The role of genetic abnormality of delta-sarcoglycan (delta-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 delta-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 similar to-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 similar to-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 similar to-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 similar to-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 similar to-110) resulted in a decrease of delta-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 delta-SG-283R interacts normally to beta- and gamma-SG, but significantly decreased localization of beta/delta/gamma-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.(-100 similar to-110) and A848G confers higher susceptibility to DCM in the Mongoloid population.
[1]Shanghai Jiao Tong Univ, Affiliated Xinhua Hosp, Sch Med, Dept Cardiol,Mol Cardiol Res Lab, Shanghai 200030, Peoples R China.
[2]Shanghai Jiao Tong Univ, Affiliated Xinhua Hosp, Sch Med, Dept Ultrasound, Shanghai 200030, Peoples R China.
[3]Shanghai Jiao Tong Univ, Affiliated Xinhua Hosp, Sch Med, Minist Educ, Shanghai 200030, Peoples R China.
[4]Shanghai Jiao Tong Univ, Affiliated Xinhua Hosp, Sch Med, Shanghai Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China.
[5]Wenzhou Med Coll, Key Lab Lab Med, Chinese Minist Educ, Wenzhou, Peoples R China.
[6]Univ Tokyo, Inst Med Sci, Tokyo, Japan.
[7]Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA.
[8]Fudan Univ, Cent Hosp Minhang Dist, Sch Med, Dept Cardiol, Shanghai 200433, Peoples R China.
(8.0+极速模式)