Association between peroxisome proliferator-activated receptor-γ coactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population:role of altered interaction with myocyte enhancer factor 2C

摘要

＜正＞ Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-γcoactivator （PGC）-lα gene have been reported to be associated with type 2 diabetes in different populations,and studieson Chinese patients yielded controversial results.The objective of this case-control study was to explore the relationshipbetween SNPs of PGC-lα and type 2 diabetes in the southern Chinese population and to determine whether thecommon variants:Gly482Ser and Thr394Thr,in the PGC-1α gene have any impacts on interaction with myocyteenhancer factor （MEF） 2C.Methods The SNPs in all exons of the PGC-lα gene was investigated in 50 type 2 diabetic patients using polymerasechain reaction-single strand conformational polymorphism （PCR-SSCP） and direct sequencing.Thereafter,263 type 2diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment lengthpolymorphism （PCR-RFLP）.A bacterial two-hybrid system and site-directed mutagenesis were used to investigatewhether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C.Results Three frequent SNPs （Thr394Thr,Gly482Ser and Thr528Thr） were found in exons of the PGC-1α gene.Onlythe Gly482Ser variant had a different distribution between diabetic patients and healthy subjects,with the 482Ser allelemore frequent in patients than in controls （40.1% vs 29.3%,P＜0.01）.Even in controls,the 482Ser（A） carriers were morelikely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly（G） carriers.The394A-482G-528A haplotype was associated with protection from diabetes,while the 394A-482A-528A was associatedwith the susceptibility to diabetes.The bacterial two-hybrid system and site-directed mutagenesis revealed that the482Ser variant was less efficient than the 482Gly variant to interact with MEF2C,whereas the 394Thr （A） had a synergiceffect on the interaction between 482Ser variant and MEF2C.Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes inthe southern Chinese population.The underlying mechanism may be attributable,at least in part,to the alteredinteraction between the different variants （Gly482Ser,Thr394Thr） in the PGC-1α gene and MEF2C.