Limits...
Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases.

Howson JM, Krause S, Stevens H, Smyth DJ, Wenzlau JM, Bonifacio E, Hutton J, Ziegler AG, Todd JA, Achenbach P - Diabetologia (2012)

Bottom Line: We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases).The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05).

View Article: PubMed Central - PubMed

Affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK. Joanna.Howson@cimr.cam.ac.uk

ABSTRACT

Aims/hypothesis: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.

Methods: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes.

Results: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific.

Conclusions/interpretation: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.

Show MeSH

Related in: MedlinePlus

Association of positivity for ZnT8A with SNPs on chromosome 1 in up to 2,142 type 1 diabetes cases
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369141&req=5

Fig2: Association of positivity for ZnT8A with SNPs on chromosome 1 in up to 2,142 type 1 diabetes cases

Mentions: Having found no evidence of association with positivity for ZnT8A in the type 1 diabetes associated regions, the search was extended genome wide. Up to a maximum of 2,142 cases were analysed at 775,249 SNPs across the genome. Only the FCRL3 gene region on chromosome 1 attained significance at a GWAS level (p < 5 × 10−8) with all SNPs outside of this region having p values above 1 × 10−6 (Fig. 2 and ESM Fig. 1). The most associated SNP, rs7522061, (p = 1.13 × 10−16) is located in exon 4 of the FCRL3 gene (Ensembl version 63) and is in LD with rs7528684 (r2 = 0.89 in British controls), which has previously been shown to be associated with IA-2A in type 1 diabetes cases [21, 28]. The region is also associated with Graves' disease and thyroid peroxidase autoantibody positivity at rs11264798 [21, 25].Fig. 2


Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases.

Howson JM, Krause S, Stevens H, Smyth DJ, Wenzlau JM, Bonifacio E, Hutton J, Ziegler AG, Todd JA, Achenbach P - Diabetologia (2012)

Association of positivity for ZnT8A with SNPs on chromosome 1 in up to 2,142 type 1 diabetes cases
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369141&req=5

Fig2: Association of positivity for ZnT8A with SNPs on chromosome 1 in up to 2,142 type 1 diabetes cases
Mentions: Having found no evidence of association with positivity for ZnT8A in the type 1 diabetes associated regions, the search was extended genome wide. Up to a maximum of 2,142 cases were analysed at 775,249 SNPs across the genome. Only the FCRL3 gene region on chromosome 1 attained significance at a GWAS level (p < 5 × 10−8) with all SNPs outside of this region having p values above 1 × 10−6 (Fig. 2 and ESM Fig. 1). The most associated SNP, rs7522061, (p = 1.13 × 10−16) is located in exon 4 of the FCRL3 gene (Ensembl version 63) and is in LD with rs7528684 (r2 = 0.89 in British controls), which has previously been shown to be associated with IA-2A in type 1 diabetes cases [21, 28]. The region is also associated with Graves' disease and thyroid peroxidase autoantibody positivity at rs11264798 [21, 25].Fig. 2

Bottom Line: We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases).The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05).

View Article: PubMed Central - PubMed

Affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK. Joanna.Howson@cimr.cam.ac.uk

ABSTRACT

Aims/hypothesis: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.

Methods: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes.

Results: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific.

Conclusions/interpretation: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.

Show MeSH
Related in: MedlinePlus