Abstract
Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18–80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Sladek R, Rocheleau G, Rung J et al: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445: 881–885.
Scott LJ, Mohlke KL, Bonnycastle LL et al: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007; 316: 1341–1345.
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007; 316: 1331–1336.
Zeggini E, Weedon MN, Lindgren CM et al: Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007; 316: 1336–1341.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007; 39: 770–775.
Gudmundsson J, Sulem P, Steinthorsdottir V et al: Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type-2 diabetes. Nat Genet 2007; 39: 977–983.
The Wellcome Trust Case Control Consortium: Genome-wide association study of 14 000 cases of seven common diseases and 3 000 shared controls. Nature 2007; 447: 661–678.
Herbert A, Gerry NP, McQueen MB et al: A common genetic variant is associated with adult and childhood obesity. Science 2006; 312: 279–283.
Frayling TM, Timpson NJ, Weedon MN et al: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894.
Dina C, Meyre D, Gallina S et al: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.
Hinney A, Nguyen TT, Scherag A et al: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007; 2: e1361.
Loos RJ, Lindgren CM, Li S et al: Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008; 40: 768–775.
Chambers JC, Elliott P, Zabaneh D et al: Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008; 40: 716–718.
Thorleifsson G, Walters GB, Gudbjartsson DF et al: Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18–24.
Frayling TM : Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007; 8: 657–662.
Zeggini E, Scott LJ, Saxena R et al: Meta-analysis of genome-wide association data and large-scale replication idenitifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008; 40: 638–645.
Rudan P, Roberts DF, Sujoldzic A et al: Strategy of anthropological research on the island of Hvar. Coll Anthropologicum 1982; 6: 39–46.
Rudan P, Sujoldzic, Simic D et al: Population structure in eastern Adriatic: the influence of historical processes, migration patterns, isolation and ecological pressures, and their interaction. in Roberts DF, Fujiki N, Torizuka K (eds): Isolation, Migration and Health. Cambridge University Press: Cambridge (SSHB), 1992, pp 204–218.
Smolej-Narancic N, Zagar I : Overweight and fatness in Dalmatia, Croatia: comparison with the US population reference. Coll Antropol 2000; 24: 411–421.
Rudan I, Rudan D, Campbell H et al: Inbreeding and risk of late onset complex disease. J Med Genet 2003; 40: 925–932.
Pucarin-Cvetkovic J, Mustajbegovic J, Jelinic JD et al: Body mass index and nutrition as determinants of health and disease in population of Croatian Adriatic islands. Croat Med J 2006; 47: 619–626.
Pal P, Xi H, Sun G et al: Tagging SNPs in the kallikrein genes 3 and 2 on 19q13 and their associations with prostate cancer in men of European origin. Hum Genet 2007; 122: 251–259.
National Institutes of Health: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). National Institutes of Health, NIH Publication No 01-3670, Bethesda, MD, 2001.
International Diabetes Federation: The IDF consensus worldwide definition of the metabolic syndrome. April 2005, http://www.idf.org/webdata/docs/MetSyndrome_Final.pdf.
Scuteri A, Sanna S, Chen WM et al: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3: e115.
Grant SF, Li M, Bradfield JP et al: Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS One 2008; 3: e1746.
Price RA, Li W-D, Zhao H : FTO gene SNPs associated with extreme obesity in cases, controls and extremely discordant sister pairs. BMC Med Genet 2008; 9: 4.
Willer CJ, Speliotes EK, Loos RJ et al: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.
Zhang G, Karns R, Narancic NS et al: Common SNPs in FTO gene are associated with obesity related anthropometric traits in an island population from the eastern Adriatic coast of Croatia. PLoS One 2010; 5: e10375.
Grant SF, Thorleifsson G, Reynisdottir I et al: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320–323.
Cauchi S, El Achhab Y, Choquet H et al: TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 2007; 85: 777–782.
Tong Y, Lin Y, Zhang Y et al: Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large human genome epidemiology (HuGE) review and meta-analysis. BMC Med Genet 2009; 10: 15.
Altshuler D, Hirschhorn JN, Klannemark M et al: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76–80.
Lyon HN, Emilsson V, Hinney A et al: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet 2007; 3: e61.
Acknowledgements
This study was supported by a grant from the National Institutes of Health, USA (R01 DK069845) and grants from the Croatian Ministry of Science, Education and Sports (196-1962766-2751 to PR, 196-1962766-2747 to NSN, 196-0342282-0291 to ZD). RK was supported by a training grant from the National Institute of Environmental Health Sciences, USA (T32 ES010957). GZ was supported partially by a gift fund from Ellen and the late Dr George Rieveschl Jr.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Author contributions
The study was conceived and designed by RD, PR and RC. Sample and data collection was conducted by NJ, DH-A, SM, NSN, ZD and PR. Genotyping was performed by RK, SRI and GS. Statistical analysis was performed by RK, GZ, WN and RC. The draft paper was prepared by RK, GZ, ZD, NSN, RC, PR and RD. All authors read and approved the final draft.
Supplementary Information accompanies the paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Karns, R., Zhang, G., Jeran, N. et al. Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia. Eur J Hum Genet 19, 341–346 (2011). https://doi.org/10.1038/ejhg.2010.178
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2010.178
Keywords
This article is cited by
-
Association and interaction of the FTO rs1421085 with overweight/obesity in a sample of Pakistani individuals
Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity (2020)
-
Genetic Determinants of Variability in Glycated Hemoglobin (HbA1c) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care
Current Diabetes Reports (2011)
