title: A solute carrier family 22 member 3 variant rs3088442 G→A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.
abstract: Recent genome-wide association studies have identified single-nucleotide polymorphism (SNPs) within the SLC22A3 (solute carrier family 22 member 3) gene associated with coronary heart disease (CHD) in the Caucasian population. We performed molecular analysis to investigate the potential role of SLC22A3 variants in CHD. Our study showed that the common polymorphism rs3088442 G→A, which is localized in the 3' UTR of the SLC22A3 gene, was associated with a decreased risk of CHD in the Chinese population by a case control study. In silico analysis indicated that G→A substitution of SNP rs3088442 created a putative binding site for miR-147 in the SLC22A3 mRNA. By overexpressing miR-147 or inhibiting endogenous miR-147, we demonstrated that SNP rs3088442 G→A recruited miR-147 to inhibit SLC22A3 expression. Moreover, SLC22A3 deficiency significantly decreased LPS-induced monocytic inflammatory response by interrupting NF-κB and MAPK signaling cascades in a histamine-dependent manner. Notably, the expression of SLC22A3(A) was also suppressed by LPS stimulus. Our findings might indicate a negative feedback mechanism against inflammatory response by which SLC22A3 polymorphisms decreased the risk of CHD.
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Meian
authors.initials: M
authors.lastname: He
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.affiliation: the Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, and.
authors.forename: Fangqing
authors.initials: F
authors.lastname: Wu
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, the Key Laboratory of Molecular Biology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guangdong, China.
authors.forename: Suli
authors.initials: S
authors.lastname: Huang
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Xiayun
authors.initials: X
authors.lastname: Dai
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, wut@mails.tjmu.edu.cn.
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D044466:Asian People / Q000235:genetics; D015153:Blotting, Western; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002681:China; D003327:Coronary Disease / Q000208:ethnology / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D000099254:Organic Cation Transporter 3
chemical_list: D020413:3' Untranslated Regions; D006632:Histamine; D008070:Lipopolysaccharides; D035683:MicroRNAs; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3; C572377:MIRN147 microRNA, human
keywords: Atherosclerosis; Gene Expression; Histamine; Inflammation; LPS-induced Inflammatory Response; MicroRNA (miRNA); SLC22A3; Single-nucleotide Polymorphism (SNP); miR-147; rs3088442