Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR = 1.199 (95%CI: 1.002–1.434), p = 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345–0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA).
References
[1]
OECD (2010) Obesity and the Economics of Prevention: Fit not Fat.
[2]
Farooqi IS, O’Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56: 443–458.
[3]
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, et al. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42: 937–948.
[4]
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, et al. (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41: 25–34.
[5]
Jacobsson JA, Schioth HB, Fredriksson R (2012) The impact of intronic single nucleotide polymorphisms and ethnic diversity for studies on the obesity gene FTO. Obes Rev 13: 1096–1109.
[6]
Prada PO, Quaresma PG, Caricilli AM, Santos AC, Guadagnini D, et al. (2013) Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei. Diabetes 62: 137–148.
[7]
Shiri-Sverdlov R, Custers A, van Vliet-Ostaptchouk JV, van Gorp PJ, Lindsey PJ, et al. (2006) Identification of TUB as a novel candidate gene influencing body weight in humans. Diabetes 55: 385–389.
[8]
Snieder H, Wang X, Shiri-Sverdlov R, van Vliet-Ostaptchouk JV, Hofker MH, et al. (2008) TUB is a candidate gene for late-onset obesity in women. Diabetologia 51: 54–61.
[9]
Moschonis G, Tanagra S, Vandorou A, Kyriakou AE, Dede V, et al. (2010) Social, economic and demographic correlates of overweight and obesity in primary-school children: preliminary data from the Healthy Growth Study. Public Health Nutr 13: 1693–1700.
[10]
Jacobsson JA, Rask-Andersen M, Riserus U, Moschonis G, Koumpitski A, et al. (2012) Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children. Int J Obes (Lond) 36: 119–129.
[11]
Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000) Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320: 1240–1243.
[12]
Tanner JM (1955) Growth at Adolescence. Oxford: Blackwell Scientific.
[13]
Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 76: 887–893.
[14]
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.
[15]
Skol AD, Scott LJ, Abecasis GR, Boehnke M (2006) Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 38: 209–213.
[16]
Sjoberg A, Moraeus L, Yngve A, Poortvliet E, Al-Ansari U, et al. (2011) Overweight and obesity in a representative sample of schoolchildren - exploring the urban-rural gradient in Sweden. Obes Rev 12: 305–314.
[17]
Barrett JC (2009) Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009: pdb ip71.
[18]
Mujica AO, Hankeln T, Schmidt ER (2001) A novel serine/threonine kinase gene, STK33, on human chromosome 11p15.3. Gene 280: 175–181.
[19]
Mujica AO, Brauksiepe B, Saaler-Reinhardt S, Reuss S, Schmidt ER (2005) Differential expression pattern of the novel serine/threonine kinase, STK33, in mice and men. FEBS J 272: 4884–4898.
[20]
Brauksiepe B, Mujica AO, Herrmann H, Schmidt ER (2008) The Serine/threonine kinase Stk33 exhibits autophosphorylation and phosphorylates the intermediate filament protein Vimentin. BMC Biochem 9: 25.
[21]
Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, et al. (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137: 821–834.
[22]
Kranenburg O (2005) The KRAS oncogene: past, present, and future. Biochim Biophys Acta 1756: 81–82.
[23]
Luo T, Masson K, Jaffe JD, Silkworth W, Ross NT, et al. (2012) STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability. Proc Natl Acad Sci U S A 109: 2860–2865.
[24]
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229.
