Taunk, K., Vannuruswamy, G., RoyChoudhury, S., Adhav, R., Seal, S., Mane, A., Bayatigeri, S., Santra, M.K., et al. (2016). Urinary proteome alterations in HER2 enriched breast cancer revealed by multipronged quantitative proteomics. Proteomics 16, 2403–2418.CrossRefGoogle Scholar
  21. Gala-Błądzińska, A., Żyłka, A., Dumnicka, P., Kuśnierz-Cabala, B., Kaziuk, M.B., and Kuźniewski, M. (2017). Sterile leukocyturia affects urine neutrophil gelatinase-associated lipocalin concentration in type 2 diabetic patients. Arch Med Sci 2, 321–327.CrossRefGoogle Scholar
  22. Gao, Y.H. (2013). Urine—an untapped goldmine for biomarker discovery? Sci China Life Sci 56, 1145–1146.CrossRefGoogle Scholar
  23. Gao, Y. (2014). Roadmap to the urine biomarker era. MOJ Proteom Bioinform 1, 00005.Google Scholar
  24. Greco, S.A., Chia, J., Inglis, K.J., Cozzi, S.J., Ramsnes, I., Buttenshaw, R. L., Spring, K.J., Boyle, G.M., Worthley, D.L., Leggett, B.A., et al. (2010). Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation. BMC Cancer 10, 494.CrossRefGoogle Scholar
  25. Guo, Z., Liu, X., Li, M., Shao, C., Tao, J., Sun, W., and Li, M. (2015a). Differential urinary glycoproteome analysis of type 2 diabetic nephropathy using 2D-LC-MS/MS and iTRAQ quantification. J Transl Med 13, 371.CrossRefGoogle Scholar
  26. Guo, Z., Zhang, Y., Zou, L., Wang, D., Shao, C., Wang, Y., Sun, W., and Zhang, L. (2015b). A proteomic analysis of individual and gender variations in normal human urine and cerebrospinal fluid using iTRAQ quantification. PLoS ONE 10, e0133270.CrossRefGoogle Scholar
  27. Hauck, S.M., Dietter, J., Kramer, R.L., Hofmaier, F., Zipplies, J.K., Amann, B., Feuchtinger, A., Deeg, C.A., and Ueffing, M. (2010). Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry. Mol Cell Proteomics 9, 2292–2305.CrossRefGoogle Scholar
  28. Huang, J.T.J., Chaudhuri, R., Albarbarawi, O., Barton, A., Grierson, C., Rauchhaus, P., Weir, C.J., Messow, M., Stevens, N., McSharry, C., et al. (2012). Clinical validity of plasma and urinary desmosine as biomarkers for chronic obstructive pulmonary disease. Thorax 67, 502–508.CrossRefGoogle Scholar
  29. Jeong, H.C., Kim, G.I., Cho, S.H., Lee, K.H., Ko, J.J., Yang, J.H., and Chung, K.H. (2011). Proteomic analysis of human small cell lung cancer tissues: up-regulation of coactosin-like protein-1. J Proteome Res 10, 269–276.CrossRefGoogle Scholar
  30. Jia, L.L., Liu, X.J., Liu, L., Li, M.X., and Gao, Y.H. (2014). Urimem, a membrane that can store urinary proteins simply and economically, makes the large-scale storage of clinical samples possible. Sci China Life Sci 57, 336–339.CrossRefGoogle Scholar
  31. Ward, B.J., Kardoush, M.I., and Ndao, M. (2017). Serum carbonic anhydrase 1 is a biomarker for diagnosis of human schistosoma mansoni infection. Am J Tropical Med Hygiene 96, 842–849.CrossRefGoogle Scholar
  32. Koch, M., Mitulovic, G., Hanzal, E., Umek, W., Seyfert, S., Mohr, T., Koelbl, H., and Laterza, R.M. (2016). Urinary proteomic pattern in female stress urinary incontinence: a pilot study. Int Urogynecol J 27, 1729–1734.CrossRefGoogle Scholar
  33. Krzemien, G., Panczyk-Tomaszewska, M., Adamczuk, D., Kotula, I., Demkow, U., and Szmigielska, A. (2018). Neutrophil gelatinase-associated lipocalin: a biomarker for early diagnosis of urinary tract infections in infants. Adv Exp Med Biol 1047, 71–80.CrossRefGoogle Scholar
  34. Li, L., Cui, Y., Ji, J.F., and Jiang, W.G. (2017). Clinical correlation between WISP2 and beta-catenin in gastric cancer. Anticancer Res 37, 4469–4473.Google Scholar
  35. Li, M.L., Zhao, M.D., and Gao, Y.H. (2014). Changes of proteins induced by anticoagulants can be more sensitively detected in urine than in plasma. Sci China Life Sci 57, 649–656.CrossRefGoogle Scholar
  36. Liu, E., Nisenblat, V., Farquhar, C., Fraser, I., Bossuyt, P.M., Johnson, N., and Hull, M.L. (2015). Urinary biomarkers for the non-invasive diagnosis of endometriosis. The Cochrane Database of Systematic Reviews, CD012019.Google Scholar
  37. Liu, Z., Ma, Y., Yang, J., and Qin, H. (2011). Upregulated and downregulated proteins in hepatocellular carcinoma: a systematic review of proteomic profiling studies. Omics 15, 61–71.CrossRefGoogle Scholar
  38. Lubell, T.R., Barasch, J.M., Xu, K., Ieni, M., Cabrera, K.I., and Dayan, P.S. (2017). Urinary neutrophil gelatinase-associated lipocalin for the diagnosis of urinary tract infections. Pediatrics 140.Google Scholar
  39. Matsumoto, K.I., Maniwa, T., Tanaka, T., Satoh, K., Okunishi, H., and Oda, T. (2012). Proteomic analysis of calcified abdominal and thoracic aortic aneurysms. Int J Mol Med 30, 417–429.CrossRefGoogle Scholar
  40. Morrissey, J.J., London, A.N., Lambert, M.C., and Kharasch, E.D. (2011). Sensitivity and specificity of urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for the diagnosis of renal cell carcinoma. Am J Nephrol 34, 391–398.CrossRefGoogle Scholar
  41. Motawi, T.K., Shehata, N.I., ElNokeety, M.M., and El-Emady, Y.F. (2018). Potential serum biomarkers for early detection of diabetic nephropathy. Diabetes Res Clin Pract 136, 150–158.CrossRefGoogle Scholar
  42. Naboulsi, W., Megger, D.A., Bracht, T., Kohl, M., Turewicz, M., Eisenacher, M., Voss, D.M., Schlaak, J.F., Hoffmann, A.C., Weber, F., et al. (2016). Quantitative tissue proteomics analysis reveals versican as potential biomarker for early-stage hepatocellular carcinoma. J Proteome Res 15, 38–47.CrossRefGoogle Scholar
  43. Nylund, K.M., Ruokonen, H., Sorsa, T., Heikkinen, A.M., Meurman, J.H., Ortiz, F., Tervahartiala, T., Furuholm, J., and Bostanci, N. (2017). Association of the salivary triggering receptor expressed on myeloid cells/its ligand peptidoglycan recognition protein 1 axis with oral inflammation in kidney disease. J Periodontol, 1–17.Google Scholar
  44. Onile, O.S., Calder, B., Soares, N.C., Anumudu, C.I., and Blackburn, J.M. (2017). Quantitative label-free proteomic analysis of human urine to identify novel candidate protein biomarkers for schistosomiasis. PLoS Negl Trop Dis 11, e0006045.CrossRefGoogle Scholar
  45. Qin, W., and Gao, Y. (2015). Elution of urinary proteins preserved on nitrocellulose membrane with heating (in Chinese). Chin J Biotechnol 31, 1387–1392.Google Scholar
  46. Reszka, E. (2012). Selenoproteins in bladder cancer. Clin Chim Acta 413, 847–854.CrossRefGoogle Scholar
  47. Rohatgi, A., Ayers, C.R., Khera, A., McGuire, D.K., Das, S.R., Matulevicius, S., Timaran, C.H., Rosero, E.B., and de Lemos, J.A. (2009). The association between peptidoglycan recognition protein-1 and coronary and peripheral atherosclerosis: Observations from the Dallas Heart Study. Atherosclerosis 203, 569–575.CrossRefGoogle Scholar
  48. Sedic, M., Kraljevic Pavelic, S., Cindric, M., Vissers, J.P.C., Peronja, M., Josic, D., Cuk, M., Fumic, K., Pavelic, K., and Baric, I. (2011). Plasma biomarker identification in S-adenosylhomocysteine hydrolase deficiency. Electrophoresis 32, 1970–1975.CrossRefGoogle Scholar
  49. Shao, C., Li, M., Li, X., Wei, L., Zhu, L., Yang, F., Jia, L., Mu, Y., Wang, J., Guo, Z., et al. (2011). A tool for biomarker discovery in the urinary proteome: a manually curated human and animal urine protein biomarker database. Mol Cell Proteomics 10, M111 010975.CrossRefGoogle Scholar
  50. Shen, B., Lin, R., Wang, C.C., Rei, J., Sun, Y., Yang, Y.L., and Lin, Y.Y. (2017). ADAM33 gene polymorphisms identified to be associated with asthma in a Chinese Li population. Biomed Rep 6, 323–328.CrossRefGoogle Scholar
  51. Shyam, R., Patel, M.L., Sachan, R., Kumar, S., and Pushkar, D.K. (2017). Role of urinary neutrophil gelatinase-associated lipocalin as a biomarker of acute kidney injury in patients with circulatory shock. Ind J Crit Care Med 21, 740–745.CrossRefGoogle Scholar
  52. Siddiqi, Z., Karoli, R., Kaul, A., Fatima, J., Varshney, S., and Beg, M.S. (2017). Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as early markers of diabetic nephropathy. Ann Afr Med 16, 101–106.CrossRefGoogle Scholar
  53. Silva, S., Bronze, M.R., Figueira, M.E., Siwy, J., Siwy, J., Mischak, H., Combet, E., and Mullen, W. (2015). Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double-blind study. Am J Clin Nutrit 101, 44–54.CrossRefGoogle Scholar
  54. Smith, E.R., Zurakowski, D., Saad, A., Scott, R.M., and Moses, M.A. (2008). Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res 14, 2378–2386.CrossRefGoogle Scholar
  55. Tachibana, K., Saito, M., Imai, J.I., Ito, E., Yanagisawa, Y., Honma, R., Saito, K., Ando, J., Momma, T., Ohki, S., et al. (2017). Clinicopathological examination of dipeptidase 1 expression in colorectal cancer. Biomed Rep 6, 423–428.Google Scholar
  56. Toiyama, Y., Inoue, Y., Yasuda, H., Saigusa, S., Yokoe, T., Okugawa, Y., Tanaka, K., Miki, C., and Kusunoki, M. (2011). DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness. J Gastroenterol 46, 153–163.CrossRefGoogle Scholar
  57. Valdimarsson, S., Jodal, U., Barregård, L., and Hansson, S. (2017). Urine neutrophil gelatinase-associated lipocalin and other biomarkers in infants with urinary tract infection and in febrile controls. Pediatr Nephrol 32, 2079–2087.CrossRefGoogle Scholar
  58. Wang, D.B., Lu, X.K., Zhang, X., Li, Z.G., and Li, C.X. (2016). Carbonic anhydrase 1 is a promising biomarker for early detection of non-small cell lung cancer. Tumor Biol 37, 553–559.CrossRefGoogle Scholar
  59. Willis, N.D., Cox, T.R., Rahman-Casañs, S.F., Smits, K., Przyborski, S.A., van den Brandt, P., van Engeland, M., Weijenberg, M., Wilson, R.G., de Bruïne, A., et al. (2008). Lamin A/C is a risk biomarker in colorectal cancer. PLoS ONE 3, e2988.CrossRefGoogle Scholar
  60. Wisniewski, J.R., Zougman, A., Nagaraj, N., and Mann, M. (2009). Universal sample preparation method for proteome analysis. Nat Methods 6, 359–362.CrossRefGoogle Scholar
  61. Wu, J., and Gao, Y. (2015). Physiological conditions can be reflected in human urine proteome and metabolome. Expert Rev Proteomics 12, 623–636.CrossRefGoogle Scholar
  62. Wu, T., Du, Y., Han, J., Singh, S., Xie, C., Guo, Y., Zhou, X.J., Ahn, C., Saxena, R., and Mohan, C. (2013). Urinary angiostatin—a novel putative marker of renal pathology chronicity in lupus nephritis. Mol Cell Proteomics 12, 1170–1179.CrossRefGoogle Scholar
  63. Wu, Z., Wu, L., Weng, D., Xu, D., Geng, J., and Zhao, F. (2009). Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma. J Exp Clin Cancer Res 28, 8.CrossRefGoogle Scholar
  64. Yao, H., Chen, X., Lin, L., Wu, C., Fu, X., Wang, H., Yao, Z., Chen, W., Huang, L., Tang, R., et al. (2014). The spectrum of α- and β-thalassemia mutations of the Li people in Hainan Province of China. Blood Cells Mol Dis 53, 16–20.CrossRefGoogle Scholar
  65. Yao, H.X., Chen, Z.B., and Ding, Y.P. (2002). Serum levels of erythropoietin and transferrin receptor in thalassemia of the Li nationality (in Chinese). J Exp Hematol 10, 483–484.Google Scholar
  66. Yin, G.N., Lee, H.W., Cho, J.Y., and Suk, K. (2009). Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res 1265, 158–170.CrossRefGoogle Scholar
  67. Zheng, H., Yde, C.C., Clausen, M.R., Kristensen, M., Lorenzen, J., Astrup, A., and Bertram, H.C. (2015). Metabolomics investigation to shed light on cheese as a possible piece in the French paradox puzzle. J Agric Food Chem 63, 2830–2839.CrossRefGoogle Scholar
  68. Zürbig, P., Decramer, S., Dakna, M., Jantos, J., Good, D.M., Coon, J.J., Bandin, F., Mischak, H., Bascands, J.L., and Schanstra, J.P. (2009). The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease. Proteomics 9, 2108–2117.CrossRefGoogle Scholar

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© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.Department of PathophysiologyInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical CollegeBeijingChina
  3. 3.Department of Epidemiology and Statistics, Institute of Basic Medical SciencesChinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical CollegeBeijingChina
  4. 4.Department of Biochemistry and Molecular BiologyBeijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key LaboratoryBeijingChina

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