Abstract
BackgroundThe beta-2-Adrenergic receptor (ADRB2) gene on chromosome 5q33.1 is an important immunoregulatory factor. We and others have previously implicated chromosomal region 5q31-33 for contribution to the genetic susceptibility to Graves disease (GD) in East-Asian populations. Two recent studies showed associations between the single nucleotide polymorphism (SNP) rs1042714 in the ADRB2 gene and GD. In this study, we aimed to fully investigate whether the ADRB2 gene conferred susceptibility to GD in Chinese population, and to perform a meta-analysis of association between ADRB2 and GD.MethodsApproximately 1 kb upstream the transcription start site and the entire coding regions of the ADRB2 gene were resequenced in 48 Han Chinese individuals to determine the linkage disequilibrium (LD) patterns. Tag SNPs were selected and genotyped in a case-control collection of 1,118 South Han Chinese subjects, which included 428 GD patients and 690 control subjects. A meta-analysis was performed with the data obtained in the present samples and those available from prior studies.ResultsFifteen SNPs in the ADRB2 gene were identified by resequencing and one SNP was novel. Ten tag SNPs were investigated further to assess association of ADRB2 in the case-control collection. Neither individual tag SNP nor haplotypes showed association with GD in Han Chinese population (P > 0.05). Our meta-analysis of the ADRB2 SNP rs1042714 measured heterogeneity between the ethnic groups (I2 = 53.1%) and no association to GD was observed in the overall three studies with a random effects model (OR = 1.13, 95% CI, 0.95 to 1.36; P = 0.18). However, significant association was found from the combined data of Caucasian population with a fixed effects model (OR = 1.18, 95% CI, 1.06 to 1.32; P = 0.002; I2 = 5.9%).ConclusionOur study indicated that the ADRB2 gene did not exert a substantial influence on GD susceptibility in Han Chinese population, but contributed to a detectable GD risk in Caucasian population. This inconsistency resulted largely from between-ethnicity heterogeneity.
Highlights
The beta-2-Adrenergic receptor (ADRB2) gene on chromosome 5q33.1 is an important immunoregulatory factor
Fifteen polymorphisms were identified through the resequencing of ADRB2 for 48 individuals (Table 1), all of which were single nucleotide polymorphism (SNP); one SNP (-332) located at position -332 upstream from the ADRB2 transcription initiation site was novel when compared with dbSNP Build 128
Among the fifteen SNPs, twelve SNPs had minor allele frequencies (MAF) great than 5% (Table 1), with frequencies ranging from 5.2% to 38.9%
Summary
The beta-2-Adrenergic receptor (ADRB2) gene on chromosome 5q33.1 is an important immunoregulatory factor. We and others have previously implicated chromosomal region 5q31-33 for contribution to the genetic susceptibility to Graves disease (GD) in East-Asian populations. Two recent studies showed associations between the single nucleotide polymorphism (SNP) rs1042714 in the ADRB2 gene and GD. Graves disease (GD) affects 0.5–1% of the general population[1], and results from the presence of autoantibodies to the thyroid-stimulating hormone receptor (TSHR), leading to over-activity of the thyroid gland. Our previous study[2], along with others[3,4], has suggested that chromosomal region 5q31-33 may contain a locus that contributes to the genetic susceptibility to GD in EasternAsian populations. Two activity-related polymorphisms (rs1042713 and rs1042714) with high allelic frequency in the general population are single nucleic acid substitutions at positions 46 (A-G) and 79 (C-G), corresponding to substitutions of glycine for arginine at amino acid position 16 and glutamate for glutamine at amino acid position 27[5,6]
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