Association between peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C.
BACKGROUND
Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1alpha and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1alpha gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C.


METHODS
The SNPs in all exons of the PGC-1alpha gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1alpha gene alter the interaction with MEF2C.


RESULTS
Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1alpha gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P < 0.01). Even in controls, the 482Ser (A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly (G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C.


CONCLUSIONS
The results suggested that the 482Ser variant of PGC-1alpha conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1alpha gene and MEF2C.
Zhang
Shao-ling
SL
Department of Endocrinology, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Lu
Wen-sheng
WS
Yan
Li
L
Wu
Mu-chao
MC
Xu
Ming-tong
MT
Chen
Li-hong
LH
Cheng
Hua
H
D000368:Aged; D044466:Asian People / Q000235:genetics*; D002681:China; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D006360:Heat-Shock Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors