title: Genetic variants of FOXA2: risk of type 2 diabetes and effect on metabolic traits in North Indians.
abstract: Here, we examined the association of genetic variants of FOXA2, an upstream activator of the beta-cell transcription factor network, with type 2 diabetes and related phenotypes in North India. We genotyped three SNPs (rs1212275, rs1055080, rs6048205) and the (TCC)( n ) repeat polymorphism in 1,656 participants comprising 1,031 patients with type 2 diabetes and 625 controls. SNPs rs1212275 and rs6048205 were uncommon (MAF < 5%) with similar distribution among patients and controls. We found a strong association of (TCC)( n ) common allele A5 with type 2 diabetes [OR = 1.66 (95% CI 1.36-2.04, p = 5.9 x 10(-7)) for A5 homozygotes]. Obese individuals with A5A5 genotype had enhanced risk when segregated from normal-weight subjects [OR = 1.92 (95% CI 1.47-2.51), p = 1.6 x 10(-6)]. A5 was also nominally associated with higher fasting glucose (p = 0.02) and lower fasting insulin (p = 0.0028) and C-peptide (p = 0.036) levels among controls. At the rs1055080 locus, GG was found to provide reduced risk among normal-weight subjects [OR = 0.59 (95% CI 0.40-0.88), p = 0.011]. Combination of protective GG and non-risk genotypes of (TCC)( n ) showed reduced risk of type 2 diabetes both among normal-weight [OR = 0.43 (95% CI 0.29-0.65), p = 1.2 x 10(-6)] and obese individuals [0.47 (95% CI 0.34-0.64), p = 4.3 x 10(-5)]. For the first time we demonstrated that FOXA2 variants may affect risk of type 2 diabetes and metabolic traits in North India, however replication analyses in other cohorts are required to confirm the findings.
authors.affiliation: Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India.
authors.forename: Rubina
authors.initials: R
authors.lastname: Tabassum
authors.affiliation: Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Chavali
authors.affiliation: Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India.
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Dwivedi
authors.affiliation: Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, 110 029, India.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tandon
authors.affiliation: Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India. db@igib.res.in.
authors.forename: Dwaipayan
authors.initials: D
authors.lastname: Bharadwaj
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D006801:Humans; D007194:India / Q000453:epidemiology; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; C496502:FOXA2 protein, human; D007328:Insulin; D051542:Hepatocyte Nuclear Factor 3-beta
references.citation: Diabetes Care. 2004 May;27(5):1047-53
references.pmid: 15111519
references.citation: Curr Opin Genet Dev. 1999 Jun;9(3):295-300
references.pmid: 10377278
references.citation: Genes Dev. 2001 Jul 1;15(13):1706-15
references.pmid: 11445544
references.citation: Trends Endocrinol Metab. 2000 Sep;11(7):281-5
references.pmid: 10920385
references.citation: J Clin Invest. 2004 Aug;114(4):512-20
references.pmid: 15314688
references.citation: Mol Cell Biol. 1997 Oct;17(10):6002-13
references.pmid: 9315659
references.citation: Diabetologia. 2001 Sep;44(9):1094-101
references.pmid: 11596662
references.citation: Development. 2000 Dec;127(24):5533-40
references.pmid: 11076772
references.citation: J Genet. 2008 Apr;87(1):3-20
references.pmid: 18560169
references.citation: Diabetologia. 2000 Sep;43(9):1197-200
references.pmid: 11043867
references.citation: Bioinformatics. 2005 Oct 15;21(20):3918-25
references.pmid: 16105896
references.citation: J Biol Chem. 2002 May 17;277(20):17564-70
references.pmid: 11875061
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Science. 1998 Jul 31;281(5377):692-5
references.pmid: 9685261
references.citation: PLoS Genet. 2006 Dec;2(12):e215
references.pmid: 17194221
references.citation: Lancet. 2004 Jan 10;363(9403):157-63
references.pmid: 14726171
references.citation: Nature. 2004 Dec 23;432(7020):1027-32
references.pmid: 15616563
references.citation: Mol Cell Proteomics. 2005 Aug;4(8):1029-37
references.pmid: 15886397
references.citation: Hum Hered. 2000 Nov-Dec;50(6):370-81
references.pmid: 10899756
references.citation: Diabetes Care. 2003 Jan;26 Suppl 1:S5-20
references.pmid: 12502614
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: J Clin Invest. 2003 Aug;112(3):345-56
references.pmid: 12865419
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: Diabetologia. 2000 Jan;43(1):121-4
references.pmid: 10672453