title: Genetic variants in ABCA1 promoter affect transcription activity and plasma HDL level in pigs.
abstract: Excess accumulation of cholesterol in plasma may result in coronary artery disease. Numerous studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for plasma high density lipoprotein (HDL) formation. Higher plasma levels of HDL are associated with lower risk for cardiovascular disease. Studies of human disease and animal models had shown that an increased hepatic ABCA1 activity relates to an enhanced plasma HDL level. In this study, we hypothesized that functional mutations in the ABCA1 promoter in pigs may affect gene transcription activity, and consequently the HDL level in plasma. The promoter region of ABCA1 was comparatively scanned by direct sequencing with pool DNA of high- and low-HDL groups (n=30 for each group). Two polymorphisms, c. - 608A>G and c. - 418T>A, were revealed with reverse allele distribution in the two groups. The two polymorphisms were completely linked and formed only G-A or A-T haplotypes when genotyped in a larger population (n=526). Furthermore, we found that the G-A/G-A genotype was associated with higher HDL and ABCA1 mRNA level than A-T/A-T genotype. Luciferase assay also revealed that G-A haplotype promoter had higher activity than A-T haplotype. Single-nucleotide mutant assay showed that c.-418T>A was the causal mutation for ABCA1 transcription activity alteration. Conclusively, we identified two completely linked SNPs in porcine ABCA1 promoter region which have influence on the plasma HDL level by altering ABCA1 gene transcriptional activity.
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Xiao-yong
authors.initials: XY
authors.lastname: Dang
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Chu
authors.affiliation: Laboratory Department, Jiangsu Province Official Hospital, Nanjing 210024, PR China.
authors.forename: Heng-chuan
authors.initials: HC
authors.lastname: Shi
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Shi-gang
authors.initials: SG
authors.lastname: Yu
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Hai-yin
authors.initials: HY
authors.lastname: Han
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Gu
authors.affiliation: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address: jiechen@njau.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D008075:Lipoproteins, HDL / Q000097:blood*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013552:Swine; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D064286:ATP Binding Cassette Transporter 1; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D014157:Transcription Factors
keywords: ABCA1; HDL; Polymorphisms; Promoter