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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.

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Related in: MedlinePlus

Association of ZnT8A with SNPs in the MHC region of chromosome 6. SNPs are analysed in up to 1,021 type 1 diabetes cases at the WTCCC SNPs (crosses) and up to 1,123 type 1 diabetes cases at the T1DGC SNPs (dots). −log(p value for association with ZnT8A positivity) is plotted against physical position in megabases (Mb). The physical locations of the HLA classical loci are also given
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Fig1: Association of ZnT8A with SNPs in the MHC region of chromosome 6. SNPs are analysed in up to 1,021 type 1 diabetes cases at the WTCCC SNPs (crosses) and up to 1,123 type 1 diabetes cases at the T1DGC SNPs (dots). −log(p value for association with ZnT8A positivity) is plotted against physical position in megabases (Mb). The physical locations of the HLA classical loci are also given

Mentions: Outside of the HLA, no evidence of association with positivity for ZnT8A was obtained in the type 1 diabetes associated regions with the British cases (p > 0.03). None of the classical HLA loci, HLA-DRB1, HLA-DQB1, HLA-A, HLA-B and HLA-C, were associated with ZnT8A (p > 0.05; Fig. 1). Evidence of association in the HLA region mapped to the class I region (Fig. 1). The most strongly associated SNP was rs2855812 (p = 2.25 × 10−5) in MICB in the T1DGC cases, and rs9258750 (p = 3.00 × 10−4) near HLA-A in the WTCCC cases. The genotyping of these SNPs was extended to over 2,100 cases in which ZnT8A was measured (electronic supplementary material [ESM] Table 1). The rs9258750 SNP showed more evidence of association with positivity for ZnT8A (p = 2.06 × 10−9; OR for the major A allele 1.82 [95% CI 1.49, 2.23]) than rs2855812 (p = 5.80 × 10−5; OR for the minor T allele 1.33 [95% CI 1.16, 1.53]). The two SNPs were not in linkage disequilibrium (LD) (r2 = 0.02, D′ = 0.33) and hence appear to mark independent effects (p = 7.2 × 10−4 for the addition of rs2855812 to rs9258750, and p = 5.83 × 10−8 for the addition of rs9258750 to rs2855812). rs9258750 was in LD with HLA-A*24 (r2 = 0.54, D′ = 0.98). HLA-A*24 was associated with ZnT8A positivity (p = 2.03 × 10−4), but this was due to rs9258750: p = 0.95 for the addition of HLA-A*24 to rs9258750, compared with p = 0.0015 for the addition of rs9258750 to HLA-A*24 in regression models. The association of rs9258750 with positivity for ZnT8A was confirmed in an independent family dataset of white European ancestry (p = 0.0014; OR for the major A allele 1.57 [95% CI 1.19, 2.06] in the 833 affected family members successfully genotyped).Fig. 1


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 ZnT8A with SNPs in the MHC region of chromosome 6. SNPs are analysed in up to 1,021 type 1 diabetes cases at the WTCCC SNPs (crosses) and up to 1,123 type 1 diabetes cases at the T1DGC SNPs (dots). −log(p value for association with ZnT8A positivity) is plotted against physical position in megabases (Mb). The physical locations of the HLA classical loci are also given
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Association of ZnT8A with SNPs in the MHC region of chromosome 6. SNPs are analysed in up to 1,021 type 1 diabetes cases at the WTCCC SNPs (crosses) and up to 1,123 type 1 diabetes cases at the T1DGC SNPs (dots). −log(p value for association with ZnT8A positivity) is plotted against physical position in megabases (Mb). The physical locations of the HLA classical loci are also given
Mentions: Outside of the HLA, no evidence of association with positivity for ZnT8A was obtained in the type 1 diabetes associated regions with the British cases (p > 0.03). None of the classical HLA loci, HLA-DRB1, HLA-DQB1, HLA-A, HLA-B and HLA-C, were associated with ZnT8A (p > 0.05; Fig. 1). Evidence of association in the HLA region mapped to the class I region (Fig. 1). The most strongly associated SNP was rs2855812 (p = 2.25 × 10−5) in MICB in the T1DGC cases, and rs9258750 (p = 3.00 × 10−4) near HLA-A in the WTCCC cases. The genotyping of these SNPs was extended to over 2,100 cases in which ZnT8A was measured (electronic supplementary material [ESM] Table 1). The rs9258750 SNP showed more evidence of association with positivity for ZnT8A (p = 2.06 × 10−9; OR for the major A allele 1.82 [95% CI 1.49, 2.23]) than rs2855812 (p = 5.80 × 10−5; OR for the minor T allele 1.33 [95% CI 1.16, 1.53]). The two SNPs were not in linkage disequilibrium (LD) (r2 = 0.02, D′ = 0.33) and hence appear to mark independent effects (p = 7.2 × 10−4 for the addition of rs2855812 to rs9258750, and p = 5.83 × 10−8 for the addition of rs9258750 to rs2855812). rs9258750 was in LD with HLA-A*24 (r2 = 0.54, D′ = 0.98). HLA-A*24 was associated with ZnT8A positivity (p = 2.03 × 10−4), but this was due to rs9258750: p = 0.95 for the addition of HLA-A*24 to rs9258750, compared with p = 0.0015 for the addition of rs9258750 to HLA-A*24 in regression models. The association of rs9258750 with positivity for ZnT8A was confirmed in an independent family dataset of white European ancestry (p = 0.0014; OR for the major A allele 1.57 [95% CI 1.19, 2.06] in the 833 affected family members successfully genotyped).Fig. 1

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