Association of Variants in RETN With Plasma Resistin Levels and Diabetes-Related Traits in the Framingham Offspring Study

Diabetes - Tập 58 Số 3 - Trang 750-756 - 2009
Marie‐France Hivert1,2, Man Li3, Jarred B. McAteer4,5, Josée Dupuis3, Caroline S. Fox6,7, L. Adrienne Cupples3, James B. Meigs1,2, Jose C. Florez4,1,5
1Department of Medicine, Harvard Medical School, Boston, Massachusetts
2General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
3Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
4Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
5Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
6Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
7National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts

Tóm tắt

OBJECTIVE— The RETN gene encodes the adipokine resistin. Associations of RETN with plasma resistin levels, type 2 diabetes, and related metabolic traits have been inconsistent. Using comprehensive linkage disequilibrium mapping, we genotyped tag single nucleotide polymorphisms (SNPs) in RETN and tested associations with plasma resistin levels, risk of diabetes, and glycemic traits. RESEARCH DESIGN AND METHODS— We examined 2,531 Framingham Offspring Study participants for resistin levels, glycemic phenotypes, and incident diabetes over 28 years of follow-up. We genotyped 21 tag SNPs that capture common (minor allele frequency >0.05) or previously reported SNPs at r2 > 0.8 across RETN and its flanking regions. We used sex- and age-adjusted linear mixed-effects models (with/without BMI adjustment) to test additive associations of SNPs with traits, adjusted Cox proportional hazards models accounting for relatedness for incident diabetes, and generated empirical P values (Pe) to control for type 1 error. RESULTS— Four tag SNPs (rs1477341, rs4804765, rs1423096, and rs10401670) on the 3′ side of RETN were strongly associated with resistin levels (all minor alleles associated with higher levels, Pe<0.05 after multiple testing correction). rs10401670 was also associated with fasting plasma glucose (Pe = 0.02, BMI adjusted) and mean glucose over follow-up (Pe = 0.01; BMI adjusted). No significant association was observed for adiposity traits. On meta-analysis, the previously reported association of SNP −420C/G (rs1862513) with resistin levels remained significant (P = 0.0009) but with high heterogeneity across studies (P < 0.0001). CONCLUSIONS— SNPs in the 3′ region of RETN are associated with resistin levels, and one of them is also associated with glucose levels, although replication is needed.

Từ khóa


Tài liệu tham khảo

Scherer PE: Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55:1537–1545,2006

McTernan PG, Kusminski CM, Kumar S: Resistin. Curr Opin Lipidol 17:170–175,2006

Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 409:307–312,2001

Fain JN, Cheema PS, Bahouth SW: Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun 300:674–678,2003

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 309:286–290,2003

Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA: Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 300:472–476,2003

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808,2003

Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Catapano AL: Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol 156:279–284,2007

Osawa H, Tabara Y, Kawamoto R, Ohashi J, Ochi M, Onuma H, Nishida W, Yamada K, Nakura J, Kohara K, Miki T, Makino H: 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 30:1501–1506,2007

Hivert MF, Sullivan LM, Fox CS, Nathan DM, D’Agostino RB Sr, Wilson PW, Meigs JB: Associations of adiponectin, resistin, and TNF{alpha} with insulin resistance. J Clin Endocrinol Metab 93:3165–3172,2008

Menzaghi C, Coco A, Salvemini L, Thompson R, De Cosmo S, Doria A, Trischitta V: Heritability of serum resistin and its genetic correlation with insulin resistance-related features in nondiabetic Caucasians. J Clin Endocrinol Metab 91:2792–2795,2006

Azuma K, Oguchi S, Matsubara Y, Mamizuka T, Murata M, Kikuchi H, Watanabe K, Katsukawa F, Yamazaki H, Shimada A, Saruta T: Novel resistin promoter polymorphisms: association with serum resistin level in Japanese obese individuals. Horm Metab Res 36:564–570,2004

Cho YM, Youn BS, Chung SS, Kim KW, Lee HK, Yu KY, Park HJ, Shin HD, Park KS: Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. Diabetologia 47:559–565,2004

Osawa H, Onuma H, Ochi M, Murakami A, Yamauchi J, Takasuka T, Tanabe F, Shimizu I, Kato K, Nishida W, Yamada K, Tabara Y, Yasukawa M, Fujii Y, Ohashi J, Miki T, Makino H: Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes. Biochem Biophys Res Commun 335:596–602,2005

Bouchard L, Weisnagel SJ, Engert JC, Hudson TJ, Bouchard C, Vohl MC, Perusse L: Human resistin gene polymorphism is associated with visceral obesity and fasting and oral glucose stimulated C-peptide in the Quebec Family Study. J Endocrinol Invest 27:1003–1009,2004

Engert JC, Vohl M-C, Williams SM, Lepage P, Faith J, Dore C, Renaud Y, Burtt NP, Villeneuve A, Hirschhorn JN, Altshuler D, Groop LC, Despres J-P, Gaudet D, Hudson TJ: 5′ flanking variants of resistin are associated with obesity. Diabetes 51:1629–1634,2002

Mattevi VS, Zembrzuski VM, Hutz MH: A resistin gene polymorphism is associated with body mass index in women. Hum Genet 115:208–212,2004

Norata GD, Ongari M, Garlaschelli K, Tibolla G, Grigore L, Raselli S, Vettoretti S, Baragetti I, Noto D, Cefalu AB, Buccianti G, Averna M, Catapano AL: Effect of the −420C/G variant of the resistin gene promoter on metabolic syndrome, obesity, myocardial infarction and kidney dysfunction. J Intern Med 262:104–112,2007

Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G: A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52:1611–1618,2003

Ukkola O, Kesaniemi YA, Tremblay A, Bouchard C, Kesaniemi YA: Two variants in the resistin gene and the response to long-term overfeeding. Eur J Clin Nutr 58:654–659,2004

Xu JY, Sham PC, Xu A, Tso AWK, Wat NMS, Cheng KY, Fong CHY, Janus ED, Lam KSL: Resistin gene polymorphisms and progression of glycaemia in southern Chinese: a 5-year prospective study. Clin Endocrinol 66:211–217,2007

Pizzuti A, Argiolas A, Di Paola R, Baratta R, Rauseo A, Bozzali M, Vigneri R, Dallapiccola B, Trischitta V, Frittitta L: An ATG repeat in the 3′-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance. J Clin Endocrinol Metab 87:4403–4406,2002

Conneely KN, Silander K, Scott LJ, Mohlke KL, Lazaridis KN, Valle TT, Tuomilehto J, Bergman RN, Watanabe RM, Buchanan TA, Collins FS, Boehnke M: Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects. Diabetologia 47:1782–1788,2004

Gouni-Berthold I, Giannakidou E, Faust M, Kratzsch J, Berthold HK, Krone W: Resistin gene 3′-untranslated region +62G–>A polymorphism is associated with hypertension but not diabetes mellitus type 2 in a German population. J Intern Med 258:518–526,2005

Kunnari A, Ukkola O, Kesaniemi YA: Resistin polymorphisms are associated with cerebrovascular disease in Finnish type 2 diabetic patients. Diabet Med 22:583–589,2005

Ochi M, Osawa H, Onuma H, Murakami A, Nishimiya T, Shimada F, Kato K, Shimizu I, Shishino K, Murase M, Fujii Y, Ohashi J, Makino H: The absence of evidence for major effects of the frequent SNP +299G>A in the resistin gene on susceptibility to insulin resistance syndrome associated with Japanese type 2 diabetes. Diabetes Res Clin Pract 61:191–198,2003

Wang H, Chu WS, Hemphill C, Elbein SC: Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J Clin Endocrinol Metab 87:2520–2524,2002

Ma X, Warram JH, Trischitta V, Doria A: Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians. J Clin Endocrinol Metab 87:4407–4410,2002

Ochi M, Osawa H, Hirota Y, Hara K, Tabara Y, Tokuyama Y, Shimizu I, Kanatsuka A, Fujii Y, Ohashi J, Miki T, Nakamura N, Kadowaki T, Itakura M, Kasuga M, Makino H: Frequency of the G/G genotype of resistin single nucleotide polymorphism at -420 appears to be increased in younger-onset type 2 diabetes. Diabetes 56:2834–2838,2007

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419,1985

Gutt M, Davis CL, Spitzer SB, Llabre MM, Kumar M, Czarnecki EM, Schneiderman N, Skyler JS, Marks JB: Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures. Diabetes Res Clin Pract 47:177–184,2000

Maurovich-Horvat P, Massaro J, Fox CS, Moselewski F, O'Donnell CJ, Hoffmann U: Comparison of anthropometric, area- and volume-based assessment of abdominal subcutaneous and visceral adipose tissue volumes using multi-detector computed tomography. Int J Obes 31:500–506,2007

Nathan DM: Labile glycosylated hemoglobin contributes to hemoglobin A1 as measured by liquid chromatography or electrophoresis. Clin Chem 27:1261–1263,1981

Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211,1998

Therneau T, Grambsch P: Modeling Survival Data: Extending the Cox Model. New York, Springer,2001

Therneau TM, Grambsch PM, Pankratz VS: Penalized survival models and frailty. J Comput Graph Stat 12:156–175,2003

DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 7:177–188,1986

Yamauchi J, Osawa H, Takasuka T, Ochi M, Murakami A, Nishida W, Onuma H, Takata Y, Tabara Y, Miki T, Ohashi J, Makino H: Serum resistin is reduced by glucose and meal loading in healthy human subjects. Metabolism 57:149–156,2008

Osawa H, Yamada K, Onuma H, Murakami A, Ochi M, Kawata H, Nishimiya T, Niiya T, Shimizu I, Nishida W, Hashiramoto M, Kanatsuka A, Fujii Y, Ohashi J, Makino H: 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 75:678–686,2004

Li K, Wang S-W, Li Y, Martin RE, Li L, Lu M, Lamhamedi-Cherradi S-E, Hu G, Demissie-Sanders S, Zheng J, Chung F, Oates T, Yao Z: Identification and expression of a new type II transmembrane protein in human mast cells. Genomics 86:68–75,2005

Thông tin
Thông tin xuất bản

Diabetes

Tập 58 Số 3

750-756

Thông tin tác giả