Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk
Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk
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DOI：
10.1007/s00125-009-1438-0
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发表时间：
2009-09-01
期刊：
影响因子：
8.2
通讯作者：
Ziegler, A. G.
中科院分区：
文献类型：
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作者：
Achenbach, P.;Lampasona, V.;Ziegler, A. G.
我们的目的是确定锌转运蛋白 8 (ZnT8) 自身抗体、ZnT8 编码基因 SLC30A8 的基因型与 1 型糖尿病风险之间的关系。对 1,633 名具有 1 型糖尿病一级家族史并从出生起进行前瞻性随访的儿童的血清中检测了 ZnT8 自身抗体 (ZnT8A)。通过基于蛋白 A 的放射性结合测定和人 ZnT8 的 COOH 末端（R325、W325 或 Q325 变体）或 NH2 末端构建体来测量抗体。对 1,170 名儿童进行了单核苷酸多态性 (SNP) rs13266634 的 SLC30A8 基因分型。58 名儿童早在 9 个月大（中位 3 岁）时就产生了针对 COOH 末端 ZnT8 构建体 (ZnT8A-COOH) 的抗体。在 128 名患有胰岛素、GAD 和/或胰岛素瘤相关蛋白 2 自身抗体的儿童中，有 55 名 (43%) 检测到了这些抗体；在 42 名进展为糖尿病的儿童中，有 34 名 (81%) 检测到了这些抗体。 ZnT8A-COOH 的额外存在对胰岛自身抗体阳性儿童的糖尿病风险进行分层 (p < 0.0001)。 SLC30A8 基因型强烈影响 ZnT8A-COOH 阳性儿童的 ZnT8A 类型和糖尿病风险。针对 ZnT8 R325 变体的抗体结合与相应的 SLC30A8 R325 编码等位基因的数量严格相关，而针对 W325 变体的结合在具有 SLC30A8 W325 编码等位基因的儿童中最高（p = 0.001）。此外，携带纯合子 SLC30A8 SNP rs13266634 基因型的 ZnT8A-COOH 阳性儿童比杂合子儿童进展为糖尿病的速度更快（5 年内为 59% [95% CI 42.3-75.7%] vs 22% [95% CI 0-44.3%]；p = 0.01）。 ZnT8 的 COOH 末端区域是儿童 1 型糖尿病的一个高度相关的预后特征。 SLC30A8 基因分型进一步改善了 ZnT8A-COOH 阳性儿童的风险分层。
Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk.ZnT8 autoantibodies (ZnT8A) were measured in sera of 1,633 children with a first-degree family history of type 1 diabetes and who were prospectively followed from birth. Antibodies were measured by Protein A-based radiobinding assays and COOH-terminal (R325, W325 or Q325 variants) or NH2-terminal constructs of human ZnT8. SLC30A8 genotyping at single-nucleotide polymorphism (SNP) rs13266634 was performed on 1,170 children.Antibodies against COOH-terminal ZnT8 constructs (ZnT8A-COOH) developed in 58 children as early as 9 months of age (median 3 years). They were detected in 55 of 128 (43%) children with autoantibodies to insulin, GAD and/or insulinoma-associated protein 2 and 34 of 42 (81%) who progressed to diabetes. The additional presence of ZnT8A-COOH stratified diabetes risk in islet autoantibody-positive children (p < 0.0001). SLC30A8 genotype strongly influenced ZnT8A type and diabetes risk in ZnT8A-COOH-positive children. Antibody binding against the ZnT8 R325 variant was strictly correlated with the number of the corresponding SLC30A8 R325-encoding alleles, whereas binding against the W325 variant was highest in children who had SLC30A8 W325-encoding alleles (p = 0.001). Moreover, ZnT8A-COOH-positive children who carried homozygous SLC30A8 SNP rs13266634 genotypes progressed faster to diabetes than those who were heterozygous (59% [95% CI 42.3-75.7%] vs 22% [95% CI 0-44.3%] within 5 years; p = 0.01).Autoimmunity against the COOH-terminal region of ZnT8 is a highly relevant prognostic feature in childhood type 1 diabetes. Risk stratification in ZnT8A-COOH-positive children is further improved by SLC30A8 genotyping.