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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2007

Open Access 01-09-2007 | Research

Genome-wide association with diabetes-related traits in the Framingham Heart Study

Authors: James B Meigs, Alisa K Manning, Caroline S Fox, Jose C Florez, Chunyu Liu, L Adrienne Cupples, Josée Dupuis

Published in: BMC Medical Genetics | Special Issue 1/2007

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Abstract

Background

Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants.

Methods

We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0–120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age2-adjusted residual trait values, and Cox survival models to test incident diabetes.

Results

We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r2 < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r2 = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits.

Conclusion

Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://​www.​ncbi.​nlm.​nih.​gov/​projects/​gap/​cgi-bin/​study.​cgi?​id=​phs000007. Framingham 100K data replicate the TCF7L2 association with diabetes.
Literature
1.
King H, Aubert RE, Herman WH: Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998, 21 (9): 1414-1431. 10.2337/diacare.21.9.1414.CrossRefPubMed
2.
Ritz E, Rychlik I, Locatelli F, Halimi S: End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. American Journal of Kidney Diseases. 1999, 34 (5): 795-808.CrossRefPubMed
3.
Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H: Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study. Diabetologia. 1999, 42 (2): 139-145. 10.1007/s001250051131.CrossRefPubMed
4.
Meigs JB, Cupples LA, Wilson PWF: Parental transmission of type 2 diabetes mellitus: the Framingham Offspring Study. Diabetes. 2000, 49: 2201-2207. 10.2337/diabetes.49.12.2201.CrossRefPubMed
5.
Florez JC, Hirschhorn J, Altshuler D: The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genomics Hum Genet. 2003, 4: 257-291. 10.1146/annurev.genom.4.070802.110436.CrossRefPubMed
6.
Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science. 1996, 273 (5281): 1516-1517. 10.1126/science.273.5281.1516.CrossRefPubMed
7.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000, 26 (1): 76-80. 10.1038/79216.CrossRefPubMed
8.
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM: Large-scale association studies of variants in genes encoding the pancreatic b-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003, 52 (2): 568-572. 10.2337/diabetes.52.2.568.CrossRefPubMed
9.
Florez JC, Burtt N, de Bakker PIW, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004, 53 (5): 1360-1368. 10.2337/diabetes.53.5.1360.CrossRefPubMed
10.
Barroso I, Luan J, Middelberg RPS, Harding A-H, Franks PW, Jakes RW, Clayton D, Schafer AJ, O'Rahilly S, Wareham NJ: Candidate gene association study in type 2 diabetes indicates a role for genes involved in β-cell function as well as insulin action. PLoS Biology. 2003, 1 (1): 41-55. 10.1371/journal.pbio.0000020.CrossRef
11.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006, 38 (3): 320-323. 10.1038/ng1732.CrossRefPubMed
12.
Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D, Group tDPPR: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006, 355 (3): 241-250. 10.1056/NEJMoa062418.PubMedCentralCrossRefPubMed
13.
Beysen D, Raes J, Leroy BP, Lucassen A, Yates JRW, Clayton-Smith J, Ilyina H, Brooks SS, Christin-Maitre S, Fellous M, Fryns JP, Kim JR, Lapunzina P, Lemyre E, Meire F, Messiaen LM, Oley C, Splitt M, Thomson J, Peer YVd, Veitia RA, De Paepe A, De Baere E: Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. Am J Hum Genet. 2005, 77 (2): 205-218. 10.1086/432083.PubMedCentralCrossRefPubMed
14.
Drake JA, Bird C, Nemesh J, Thomas DJ, Newton-Cheh C, Reymond A, Excoffier L, Attar H, Antonarakis SE, Dermitzakis ET, Hirschhorn JN: Conserved noncoding sequences are selectively constrained and not mutation cold spots. 2006, 38 (2): 223-227.
15.
16.
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science. 2002, 296 (5576): 2225-2229. 10.1126/science.1069424.CrossRefPubMed
17.
Pe'er I, de Bakker PIW, Maller J, Yelensky R, Altshuler D, Daly MJ: Evaluating and improving power in whole-genome association studies using fixed marker sets. 2006, 38 (6): 663-667.
18.
Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006, 38 (2): 209-213. 10.1038/ng1706.CrossRefPubMed
19.
Cupples LA, Arruda H, Benjamin EJ, D'Agostino SRB, Demissie S, DeStefano AL, Dupuis J, Falls K, CS F, Gottlieb DJ, Govindaraju DR, Guo CY, Heard-Costa N, Hwang SJ, Kathiresan S, Kiel DP, Laramie JM, Larson MG, Levy D, Liu CY, Lunetta KL, Mailman MD, Manning AK, Meigs JB, Murabito JM, Newton-Cheh C, O'Connor GT, O'Donnell CJ, Pandey MA, Seshadri S, Vasan RS, Wang ZY, Wilk JB, Wolf PA, Yang Q, Atwood LD: The Framingham Heart Study 100K SNP genome-wide association study resource: Overview of 17 phenotype working group reports. BMC Med Genet. 2007, 8 (Suppl 1): S1-PubMedCentralCrossRefPubMed
20.
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. 1985, 28 (7): 412-419. 10.1007/BF00280883.CrossRefPubMed
21.
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. 2000, 47 (3): 177-184. 10.1016/S0168-8227(99)00116-3.CrossRefPubMed
22.
Hanley AJ, Williams K, Gonzalez C, D'Agostino RB, Wagenknecht LE, Stern MP, Haffner SM: Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study. Diabetes. 2003, 52 (2): 463-469. 10.2337/diabetes.52.2.463.CrossRefPubMed
23.
Meigs JB, Nathan DM, Wilson PWF, Cupples LA, Singer DE: Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance: the Framingham Offspring Study. Annals of Internal Medicine. 1998, 128: 524-533.CrossRefPubMed
24.
Meigs JB, D'Agostino RB, Nathan DM, Rifai N, Wilson PW: Longitudinal association of glycemia and microalbuminuria: the Framingham Offspring Study. Diabetes Care. 2002, 25 (6): 977-983. 10.2337/diacare.25.6.977.CrossRefPubMed
25.
Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB, Wilson PW: Insulin Resistance, the Metabolic Syndrome, and Incident Cardiovascular Events in The Framingham Offspring Study. Diabetes. 2005, 54: 3252-3257. 10.2337/diabetes.54.11.3252.CrossRefPubMed
26.
Horvath S, Wei E, Xu X, Palmer LJ, Baur M: Family-based association test method: age of onset traits and covariates. Genet Epidemiol. 2001, 21 (Suppl 1): S403-408.PubMed
27.
Hanson RL, Ehm MG, Pettitt DJ, Prochazka M, Thompson DB, Timberlake D, Foroud T, Kobes S, Baier L, Burns DK, Almasy L, Blangero J, Garvey WT, Bennett PH, Knowler WC: An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet. 1998, 63 (4): 1130-1138. 10.1086/302061.PubMedCentralCrossRefPubMed
28.
Therneau TM, Grambsch PM: Modeling Survival Data: Extending the Cox Model. 2001, New York: Springer
29.
30.
Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ, Weber RJ, Haussler D, Kent WJ: The UCSC Genome Browser Database. Nucleic Acids Res. 2003, 31 (1): 51-54. 10.1093/nar/gkg129.PubMedCentralCrossRefPubMed
31.
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D: The human genome browser at UCSC. Genome Res. 2002, 12 (6): 996-1006. 10.1101/gr.229102. Article published online before print in May 2002.PubMedCentralCrossRefPubMed
32.
Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, McCarthy MI: Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes. 2006, 55 (9): 2640-2644. 10.2337/db06-0355.CrossRefPubMed
33.
Zhang C, Qi L, Hunter DJ, Meigs JB, Manson JE, van Dam RM, Hu FB: Variant of Transcription Factor 7-Like 2 (TCF7L2) Gene and the Risk of Type 2 Diabetes in Large Cohorts of U.S. Women and Men. Diabetes. 2006, 55 (9): 2645-2648. 10.2337/db06-0643.CrossRefPubMed
34.
Scott LJ, Bonnycastle LL, Willer CJ, Sprau AG, Jackson AU, Narisu N, Duren WL, Chines PS, Stringham HM, Erdos MR, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Collins FS, Boehnke M: Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes. 2006, 55 (9): 2649-2653. 10.2337/db06-0341.CrossRefPubMed
35.
Damcott CM, Pollin TI, Reinhart LJ, Ott SH, Shen H, Silver KD, Mitchell BD, Shuldiner AR: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: Replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes. 2006, 55 (9): 2654-2659. 10.2337/db06-0338.CrossRefPubMed
36.
Saxena R, Gianniny L, Burtt NP, Lyssenko V, Guiducci C, Sjögren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, Lindblad U, Daly MJ, Tuomi T, Hirschhorn JN, Groop L, Altshuler D: Common SNPs in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in non-diabetic individuals. Diabetes. 2006.
37.
Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, Stetsyuk V, Scharfmann R, Staels B, Fruhbeck G, Froguel P: Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes. 2006, 55 (10): 2903-2908. 10.2337/db06-0474.CrossRefPubMed
38.
van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, Strengman E, van Haeften TW, Hofker MH, Wijmenga C: Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia. 2006
39.
Field SF, Howson JM, Smyth DJ, Walker NM, Dunger DB, Todd JA: Analysis of the type 2 diabetes gene, TCF7L2, in 13,795 type 1 diabetes cases and control subjects. Diabetologia. 2006
40.
Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, Li KW, Palmen J, Miller MA, Cappuccio FP, Elkeles R, Godsland I, Miller GJ, Talmud PJ: Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med. 2006
41.
Nicolae DL, Wen X, Voight BF, Cox NJ: Coverage and characteristics of the Affymetrix GeneChip Human Mapping 100K SNP set. PLoS Genet. 2006, 2 (5): e67-10.1371/journal.pgen.0020067.PubMedCentralCrossRefPubMed
Metadata
Title
Genome-wide association with diabetes-related traits in the Framingham Heart Study
Authors
James B Meigs
Alisa K Manning
Caroline S Fox
Jose C Florez
Chunyu Liu
L Adrienne Cupples
Josée Dupuis
Publication date
01-09-2007
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue Special Issue 1/2007
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-8-S1-S16

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