Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass

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