A Solute Carrier Family 22 Member 3 Variant rs3088442 G→A Associated with Coronary Heart Disease Inhibits Lipopolysaccharide-induced Inflammatory Response

Lu Li; Meian He; Li Zhou; Xiaoping Miao; Fangqing Wu; Suli Huang; Xiayun Dai; Tian Wang; Tangchun Wu

doi:10.1074/jbc.M114.584953

A Solute Carrier Family 22 Member 3 Variant rs3088442 G→A Associated with Coronary Heart Disease Inhibits Lipopolysaccharide-induced Inflammatory Response*

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 ^§Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, and
the ^¶Key Laboratory of Molecular Biology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guangdong, China

↵2 To whom correspondence should be addressed. Tel.: 86-27-83692347; Fax: 86-27-83692560; E-mail: wut{at}mails.tjmu.edu.cn.

↵1 These authors contributed equally to this work.

Background: Polymorphisms within solute carrier family 22 member 3 (SLC22A3) affects the risk of cardiovascular disease.

Results: The polymorphism rs3088442 decreases SLC22A3 mRNA stability and inhibits lipopolysaccharide-induced inflammatory responses.

Conclusion: This polymorphism decreased CHD risk by controlling vascular inflammation.

Significance: Our findings will elucidate the relationship between SLC22A3 variants, inflammation, and CHD pathogenesis.

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.