Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

Abstract

Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. Aim: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. Subjects and methods: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. Results: Associations were observed between ENPP1 polymorphisms and BMI (P ¼ 0.0037) and leptin (P ¼ 0.0068). ALPL markers were associated with WHR (P ¼ 0.0026) and EGFR (P ¼ 0.0001). The ANKH gene was associated with all four studied obesity-related traits (Po0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. Conclusion: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

Lipid accumulation and alkaline phosphatase activity in human preadipocytes isolated from different body fat depots

“…31 Lastly, in humans, a recent study demonstrated that polymorphisms in the tissue-non-specific ALP gene are associated with body fat distribution. 32 Intracellular lipid accumulation and ALP activity were only measured at baseline and on day 12 of the differentiation period. The latter represents a time point at which all the proteins that are characteristic of mature adipocytes are already being expressed.…”

A significant association exists between receptor tyrosine kinase-like orphan receptor 2 gene variants and the OPG/RANKL ratio in human plasma

“…The analysis was applied to evaluate the magnitude and relative importance of the various familial sources (including the additive genetic component and heritability) on their variability. Application of this method was previously described by us elsewhere [37,38]. Briefly, the maximum likelihood ratio test (LRT) was used to estimate the relative contribution of the various familial sources on the phenotype variation: V AD , V SP , V HS , and V SIB -variance components attributable to additive genetic factors, as well as the common environment shared by spouses, household members, and siblings.…”

“…To test the association between ROR2 polymorphisms and the study phenotypes, we carried out the pedigreebased disequilibrium test (PDT) [38,39] as implemented in the MAN-9 package. PDT examines the association between the marker genotypes and the quantitative phenotype variation and exploits the complete pedigree data, including the non-genotyped pedigree members.…”

“…PDT examines the association between the marker genotypes and the quantitative phenotype variation and exploits the complete pedigree data, including the non-genotyped pedigree members. As a result, its power to detect association is considerably higher compared with commonly used transmission disequilibrium tests [38]. The significance of the polymorphism's association is assessed by LRT, by comparing the additive model of inheritance vs. the model, assuming no polymorphism effect, i.e., where all three genotypespecific means are set as equal.…”

“…In order to test the hypothesis of two independent functional polymorphisms in proximal and central segments of ROR2 locus, we applied the bivariate extension of variance decomposition analysis [38]. Specifically, the model incorporated two parameters for additive effects of the competing DNA markers, corresponding to the SNPs located in proximal and central ROR2 regions.…”