A promoter polymorphism of the alpha2-HS glycoprotein gene is associated with its transcriptional activity.
alpha2-Heremans Schmid glycoprotein (AHSG), also designated fetuin-A, is an abundant plasma protein that is expressed in hepatocytes. AHSG/fetuin-A has diverse biological functions including regulation of calcium homeostasis and inhibition of insulin receptor tyrosine kinase activity. The aim of this study was to detect single nucleotide polymorphisms (SNPs) of the AHSG gene that can be involved in regulation of AHSG/fetuin-A expression. By a cycle sequencing method, two common SNPs in the promoter region of AHSG gene, -799A/T (rs2248690, dbSNP ID) and -425G/T (rs2077119), were identified. A reporter gene assay using HepG2 cells showed that the -799A allele had significantly higher promoter activity compared with the -799T allele. The overexpression of c-Fos/c-Jun significantly repressed transcriptional activity and a gel shift assay showed that the -799T DNA fragment had a greater affinity for transcription factor AP-1 than the -799A. In 40 unrelated healthy subjects, serum AHSG/fetuin-A levels increased with the following order of genotypes: -799TT<-799AT<-799AA (mean+/-S.E.M.; 222.1+/-11.0, 291.8+/-8.1, and 349.0+/-13.0 microg/ml, respectively, P<0.001). In conclusion, SNP rs2248690 in the promoter region of the AHSG gene affects the AHSG gene transcription, possibly by producing different association with AP-1.
Inoue
Mari
M
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan.
Takata
Hiroshi
H
Ikeda
Yukio
Y
Suehiro
Tadashi
T
Inada
Shojiro
S
Osaki
Fumiaki
F
Arii
Kaoru
K
Kumon
Yoshitaka
Y
Hashimoto
Kozo
K
D000328:Adult; D001798:Blood Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D014644:Genetic Variation; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; D001798:Blood Proteins; D017931:DNA Primers; D018808:Transcription Factor AP-1; D060749:alpha-2-HS-Glycoprotein