Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers

Abstract

Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients’ sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 ± 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions.

Effect of Interaction between Early Menarche and Genetic Polymorphisms on Triglyceride

“…Quality control procedures were adopted, such as missing genotype frequency > 0.5% and minor allele frequency (MAF) ≤ 0.05. After sample and genotype quality controls, 344,396 SNPs for 3180 individuals were available in the KARE database [ 26 , 27 ]. The KARE data used to support the findings of this study are restricted by the Institutional Review Board of the Korean National Institute of Health, who can contact at National Biobank of Korea ( http://koreabiobank.re.kr , 82–1661-9070).…”

“…In our study, 344,396 SNPs were mapped to genes within 20 kb boundaries. Pathways consisting of <20 or >200 genes were excluded from further analysis, to reduce the multiple testing issue and avoid testing overly narrow or broad functional categories [ 22 , 27 ]. A false discovery rate (FDR) was used for multiple testing correction, with q values < 0.05 considered significant.…”

“…Improved GSEA approaches use a comprehensive pathway and gene set database from SNP data. Pathway-related information is obtained from the KEGG (Kyoto Encyclopedia of Genes and Genomes pathway database), BioCarta, and GO (gene ontology) databases [ 27 ].…”

Pathogenic Single Nucleotide Polymorphisms on Autophagy-Related Genes

“…In contrast, nucleotide changes on ALFY were identified in patients with microcephaly [ 94 ], as well as in oropharynx cancer [ 95 ]. WIPI4 pathogenic SNPs have been shown to cause neurological disorders, such as neurodegeneration with brain iron accumulation (NBIA) and Rett syndrome [ 96 , 97 , 98 ], while polymorphisms on WIPI2 and WIPI3 have been associated with osteoporosis [ 99 ] and a neurodevelopmental syndrome [ 100 ]. Two variants of ATG2A have been linked with both granuloma formation in Crohn’s disease and hyperuricemia [ 101 , 102 ].…”

Novel Direction in Mechanisms Underlying Lead Toxicity: Evidence and Prospective

“…Further, Genome Wide Association Studies (GWAS)-based pathway analysis revealed significant upregulation of nuclear receptor and VEGF pathways by body lead burden, with regard to the prevalence of osteoporosis in smokers. Their study findings highlight the probable interactions that intracellular pathways of angiogenesis and nuclear hormone signalling may play between exposure to lead and genetic variation, especially in individuals with diminished bone mineral density [3].…”