title: Validation of type 2 diabetes risk variants identified by genome-wide association studies in Han Chinese population: a replication study and meta-analysis.
abstract: BACKGROUND
  Several genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated.
  
  
  METHODS
  We analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese.
  
  
  RESULTS
  Five risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations.
  
  
  CONCLUSIONS
  We confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital HsinChu branch, Taipei, Taiwan; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Pi-Hua
authors.initials: PH
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Kuo
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tien-Jyun
authors.initials: TJ
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Der
authors.initials: YD
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jiun-Yi
authors.initials: JY
authors.lastname: Nong
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Clinical Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004843:Epistasis, Genetic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012306:Risk; D012307:Risk Factors; D013624:Taiwan
references.citation: Diabetes Care. 2013 Jan;36 Suppl 1:S11-66
references.pmid: 23264422
references.citation: PLoS Med. 2009 Jul 21;6(7):e1000097
references.pmid: 19621072
references.citation: Nat Genet. 2008 Sep;40(9):1098-102
references.pmid: 18711366
references.citation: PLoS One. 2010 Feb 10;5(2):e9153
references.pmid: 20161779
references.citation: J Diabetes. 2013 Jun;5(2):136-45
references.pmid: 23298195
references.citation: N Engl J Med. 2008 Nov 20;359(21):2220-32
references.pmid: 19020324
references.citation: Diabetes. 2008 Oct;57(10):2834-42
references.pmid: 18633108
references.citation: Nat Genet. 2010 Oct;42(10):864-8
references.pmid: 20818381
references.citation: Diabetologia. 2008 Nov;51(11):2134-7
references.pmid: 18766326
references.citation: Mol Biol Rep. 2012 Mar;39(3):2447-54
references.pmid: 21643948
references.citation: JAMA. 2013 Sep 4;310(9):948-59
references.pmid: 24002281
references.citation: Diabetologia. 2008 Jul;51(7):1146-52
references.pmid: 18493736
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666
references.citation: PLoS Genet. 2010 Feb 19;6(2):e1000847
references.pmid: 20174558
references.citation: Diabetologia. 2011 Nov;54(11):2811-9
references.pmid: 21826484
references.citation: Nat Genet. 2007 Aug;39(8):951-3
references.pmid: 17603484
references.citation: Diabetes. 2007 Oct;56(10):2631-7
references.pmid: 17579206
references.citation: PLoS One. 2010 Nov 17;5(11):e14022
references.pmid: 21103332
references.citation: BMC Med Genet. 2010 Jun 15;11:97
references.pmid: 20550665
references.citation: Nat Genet. 2008 Sep;40(9):1092-7
references.pmid: 18711367
references.citation: J Clin Endocrinol Metab. 2008 Oct;93(10):4107-12
references.pmid: 18628523
references.citation: PLoS One. 2012;7(4):e35060
references.pmid: 22506066
references.citation: Science. 2007 Jun 1;316(5829):1341-5
references.pmid: 17463248
references.citation: Nat Genet. 2008 May;40(5):638-45
references.pmid: 18372903
references.citation: Nat Genet. 2011 Dec 11;44(1):67-72
references.pmid: 22158537
references.citation: Mol Biol Rep. 2012 Jan;39(1):17-23
references.pmid: 21437630
references.citation: BMC Med Genet. 2010 May 28;11:81
references.pmid: 20509872
references.citation: Science. 2007 Jun 1;316(5829):1331-6
references.pmid: 17463246
references.citation: J Clin Endocrinol Metab. 2010 Jan;95(1):390-7
references.pmid: 19892838
references.citation: J Hum Genet. 2010 Dec;55(12):810-5
references.pmid: 20927120
references.citation: PLoS Genet. 2010 Sep 16;6(9):e1001127
references.pmid: 20862305
references.citation: Gene. 2012 Mar 10;495(2):115-9
references.pmid: 22245614
references.citation: Bioinformatics. 2003 Jan;19(1):149-50
references.pmid: 12499305
references.citation: J Nutr Biochem. 2013 Jan;24(1):353-9
references.pmid: 22981370
references.citation: Diabetes. 2008 Aug;57(8):2226-33
references.pmid: 18469204
references.citation: J Clin Endocrinol Metab. 2007 Sep;92(9):3733-7
references.pmid: 17609304
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: PLoS One. 2009 Oct 28;4(10):e7643
references.pmid: 19862325
references.citation: Acta Pharmacol Sin. 2010 Jun;31(6):709-17
references.pmid: 20523342
references.citation: N Engl J Med. 2008 Nov 20;359(21):2208-19
references.pmid: 19020323
references.citation: J Mol Med (Berl). 2012 Jul;90(7):847-58
references.pmid: 22527884
references.citation: Genet Mol Res. 2012 May 24;11(2):1592-8
references.pmid: 22653633
references.citation: Science. 2007 Jun 1;316(5829):1336-41
references.pmid: 17463249