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Variation in the FFAR1 gene modifies BMI, body composition and plasma lipids but not plasma insulin or Beta-cell function in overweight subjects
Background
FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids.
Methodology/Principal Findings
For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m2 higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI-increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six.
Conclusions/Significance
Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function
Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer
BACKGROUND: Body mass index (BMI) has been implicated as a primary factor influencing cancer development. However, understanding the relationship between these two complex traits has been confounded by both environmental and genetic heterogeneity. METHODS: In order to gain insight into the genetic factors linking BMI and cancer, we performed chemical carcinogenesis on a genetically heterogeneous cohort of interspecific backcross mice ((Mus Spretus × FVB/N) F1 × FVB/N). Using this cohort, we performed quantitative trait loci (QTL) analysis to identify regions linked to BMI. We then performed an integrated analysis incorporating gene expression, sequence comparison between strains, and gene expression network analysis to identify candidate genes influencing both tumor development and BMI. RESULTS: Analysis of QTL linked to tumorigenesis and BMI identified several loci associated with both phenotypes. Exploring these loci in greater detail revealed a novel relationship between the Pannexin 3 gene (Panx3) and both BMI and tumorigenesis. Panx3 is positively associated with BMI and is strongly tied to a lipid metabolism gene expression network. Pre-treatment Panx3 gene expression levels in normal skin are associated with tumor susceptibility and inhibition of Panx function strongly influences inflammation. CONCLUSIONS: These studies have identified several genetic loci that influence both BMI and carcinogenesis and implicate Panx3 as a candidate gene that links these phenotypes through its effects on inflammation and lipid metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-016-0334-8) contains supplementary material, which is available to authorized users