No clinical utility of common polymorphisms in IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 genes previously associated with insulin resistance in overweight children from Romania and Moldova

Abstract

Background Previous genome-wide association studies (GWAS) identified IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 as candidate genes for insulin resistance and type 2 diabetes (T2D). We investigated the associations of these previously reported common variants in these genes with insulin resistance in overweight children from Romania and Moldova. Methods Six single nucleotide polymorphisms (SNPs), IGF1 (rs35767), IRS1 (rs2943634), GCKR (rs780094), PPARG (rs1801282), GCK1 (rs1799884) and KCTD15 (rs29941), were genotyped in 100 overweight children along with clinical and metabolic parameters. Homeostatic model assessment of insulin resistance (HOMA-IR) above 3.4 (defining insulin resistance) was used as the outcome. Results Children differed in insulin resistance status despite having similar body mass index (BMI) standard deviation scores (SDS) (World Health Organization, [WHO] reference). The identified predictors for altered insulin metabolism were higher cholesterol levels, higher diastolic blood pressure and higher waist-to-hip-ratio (as a marker for increased abdominal fat). None of the SNPs showed significant association with increase in the risk for insulin resistance in children (p range=0.478–0.724; odds ratio [OR] range=1.924–4.842); however, the risk allele in GCKR (rs780094, p=0.06, OR=6.871) demonstrated near statistical significance. Conclusions The interrogated risk alleles did not show any significant association with insulin resistance in children in our cohort; however, the GCKR (rs780094) might be a viable candidate in larger cohorts. The lack of replication of the proposed association may point to differences in linkage disequilibrium or effect modifiers across studies.

The Oscillometric Pulse Wave Analysis Is Useful in Evaluating the Arterial Stiffness of Obese Children with Relevant Cardiometabolic Risks

“…Our previous work [ 28 ] has already shown that a part of these risk factors are linked to increased carotid intima-media thickness (CIMT) and our goal is to provide more data on the links between these factors and vascular health. More studies are needed in order to determine the genetic profile of at-risk patients [ 29 ]. It is our aim to provide additional scientific data with regard to childhood obesity and other risk factors’ effects on arterial stiffness progression and ultimately, provide grounds for more efficient preventive measures and for an earlier intervention [ 30 ] in such patients.…”

Effects of PPARG and PPARGC1A gene polymorphisms on obesity markers

“…Nutritional status across Europe is miscellaneous, but a high prevalence of childhood obesity has been reported throughout the entire continent, especially in Southern Europe ( 2 , 3 ). Overweight and obesity prevalence numbers in children from Romania are comparable to other European countries, with one recent study showing that every 1 in 4 individuals aged 6–19 years are overweight or obese ( 2 , 4 ).…”

PPARγ2 Pro12Ala Polymorphism is Associated in Children With Traits Related to Susceptibility to Type 2 Diabetes

“…Some studies in adults have reported an association between the Ala12 variant of PPARγ2 gene and a minor risk of diabetes and insulin resistance ( Ek et al, 2001 ; González Sánchez et al, 2002 ), although some others failed to find any association ( Mancini et al, 1999 ). Also studies in children have found an association between the polymorphism and insulin sensitivity ( Buzzetti et al, 2005 ; Scaglioni et al, 2006 ; Dedoussis et al, 2009 ; Jermendy et al, 2011 ), although others failed to find this association ( Johansson et al, 2009 ; De Kort and Hokken-Koelega, 2010 ; Csernus et al, 2015 ; Stryjecki et al, 2016 ; Chirita-Emandi et al, 2019 ). However, most of the studies analyzed data in a dominant model ( Stumvoll et al, 2001 ) and reported significant associations in subjects with obesity ( Hara et al, 2000 ).…”