| Obesity is a condition of excess body fat that causes or exacerbates several major health problems. It’s a highly heritable complex disease that influenced by multiple gene-gene interaction and environmental factors. Obesity always accompanied many other diseases, like angiocardiopathy, hypertension, diabetes, it may increased the mortality and brings inconvenience for our life. There were many ways to measure obesity, and the most common and useful method is to measure a Body Mass Index (BMI). Fat mass and percentage of fat mass are the common phenotypes to study obesity. As major risk factors for obesity, they have strong genetic determination with the heritability of over0.5. Recently, Genomewide association studies (GWASs), candidate gene linkage analysis have identified some obesity related genes/regions, but few accounted for majority of heritability and complicated mechanism. For further illuminated the molecular mechanism and exploring the genetic mechanism for obesity, we performed2parts of studies. First, we conducted a meta analysis for6obesity candidate genes in8different samples. A total of45SNPs located in the FTO gene demonstrated significant associations with obesity phenotypes using a Bonfferoni corrected significance level of p<1.68×10-5, and the most significant association was observed for FTO rs7185735(p=1.01×10-7for BMI,1.80×10-6for FM, and5.29X10-4for PBF). Linkage disequilibrium (LD) analysis revealed that these45SNPs were in almost complete LD (r2>0.80) and were located within the same LD block of approximately50kb. For the other5genes (CTNNBL1, PPARG, LEPR, UCP2and ADRB2),26SNPs,11SNPs and33SNPs from CTNNBL1, PPARG and LEPR showed marginal significance of associations with p ranging between1.50×10-3and4.94×10-2. Additionally, we performed a series of meta-analyses stratified by sex and ethnic groups and found some sex-specific and ethnic-specific SNPs/genes, such as rs16952725of FTO in males(p=6.87×10-4for BMI), but not in the female specific sample (p=0.55for BMI), we found that35FTO SNPs were significantly associated with BMI and FM (p<1.68×10-5) in Caucasians but not in non-Caucasians (p>0.05). In this study, we did not find confirmatory evidence for contributions of FTO, CTNNBL1, LEPR and PPARG related genomic variants to human variation in adiposity. In particular, FTO variants showed sex-specific and ethnic-specific associations with adiposity traits. In the next part of a agene-gene interaction analyses, we performed a GWAS in Chinese sample with subjects of1627and take the results of p-value which less than0.05to next gene-gene interaction analysis. Then, we replicated the interaction analysis results of p value less than1×10-4in2286Caucasians. In the stage of interaction analyses in Chinese sample, we found that the most significant interaction was Mir548X with LOC101927856, respectively, but not significant in next replication analysis. In the results of replication, There were9pairwise of interaction SNPs located in TCERG1L and CYP19A1, respectively, which have been identified that associated with obesity in the top15results. In this9pairwise SNPs, there were3ones in TCERG1L and4in CYP19A1, and the most significant result was the interaction of rs2918147and rs10519299(p=1.62×10-7in Chinese,p=1.73×10-2in Caucasian).Study shows that TCERGIL has been associated with plasma adiponectin. CYP19A1gene encoded aromatase and it may affect body fat distribution indirectly but regulated by the androgens and estrogens in adipose tissue. Additionally, CYP19A1has been identified as a potential candidate gene for human obesity by previously GWAS studies. The precise mechanism of interaction between CYP19A1and TCERGIL was still unknown. This study have discovered a pairwise interaction gene TCERG1L and CYP19A1that influenced obesity for the first time, It may established evidence for our next study for obesity in level of biological function. |
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