Polymorphism of β3-adrenergic receptor, leptin receptor, glucocorticoid receptor and tumour necrosis factor-α gene among patients with type 2 diabetes mellitus
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Date
2006
Authors
Tuan Othman, Sharifah Izwan
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Abstract
Type 2 diabetes (T2D) is a common complex disorder that develops from changing of
human nutrition and life styles. The etiology of T2D includes genetic mutations that
disturb lipid and glucose metabolism, insulin resistance, obesity and deficiency in
insulin secretion. However, major differences of genes mutations occur among various
populations with different origin and geographical backgrounds. This study was
performed to determine the incidence and pattern of β3-AR, LEPR, Tnf-α and GRL gene
polymorphisms in T2D Malay patients attending Klinik Rawatan Keluarga, HUSM,
Kelantan. A total number of 116 T2D patients and 84 normal healthy controls were
involved in this study. Mutation analysis using PCR-RFLP procedures were used to
study missense mutation in the polymorphism of Trp64Arg of the β3-AR, G-308A of the
Tnf-α and Asn363Ser of the GRL genes polymorphisms. PCR-PAGE was used to
analyze the insertion/deletion polymorphism of 3’-UTR of the LEPR gene. Then, DNA
sequencing was carried out to confirm the insertion sequence. The results showed no
significant different of genotype frequencies in the polymorphisms of Trp64Arg,
insertion/deletion of 3’-UTR, G-308A and Asn363Ser occurred between T2D patients and
controls, with 0.099, 0.164, 0.026 and 0.047 compared to 0.098, 0.131, 0.071 and 0.036
respectively (p= 0.646, 0.701, 0.090 and 0.656). LEPR gene was the most common
polymorphism appearing in T2D patients (16.4%), followed by β3-AR gene (9.9%),
GRL gene (4.7%) and Tnf-α gene (2.6%). The controls showed almost similar pattern
for the LEPR gene (13.3%) and β3-AR gene (9.8%), but Tnf-α gene polymorphism was
found to be higher than GRL (Tnf-α gene, 7.1% and GRL gene, 3.6%). Most of the T2D
patients and controls that have the mutation alleles (59.0% and controls 90.0%
respectively) have single gene mutation, followed by the combination of 2-genes
mutation in 20.7% of patients and 10.0% of controls. The most common combinations
are polymorphism of LEPR and GRL gene and also β3-AR and GRL gene in T2D
patients. Whereas the combination of LEPR and GRL gene and also β3-AR and GRL
gene in control subjects. Only one patient had the combination of 3-gene mutations and
none of the studied samples had all 4-gene mutations. Patients showed significant
association between all mutant genotypes studied with gender and positive family
history. Patients also revealed the contribution of heterozygous Trp64Arg with higher
min age, BMI and SBP, G-308A with longer duration of diabetes, and heterozygous
Asn363Ser with obesity as compared to controls. In conclusion, the analysis of the
polymorphism of Trp64Arg of the β3-AR gene, insertion/deletion of 3’-UTR of the
LEPR gene, G-308A of the Tnf-α gene and Asn363Ser of GRL gene suggest that these
polymorphisms do not directly contribute to the development of T2D when functioning
individually in these subjects. However, they may contribute to the pathogenesis of T2D
when function synergistically with several other genes.
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Master
Keywords
Biological Science , Polymorphisms , Tumour necrosis , Type 2 diabetes mellitus