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


OBJECTIVE
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.


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=0.0037) and leptin (P=0.0068). ALPL markers were associated with WHR (P=0.0026) and EGFR (P=0.0001). The ANKH gene was associated with all four studied obesity-related traits (P<0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected.


CONCLUSIONS
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.
Korostishevsky
M
M
Department of Anatomy and Anthropology, Human Population Biology Research Unit, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cohen
Z
Z
Malkin
I
I
Ermakov
S
S
Yarenchuk
O
O
Livshits
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood* / Q000235:genetics; D015992:Body Mass Index; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D020738:Leptin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009765:Obesity / Q000097:blood / Q000235:genetics; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011755:Pyrophosphatases / Q000097:blood / Q000235:genetics*; D049629:Waist-Hip Ratio; D055815:Young Adult
D020738:Leptin; D066246:ErbB Receptors; D000469:Alkaline Phosphatase; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases