Physiologic Parameters and Related Genotypes in Metabolic Function: A Twin/Sibling Study in Non-Clinical Adolescents
Date Issued
2008
Date
2008
Author(s)
Liu, Pi-Hua
Abstract
Three studies were conducted to investigate the heritability of adiponectin, leptin, BMI, and insulin sensitivity, and the association between variants of TCF7L2 gene and insulin sensitivity in adolescent twins.tudy 1. Genetic and Environmental Influences on Adiponectin, Leptin, and BMI among Adolescents in Taiwan: A Multivariate Twin/Sibling Analysisirculating levels of leptin and adiponectin are closely associated with obesity. However, it is not known whether there are common shared genes or environment exerting influences on the levels of leptin, adiponectin, and BMI. We aimed to assess the relative contribution of genes and environment to adiponectin, leptin, and BMI individually as well as simultaneously to the three measures. Our subjects included a total of 228 twin/sibling pairs aged 12 to 18 (130 monozygotic twins, 68 dizygotic twins and 30 sibling pairs) were recruited from the middle schools. Multivariate analyses were applied to twin/sibling data using structural equation modeling. The results showed that intraclass correlations for adiponectin, leptin and BMI were higher in the MZ twins than those in the DZ/SP group. The relative contribution of genes to adiponectin (39%) was comparable to those of shared environment (40%). In contrast, leptin and BMI were influenced mostly by genes (74% and 89%, respectively). The multivariate genetic analyses showed that a latent factor underlying the three measures was identified, with BMI being equivalent to this latent factor. The BMI-dependent genetic factor explains only 15% and 34% of variation of adiponectin and leptin, respectively. These data indicate a differential contribution of genetic factors for the variation of adiponectin, leptin and BMI. More importantly, only a small portion of the genetic influences on adiponectin and leptin was attributed to BMI. Our findings provided more insight into the complex regulation of adiponectin and leptin in obesity.tudy 2. Heritability of Insulin Sensitivity in Adolescent Twin/Sibling: OGTT-Based versus Fasting-Based Indicesnsulin resistance plays a crucial role in many metabolic abnormalities and metabolic syndrome. The aim of the present study was to investigate whether the variation of a wide variety of fasting- and OGTT-based insulin sensitivity indices was attributable to genetic or environmental factors in a sample of healthy adolescent twin/siblings. We recruited a total of 228 twin/sibling pairs aged 12 to 18 from the middle schools for a 2h OGTT. Univariate twin analyses using structural equation modeling implemented in Mx software package were employed to estimate genetic and environmental contributions on fasting- and OGTT-based insulin sensitivity indices. Our results showed that moderate to high broad heritability (27%-78%) was estimated for all insulin sensitivity indices except for GSI. In addition, no significant sex differences were found. For all fasting-based indices that were better explained by ADE model, the additive genetic influences accounted for around 25% of the total variance, whereas the estimates of broad heritability were around 55%. For OGTT-based insulin sensitivity indices that were better explained by ADE model, 63%-78% of the total variance was attributed to genetic influences. For those indices that were better explained by ACE model, significant additive genetic influences were observed. Among them, the broad heritability of SIisOGTT index was as high as 75%. These findings revealed that among a wide variety of insulin sensitivity indices in non-referred adolescents, the broad heritability estimates were greater for OGTT-based than for fasting-based indices. The findings may help in the search for genes underlying the variation in complex traits that are affected by insulin sensitivity.tudy 3. Association of the TCF7L2 Genetic Polymorphisms with Insulin Resistance and Related Metabolic Phenotypes in Chinese AdolescentsFC7L2 genetic variants are strongly associated with type 2 diabetes and impaired insulin secretion in European and Taiwanese. However, the mechanism underlying the association remained unknown in the Chinese population. Therefore, we genotyped 18 common single nucleotide polymorphisms (SNPs) of TCF7L2 gene in 525 non-clinical adolescent twin/sibling in Taiwan. Oral glucose tolerance test (OGTT) was performed and quantitative metabolic parameters were measured for each participant. Among the 18 SNPs, rs290487 C allele were significantly associated with elevated 60, 90, and 120-min glucose concentrations (p = 0.001, 0.014 and 0.021) and 60 and 90-min insulin concentrations (p = 0.017 and 0.019) during OGTT, which suggested increased insulin resistance. We did not observe significant association of rs290487 with measures of insulin secretion including the homeostasis model assessment of beta cell and the insulinogenic index. Another SNP rs10749127 located in intron 4 was also significantly associated features of the metabolic syndrome including elevated systolic and diastolic pressures (p = 0.024 and 2x10-4), triglycerides (p = 7x10-4), uric acid levels (p = 0.011), and possibly higher body mass index (p = 0.059). In conclusion, the risk-conferring TCF7L2 genetic variant in the Chinese population is associated with increased insulin resistance but not impaired beta-cell function in healthy adolescents. These findings underscore the emerging evidence implicating the role of Wnt signaling in insulin resistance and metabolic syndrome.
Subjects
Metabolic phenotype
Adipokine
TCF7L2 gene
Insulin sensitivity
Heritability
Twin study
SDGs
Type
thesis
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