Recent genome-wide association studies （GWAS） have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms （SNPs）, especially rs2736100...Recent genome-wide association studies （GWAS） have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms （SNPs）, especially rs2736100 located in the telomerase reverse transcriptase （TERT） gene show unique and significant association with non-small cell lung cancer （NSCLC） in a few subpopulations including women, nonsmokers, East Asians and those with adenocarcinoma, Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental （e.g., less-smoking） and physiological factors （gender and age） that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor （EGFR） mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity, By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.展开更多
The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level i...The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.展开更多
基金supported in part by American Cancer SocietyIL Division (Grant No. 189273) (to W. Liu)Start-Up Fund of the College of Pharmacy, Purdue University (Grant No. 003055) (to W. Liu)
文摘Recent genome-wide association studies （GWAS） have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms （SNPs）, especially rs2736100 located in the telomerase reverse transcriptase （TERT） gene show unique and significant association with non-small cell lung cancer （NSCLC） in a few subpopulations including women, nonsmokers, East Asians and those with adenocarcinoma, Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental （e.g., less-smoking） and physiological factors （gender and age） that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor （EGFR） mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity, By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.
基金supported in part by a NIH grant,No.R01 DK106540(to WL).
文摘The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.
