title: A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.
abstract: The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Ultrasound, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ying
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Joyce
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Laboratory Medicine of the Chinese Ministry of Education, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Cardiology, the Central Hospital of Minhang District, Fudan University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yuepeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D024721:E-Box Elements / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D012307:Risk Factors; D049031:Sarcoglycans / Q000737:chemistry / Q000235:genetics*
chemical_list: D049031:Sarcoglycans