title: Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes.
abstract: Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.
authors.affiliation: Latvian Biomedical Research and Study Centre, Ratsupites Street 1, LV-1067 Riga, Latvia. ineta@biomed.lu.lv
authors.forename: Ineta
authors.initials: I
authors.lastname: Kalnina
authors.forename: Linda
authors.initials: L
authors.lastname: Zaharenko
authors.forename: Iveta
authors.initials: I
authors.lastname: Vaivade
authors.forename: Vita
authors.initials: V
authors.lastname: Rovite
authors.forename: Liene
authors.initials: L
authors.lastname: Nikitina-Zake
authors.forename: Raitis
authors.initials: R
authors.lastname: Peculis
authors.forename: Davids
authors.initials: D
authors.lastname: Fridmanis
authors.forename: Kristine
authors.initials: K
authors.lastname: Geldnere
authors.forename: Josefin A
authors.initials: JA
authors.lastname: Jacobsson
authors.forename: Markus S
authors.initials: MS
authors.lastname: Almen
authors.forename: Valdis
authors.initials: V
authors.lastname: Pirags
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Janis
authors.initials: J
authors.lastname: Klovins
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D011506:Proteins; C530715:TMEM18 protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
keywords: Add; Association study; BMI; CEU; CI; EMP2; FTO; GWA; ICD-10; IRX3; International Statistical Classification of Diseases 10th Revision; LD; LGDB; Latvian Genome Data Base; Latvian population; OR; Obesity; RAF; Rec; SD; SNP; T2D; TMEM18; Type 2 diabetes; Utah residents with ancestry from northern and western Europe; additive; body mass index; confidence interval; corrected empirical p-value; freq; frequency; genome wide association; iroquois homeobox 3; linkage disequilibrium; logBMI; logarithmically transformed body mass index values; n; non-significant; ns; number; odds ratio; p - values derived performing permutation tests specifying 100000 permutations and corrected for multiple testing (EMP2); p-perm; recessive; risk allele frequency; single nucleotide polymorphisms; standard deviation; the fat mass and obesity associated; transmembrane 18; type 2 diabetes