The role of established East Asian obesity-related loci on pediatric leptin levels highlights a neuronal influence on body weight regulation in Chinese children and adolescents: the BCAMS study

Junling Fu, Ge Li, Lujiao Li, Jinhua Yin, Hong Cheng, Lanwen Han, Qian Zhang, Naishi Li, Xinhua Xiao, Struan F A Grant, Mingyao Li, Shan Gao, Jie Mi, Ming Li, Junling Fu, Ge Li, Lujiao Li, Jinhua Yin, Hong Cheng, Lanwen Han, Qian Zhang, Naishi Li, Xinhua Xiao, Struan F A Grant, Mingyao Li, Shan Gao, Jie Mi, Ming Li

Abstract

Genome-wide association studies have identified multiple variants associated with adult obesity, mostly in European-ancestry populations. We aimed to systematically assess the contribution of key loci, which had been previously shown to be associated in East Asian adults, to childhood obesity, related adipokine profiles and metabolic traits in a Chinese pediatric population. Twelve single-nucleotide polymorphisms (SNPs) plus metabolic profiles and levels of five adipokines (leptin, adiponectin, resistin, fibroblast growth factor 21 and retinol binding protein 4) were evaluated in 3,506 Chinese children and adolescents aged 6-18. After correction for multiple comparisons, six of these SNPs were robustly associated with childhood obesity: FTO-rs1558902 (P=5.6×10-5), MC4R-rs2331841 (P=4.4×10-4), GNPDA2-rs16858082 (P = 3.4×10-4), PCSK1-rs261967 (P = 0.001), SEC16B-rs516636 (P = 0.004) and MAP2K5-rs4776970 (P = 0.004), with odds ratios ranging from 1.211 to 1.421; while ITIH4-rs2535633 and BDNF-rs2030323 yielded nominal association with the same trait (P < 0.05). Moreover, the risk alleles of six SNPs displayed significant (P < 0.004) or nominal (P < 0.05) association with leptin levels, namely at in/near PCSK1, MC4R, FTO, MAP2K5, GNPDA2 and BDNF plus their cumulative genetic score yielded stronger association with increased leptin levels (P = 6.2×10-11). Our results reveal that key obesity-associated loci previously reported in Europeans, but also associated with East Asian adults, are also associated with obesity and/or metabolic quantitative traits in Chinese children. These associations coincide with six brain-expressed loci that correlate with leptin levels, thus may point to an important neuronal influence on body weight regulation in the pediatric setting.

Keywords: SNP; adipokine; children; leptin; obesity.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflict of interests regarding the publication of this paper.

Figures

Figure 1. Path diagram showing that leptin…
Figure 1. Path diagram showing that leptin significantly mediates the association between leptin-related SNPs /GPSleptin (including six leptin-related SNPs) and BMI
The path diagram shows the simple association between the six leptin-related loci FTO, MC4R, GNPDA2 , PCSK1, MAP2K5, BDNF and GPSleptin and ln-leptin (β, 0.149, 0.110, 0.089, 0.087, 0.114, 0.071,and 0.095 respectively), the association between the FTO, MC4R, GNPDA2 , PCSK1, MAP2K5, BDNF and GPSleptin and BMI adjusted for leptin (β, 0.418, 0.188, 0.170, 0.086, 0.051, 0.048, and 0.139, respectively), and the association between leptin and BMI adjusted for the individual SNP or GPSleptin (β, 2.582, 2.586, 2.586, 2.588, 2.589, 2.589 and 2.571, respectively). The simple association between the FTO, MC4R, GNPDA2, PCSK1, MAP2K5, GPSleptin and BMI (β, 0.831, 0.486, 0.384, 0.311, 0.347, 0.216 and 0.384, respectively) was significantly higher than the association between the individual SNP,GPSleptin and BMI adjusted for leptin (β Δ 0.413, 0.298, 0.214, 0.225, 0.296, 0.168 and 0.245, respectively), indicating that leptin mediated part of the association. The Sobel test confirmed that leptin significantly mediated the association between the SNPs and BMI (P = 0.002, P = 0.003, P = 0.007, P = 0.008, P = 0.003, P = 0.027 and P < 0.001, respectively). All the linear regression coefficients (β) were adjusted for gender, age, Tanner stage and residence.
Figure 2. Possible interaction between the genes…
Figure 2. Possible interaction between the genes with at the six leptin-associated loci plus LEP and LEPR
This is a prediction of the interaction between the key proteins, including PCSK1, proprotein convertase subtilisin/kexin type 1; MC4R, melanocortin 4 receptor; FTO, fat mass and obesity associated; MAP2K5, mitogen-activated protein kinase 5; GNPDA2, glucosamine-6-phosphate deaminase 2; BDNF, brain-derived neurotrophic factor; LEP, leptin and LEPR, leptin receptor. The prediction was conducted by using a STRING interaction network.

References

    1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–81.
    1. Gong WJ, Zheng W, Xiao L, Tan LM, Song J, Li XP, Xiao D, Cui JJ, Li X, Zhou HH, Yin JY, Liu ZQ. Circulating resistin levels and obesity-related cancer risk: A meta-analysis. Oncotarget. 2016;7:57694–704. .
    1. Song Y, Wang HJ, Ma J, Wang Z. Secular trends of obesity prevalence in urban Chinese children from 1985 to 2010: gender disparity. PLoS One. 2013;8:e53069.
    1. Shah S, Bonder MJ, Marioni RE, Zhu Z, McRae AF, Zhernakova A, Harris SE, Liewald D, Henders AK, Mendelson MM, Liu C, Joehanes R, Liang L, et al. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations. Am J Hum Genet. 2015;97:75–85.
    1. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H, Lindgren CM, Luan J, Magi R, Randall JC, Vedantam S, Winkler TW, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42:937–48.
    1. Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM, Hypponen E, Holst C, Valcarcel B, Thiering E, Salem RM, Schumacher FR, Cousminer DL, et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet. 2012;44:526–31.
    1. Guo Y, Lanktree MB, Taylor KC, Hakonarson H, Lange LA, Keating BJ. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. Hum Mol Genet. 2013;22:184–201.
    1. Monda KL, Chen GK, Taylor KC, Palmer C, Edwards TL, Lange LA, Ng MC, Adeyemo AA, Allison MA, Bielak LF, Chen G, Graff M, Irvin MR, et al. A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet. 2013;45:690–6.
    1. Chesi A, Grant SF. The Genetics of Pediatric Obesity. Trends Endocrinol Metab. 2015;26:711–21.
    1. Felix JF, Bradfield JP, Monnereau C, van der Valk RJ, Stergiakouli E, Chesi A, Gaillard R, Feenstra B, Thiering E, Kreiner-Moller E, Mahajan A, Pitkanen N, Joro R, et al. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Hum Mol Genet. 2016;25:389–403.
    1. Hong J, Shi J, Qi L, Cui B, Gu W, Zhang Y, Li L, Xu M, Wang L, Zhai Y, Miao L, Wang R, Bi Y, et al. Genetic susceptibility, birth weight and obesity risk in young Chinese. Int J Obes (Lond) 2013;37:673–7.
    1. Wen W, Cho YS, Zheng W, Dorajoo R, Kato N, Qi L, Chen CH, Delahanty RJ, Okada Y, Tabara Y, Gu D, Zhu D, Haiman CA, et al. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet. 2012;44:307–11.
    1. Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, Hosono N, Maeda S, Wen W, Dorajoo R, Go MJ, Zheng W, Kato N, Wu JY, et al. Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet. 2012;44:302–6.
    1. Wen W, Zheng W, Okada Y, Takeuchi F, Tabara Y, Hwang JY, Dorajoo R, Li H, Tsai FJ, Yang X, He J, Wu Y, He M, et al. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index. Hum Mol Genet. 2014;23:5492–504.
    1. Warrington NM, Howe LD, Paternoster L, Kaakinen M, Herrala S, Huikari V, Wu YY, Kemp JP, Timpson NJ, St Pourcain B, Davey Smith G, Tilling K, Jarvelin MR, et al. A genome-wide association study of body mass index across early life and childhood. Int J Epidemiol. 2015;44:700–12.
    1. Abadi A, Peralta-Romero J, Suarez F, Gomez-Zamudio J, Burguete-Garcia AI, Cruz M, Meyre D. Assessing the effects of 35 European-derived BMI-associated SNPs in Mexican children. Obesity (Silver Spring) 2016;24:1989–95.
    1. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41:25–34.
    1. Bluher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism. 2015;64:131–45.
    1. Parimisetty A, Dorsemans AC, Awada R, Ravanan P, Diotel N, Lefebvre d’Hellencourt C. Secret talk between adipose tissue and central nervous system via secreted factors-an emerging frontier in the neurodegenerative research. J Neuroinflammation. 2016;13:67.
    1. Huang T, Tobias DK, Hruby A, Rifai N, Tworoger SS, Hu FB. An Increase in Dietary Quality Is Associated with Favorable Plasma Biomarkers of the Brain-Adipose Axis in Apparently Healthy US Women. J Nutr. 2016;146:1101–8.
    1. Kilpelainen TO, Carli JF, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, Hedman AK, Drong AW, Hayes JE, Zhao J, Pers TH, Schick U, Grarup N, et al. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun. 2016;7:10494.
    1. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–72.
    1. Ruiz-Narvaez EA, Haddad SA, Rosenberg L, Palmer JR. Birth weight modifies the association between central nervous system gene variation and adult body mass index. J Hum Genet. 2016;61:193–8.
    1. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.
    1. Fasshauer M, Blüher M. Adipokines in health and disease. Trends in pharmacological sciences. 2015;36:461–70.
    1. Kadowaki T, Yamauchi T, Kubota N. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett. 2008;582:74–80.
    1. Li M, Fisette A, Zhao XY, Deng JY, Mi J, Cianflone K. Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents. Int J Obes (Lond) 2009;33:424–39.
    1. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009;58:250–9.
    1. Lim S, Yoon JW, Choi SH, Park YJ, Lee JJ, Park JH, Lee SB, Kim KW, Lim JY, Kim YB, Park KS, Lee HK, Cho SI, et al. Combined impact of adiponectin and retinol-binding protein 4 on metabolic syndrome in elderly people: the Korean Longitudinal Study on Health and Aging. Obesity (Silver Spring, Md) 2010;18:826–32.
    1. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20:111–2.
    1. Tung YC, Yeo GS, O’Rahilly S, Coll AP. Obesity and FTO: Changing Focus at a Complex Locus. Cell Metab. 2014;20:710–8.
    1. Chen Z, Yin Q, Ma G, Qian Q. KCNQ1 gene polymorphisms are associated with lipid parameters in a Chinese Han population. Cardiovasc Diabetol. 2010;9:35.
    1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707–14.
    1. Group of China Obesity Task Force Body mass index reference norm for screening overweight and obesity in Chinese children and adolescents. [Article in Chinese] Zhonghua Liu Xing Bing Xue Za Zhi. 2004;25:97–102.
    1. Li M, Yin JH, Zhang K, Wu CY. A highly sensitive enzyme-linked immunosorbent assay for measurement of leptin secretion in human adipocytes. [Article in Chinese] Zhonghua Yi Xue Za Zhi. 2008;88:3293–7.
    1. Li Q, Lu Y, Sun L, Yan J, Yan X, Fang L, Li M, Fan Z. Plasma adiponectin levels in relation to prognosis in patients with angiographic coronary artery disease. Metabolism. 2012;61:1803–8.
    1. Xu L, Ping F, Yin J, Xiao X, Xiang H, Ballantyne CM, Wu H, Li M. Elevated plasma SPARC levels are associated with insulin resistance, dyslipidemia, and inflammation in gestational diabetes mellitus. PLoS One. 2013;8:e81615.
    1. Li L, Yin J, Cheng H, Wang Y, Gao S, Li M, Grant SF, Li C, Mi J, Li M. Identification of Genetic and Environmental Factors Predicting Metabolically Healthy Obesity in Children: Data From the BCAMS Study. J Clin Endocrinol Metab. 2016;101:1816–25.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.
    1. MacKinnon DP, Fairchild AJ, Fritz MS. Mediation analysis. Annu Rev Psychol. 2007;58:593–614.

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