Abstract
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).
Highlights
Over the past 30 years, obesity has become one of the world’s leading health concerns
Large-scale meta-analysis of genome wide association data performed by the GIANT-consortium studies have so far identified at least 32 genetic loci associated with control of body mass development [3,4]
Association of rs4929949 with several measurements describing body adiposity were observed at the nominal significance level, as well as a trend towards association with insulin levels which was directionally consistent with non-significant effects reported by Speliotes et al [3], but only when BMI was not included in the model, indicating these effects to be secondary to the effect of rs4929949 on body weight
Summary
Over the past 30 years, obesity has become one of the world’s leading health concerns. A recent report by the OECD observed overweight and obesity to have reached high enough proportions in the industrialized parts of the world to be classified as a global epidemic [1]. The rise in prevalence of obesity and overweight is alarming as high BMI is associated with increased risk of developing complex diseases such as cardiovascular disease, type 2 diabetes, cancer etc. Alarming is the rise in childhood obesity observed in industrialized nations, reaching as high as 16.9% among children in the United States (2008) (http:// www.cdc.gov). The genetic influence on weight development is generally more complex as has been revealed by genome wide association studies. Large-scale meta-analysis of genome wide association data performed by the GIANT-consortium studies have so far identified at least 32 genetic loci associated with control of body mass development [3,4]. Replication in more specialized cohorts allows for secondary analysis to discern specific physiological effects of the associated loci or even identification of other associated traits
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