Genetic Association Study with Metabolic Syndrome and Metabolic-Related Traits in a Cross-Sectional Sample and a 10-Year Longitudinal Sample of Chinese Elderly Population
Background The metabolic syndrome (MetS) has been known as partly heritable, while the number of genetic studies on MetS and metabolic-related traits among Chinese elderly was limited. Methods A cross-sectional analysis was performed among 2 014 aged participants from September 2009 to June 2010 in Beijing, China. An additional longitudinal study was carried out among the same study population from 2001 to 2010. Biochemical profile and anthropometric parameters of all the participants were measured. The associations of 23 SNPs located within 17 candidate genes (MTHFR, PPARγ, LPL, INSIG, TCF7L2, FTO, KCNJ11, JAZF1, CDKN2A/B, ADIPOQ, WFS1, CDKAL1, IGF2BP2, KCNQ1, MTNR1B, IRS1, ACE) with overweight and obesity, diabetes, metabolic phenotypes, and MetS were examined in both studies. Results In this Chinese elderly population, prevalence of overweight, central obesity, diabetes, dyslipidemia, hypertension, and MetS were 48.3%, 71.0%, 32.4%, 75.7%, 68.3% and 54.5%, respectively. In the cross-sectional analyses, no SNP was found to be associated with MetS. Genotype TT of SNP rs4402960 within the gene IGF2BP2 was associated with overweight (odds ratio (OR) = 0.479, 95% confidence interval (CI): 0.316-0.724, p = 0.001) and genotype CA of SNP rs1801131 within the gene MTHFR was associated with hypertension (OR = 1.560, 95% CI: 1.194–2.240, p = 0.001). However, these associations were not observed in the longitudinal analyses. Conclusions The associations of SNP rs4402960 with overweight as well as the association of SNP rs1801131 with hypertension were found to be statistically significant. No SNP was identified to be associated with MetS in our study with statistical significance.
References
[1]
Alberti KG, Zimmet P, Shaw J (2005) IDF Epidemiology Task Force Consensus Group (2005) The metabolic syndrome - a new worldwide definition. Lancet 366: 1059–1062. doi: 10.1016/s0140-6736(05)67402-8
[2]
Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, et al. (1992) Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 41: 715–722. doi: 10.2337/diabetes.41.6.715
[3]
Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, et al. (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24: 683–689. doi: 10.2337/diacare.24.4.683
[4]
Bosy-Westphal A, Onur S, Geisler C, Wolf A, Korth O, et al. (2007) Common familial influences on clustering of metabolic syndrome traits with central obesity and insulin resistance: the Kiel obesity prevention study. Int J Obes (Lond) 31: 784–790. doi: 10.1038/sj.ijo.0803481
[5]
Henneman P, Aulchenko YS, Frants RR, van Dijk KW, Oostra BA, et al. (2008) Prevalence and heritability of the metabolic syndrome and its individual components in a Dutch isolate: the Erasmus Rucphen Family study. J Med Genet 45: 572–577. doi: 10.1136/jmg.2008.058388
[6]
Bellia A, Giardina E, Lauro D, Tesauro M, Di Fede G, et al. (2009) The Linosa Study: epidemiological and heritability data of the metabolic syndrome in a Caucasian genetic isolate. Nutr Metab Cardiovasc Dis 19: 455–461. doi: 10.1016/j.numecd.2008.11.002
[7]
He Y, Jiang Y, Wang J, Fan L, Li X, et al. (2006) Prevalence of peripheral arterial disease and its association with smoking in a population-based study in Beijing, China. J Vasc Surg 44: 333–338. doi: 10.1016/j.jvs.2006.03.032
[8]
The IDF consensus worldwide definition of the metabolic syndrome. Available: http://wwwidforg/home/indexcfm?=unode=11？20071E-AACE-41D2-9FA0-BAB6E25BA072. Accessed 2005 Apr 14.
[9]
World Health Organization (2000). The Asia-Pacific perspective: redefining obesity and its treatment. Geneva, Switzerland: World Health Organization.
[10]
World Health Organization (1999) Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Reports of a WHO Consultation. Geneva, World Health Org.
[11]
Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42: 579–589.
[12]
Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, et al. (2009) Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41: 1110–1111. doi: 10.1038/ng.443
[13]
Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, et al. (2009) Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 58: 1690–1699. doi: 10.2337/db08-1494
[14]
Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, et al. (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41: 18–24. doi: 10.1038/ng.274
[15]
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, et al. (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41: 25–34.
[16]
Bouatia-Naji N, Bonnefond A, Cavalcanti-Proen？a C, Spars？ T, Holmkvist J, et al. (2009) A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41: 89–94. doi: 10.1038/ng.277
[17]
Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, et al. (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58: 505–510. doi: 10.2337/db08-0906
[18]
Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, et al. (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41: 77–81. doi: 10.1038/ng.290
[19]
Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, et al. (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Net Genet 40: 1092–1097. doi: 10.1038/ng.207
[20]
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, et al. (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40: 638–645. doi: 10.1038/ng.120
[21]
Salonen JT, Uimari P, Aalto JM, Pirskanen M, Kaikkonen J, et al. (2007) Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium. Am J Hum Genet 81: 338–345. doi: 10.1086/520599
[22]
Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, et al. (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331–1336. doi: 10.1126/science.1142358
[23]
Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341–1345. doi: 10.1126/science.1142382
[24]
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Net Genet 39: 770–775. doi: 10.1038/ng2043
[25]
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336–1341.
[26]
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889–894. doi: 10.1126/science.1141634
[27]
Yang WS, Yang YC, Chen CL, Wu IL, Lu JY, et al. (2007) Adiponectin SNP276 is associated with obesity, the metabolic syndrome, and diabetes in the elderly. Am J Clin Nutr 86: 509–513.
[28]
Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, et al. (1999) A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol 19: 1262–1270.
[29]
Rong R, Hanson RL, Ortiz D, Wiedrich C, Kobes S, et al. (2009) Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes 58: 478–488. doi: 10.2337/db08-0877
[30]
Li X, Allayee H, Xiang AH, Trigo E, Hartiala J, et al. (2009) Variation in IGF2BP2 interacts with adiposity to alter insulin sensitivity in Mexican Americans, Obesity. 17: 729–736. doi: 10.1038/oby.2008.593
[31]
Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, et al. (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40: 1098–1102. doi: 10.1038/ng.208
[32]
Yu W, Ma RC, Hu C, So WY, Zhang R, et al. (2012) Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes. Diabetologia 55: 2655–2659. doi: 10.1007/s00125-012-2636-8
[33]
Hu C, Wang C, Zhang R, Ma X, Wang J, et al. (2009) Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population. Diabetologia 52: 1322–1325. doi: 10.1007/s00125-009-1335-6
[34]
Liu Y, Zhou DZ, Zhang D, Chen Z, Zhao T, et al. (2009) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China. Diabetologia 52: 1315–1321. doi: 10.1007/s00125-009-1375-y
[35]
Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, et al. (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12: 17–23. doi: 10.1038/ng0196-17
[36]
Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, et al. (1997) A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 15: 186–189. doi: 10.1038/ng0297-186
[37]
MacDonald PE, Ha XF, Wang J, Smukler SR, Sun AM, et al. (2001) Members of the Kv1 and Kv2 Voltage-Dependent K+ Channel Families Regulate Insulin Secretion. Mol Endocrinol 15: 1423–1435. doi: 10.1210/mend.15.8.0685
[38]
MacDonald PE, Sewing S, Wang J, Joseph JW, Smukler SR, et al. (2002) Inhibition of Kv2.1 Voltage-dependent K+ Channels in Pancreatic beta –Cells Enhances Glucose-dependent Insulin Secretion. J Biol Chem 277: 44938–44945. doi: 10.1074/jbc.m205532200
[39]
Zhang M, Houamed K, Kupershmidt S, Roden D, Satin LS (2005) Pharmacological Properties and Functional Role of Kslow Current in Mouse Pancreatic {beta}-Cells: SK Channels Contribute to Kslow Tail Current and Modulate Insulin Secretion. J Gen Physiol 126: 353–363. doi: 10.1085/jgp.200509312
[40]
Groenewoud MJ, Dekker JM, Fritsche A, Reiling E, Nijpels G, et al. (2008) Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Diabetologia 51: 1659–1663. doi: 10.1007/s00125-008-1083-z
[41]
Palmer ND, Goodarzi MO, Langefeld CD, Ziegler J, Norris JM, et al. (2008) Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Diabetes 57: 1093–1100. doi: 10.2337/db07-1169
[42]
Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, et al. (2006) A common genetic variant is associated with adult and childhood obesity. Science 312: 279–283. doi: 10.1126/science.1124779
[43]
Yabe D, Brown MS, Goldstein JL (2002) Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci USA 99: 12753–12758. doi: 10.1073/pnas.162488899
[44]
Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS (2003) Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc Natl Acad Sci USA 100: 3155–3160. doi: 10.1073/pnas.0130116100
[45]
Dina C, Meyre D, Samson C, Tichet J, Marre M, et al. (2007) Comment on “A common genetic variant is associated with adult and childhood obesity”. Science 315: 187. doi: 10.1126/science.1129402
[46]
Loos RJ, Barroso I, O'rahilly S, Wareham NJ (2007) Comment on”A common genetic variant is associated with adult and childhood obesity”. Science 315: 187. doi: 10.1126/science.1130012
[47]
Rosskopf D, Bornhorst A, Rimmbach C, Schwahn C, Kayser A, et al. (2007) Comment on “A common genetic variant is associated with adult and childhood obesity”. Science 315: 187. doi: 10.1126/science.1130571
[48]
Pollex RL, Ban MR, Young TK, Bjerregaard P, Anand SS, et al. (2007) Association between the ？455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample. BMC Med Genet 8: 80. doi: 10.1186/1471-2350-8-80
[49]
Ciullo M, Nutile T, Dalmasso C, Sorice R, Bellenguez C, et al. (2008) Identification and replication of a novel obesity locus on chromosome 1q24 in isolated populations of Cilento. Diabetes 57: 783–790. doi: 10.2337/db07-0970
[50]
Kumar J, Sunkishala RR, Karthikeyan G, Sengupta S (2007) The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population. Clin Genet 71: 415–418. doi: 10.1111/j.1399-0004.2007.00795.x
[51]
Smith AJ, Cooper JA, Li LK, Humphries SE (2007) INSIG2 gene polymorphism is not associated with obesity in Caucasian, Afro-Caribbean and Indian subjects. Int J Obes (Lond) 31: 1753–1755. doi: 10.1038/sj.ijo.0803645
[52]
Boes E, Kollerits B, Heid IM, Hunt SC, Pichler M, et al. (2008) INSIG2 Polymorphism Is Neither Associated With BMI Nor With Phenotypes of Lipoprotein Metabolism. Obesity (Silver Spring) 16: 827–833. doi: 10.1038/oby.2007.132
[53]
Oki K, Yamane K, Kamei N, Asao T, Awaya T, et al. (2009) The single nucleotide polymorphism upstream of insulin-induced gene 2 (INSIG2) is associated with the prevalence of hypercholesterolaemia, but not with obesity, in Japanese American women. Br J Nutr 101: 322–327. doi: 10.1017/s0007114508006557
[54]
Markan S, Sachdeva M, Sehrawat BS, Kumari S, Jain S, et al. (2007) MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians. Mol Cell Biochem 302: 125–131. doi: 10.1007/s11010-007-9434-5
[55]
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111–113. doi: 10.1038/ng0595-111
[56]
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methyltetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64: 169–172. doi: 10.1006/mgme.1998.2714
