Association Studies of Cytochrome P450 2J2*7 Variants in Type 2 Diabetes with Family History and Early Age of Onset
Cytochrome P450¡]CYP¡^2J2, the single member of human cytochromes P450 II J subfamily, plays an important role in the biosynthesis of biologically active cis-epoxyeicosatrienoic acids. An allelic variant named CYP 2J2*7, a relatively frequent G¡÷T substitution at position-50 relative to the transcription start site, which interrupts a critical Sp1 binding site, results in both decreased promoter activity in vitro and reduced circulating levels of CYP2J2 epoxygenase metabolites. Epoxyeicosatrienoic acid (EETs) are endogenously produced and incorporated into membrane phospholipids in the pancreas. Low concentrations of 5,6-EETs stimulate insulin secretion, whereas 8,9-, 11,12-, and 14,15-EETs stimulate glucagon secretion from the pancreas. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. EETs increased PPAR-£\ and PPAR-£^ transcription activity. PPAR-£\ and PPAR-£^ play a key role in the regulation of adipogenesis, lipid metabolism, insulin sensitivity and inflammation. Thus, genetic abnormalities in the function or expression of CYP2J2, the pathogenetic of enzymes may play a role in diabetes. The present study investigates whether CYP 2J2*7 gene polymorphism can be associated with type 2 diabetes in a Chinese population. We studied 2,073 Chinese type 2 diabetes patients and 704 control subjects without. CYP 2J2*7 gene polymorphism was determined by PCR-RFLP and real-time PCR. In both study groups, the genotype frequency distributions of this polymorphism were in Hardy-Weinberg equilibrium. The CYP2J2*7 genotype distribution or allele frequencies were not different between type 2 diabetes and control subjects. Diabetics with young age of onset¡]¡Ø35 years old¡^ had a higher frequency of T variant than that of the age of onset of greater than 35 years old and controls ( GG / GT + TT = 84.2% / 15.8% vs. 90.3% / 9.7% vs. 91.3% / 8.7%¡Fp = 0.018¡Ap = 0.027 ). CYP2J2*7 genotype had a statistically significant association with age of onset ( p for trend = 0.042 ). The HOMA-IR and HOMA-£] values were significantly higher in diabetic patients with young age of onset compared to those of late onset diabetics and controls. CYP2J2*7 polymorphism was associated with HOMA-IR and HOMA-£] in diabetics with young age of onset and controls, subjects and T variants had significant higher value of HOMA-IR and HOMA-£]¡]early onset diabetics¡GGG / GT + TT = 8.9 ¡Ó 6.1 / 6.4 ¡Ó 3.8, p=0.045¡Fcontrols¡GGG / GT + TT = 2.6 ¡Ó 1.1 / 2.1 ¡Ó 0.8, p = 0.007¡^.These findings suggest that CYP 2J2*7 polymorphism may play a role in the pathogenesis of young onset type 2 diabetes and family diabetic history.
Advisor:Yau-Jiunn Lee; Ching-Mei Hsu; Chung-Lung Cho; Hsueh-Wen Chang
School:National Sun Yat-Sen University
School Location:China - Taiwan
Source Type:Master's Thesis
Keywords:type 2 diabetes with family history and early age of onset cytochrome p450 2j2 7
Date of Publication:06/26/2006