SLC30A8

General Information

Full gene name:solute carrier family 30 (zinc transporter), member 8 Entrez Gene ID:169026 Location:8q24.11 Synonyms:ZNT8, ZnT-8 Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs13266634	0	within

NCBI Summary

The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

OMIM

OMIM ID:`OMIM ID 611145 `_

Allelic Variants (Selected Examples)

.0001 DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO

Sladek et al. (2007) identified an association between a nonsynonymous variant in SLC30A8 (arg325 to trp; R325W) and susceptibility to type 2 DIABETES (125853).

In genomewide association studies of type 2 DIABETES involving genotype data from a variety of international consortia, the DIABETES Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed the association identified by Sladek et al. (2007) of the SLC30A8 polymorphism rs13266634 with DIABETES. Strong evidence was obtained in combined samples from all studies (OR = 1.12, P = 5.3 x 10(-8)).

In a genomewide association study for type 2 DIABETES in 1,399 Icelandic cases and 5,275 controls, Steinthorsdottir et al. (2007) replicated the association between the C allele of rs13266634 and type 2 DIABETES (OR, 1.19; P = 0.000061); the association was also confirmed in study groups from Denmark, Philadelphia, and Hong Kong. The association was greater in nonobese individuals with type 2 DIABETES than in obese diabetics, indicating that the variant does not confer increased risk of type 2 DIABETES by increasing body mass index (BMI). A significant effect of rs13266634 was seen on INSULIN response, and the reduction was consistent with an additive effect.

NCBI Phenotypes

• Gene Reviews
• New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
• Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia.
• Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
• A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.
• Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
• Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.
• A genome-wide association study identifies novel risk loci for type 2 diabetes.
• Diabetes mellitus type 2
• A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
• Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
• GTR
• OMIM
• NHGRI GWA Catalog
• Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.
• Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women’s Genome Health Study.
• Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.
• Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.
• Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases.

Gene Ontology

• protein homodimerization activity
• Golgi apparatus
• zinc ion binding
• cytoplasmic membrane-bounded vesicle
• plasma membrane
• zinc ion transmembrane transporter activity
• secretory granule membrane
• secretory granule
• cellular zinc ion homeostasis
• zinc ion transmembrane transport
• positive regulation of insulin secretion
• regulation of sequestering of zinc ion
• transport vesicle membrane
• response to glucose stimulus
• sequestering of zinc ion
• glucose homeostasis
• insulin secretion
• response to interleukin-1
• response to interferon-gamma
• regulation of vesicle-mediated transport
• integral to membrane
• zinc ion transport
• transmembrane transport

KEGG Pathways

No pathways found linked to this gene.

GeneRIFs

• A non-synonymous polymorphism in SLC30A8 (rs13266634, R325W) is associated with increased risk of developing type 2 diabetes in causcasians. [PMID 17293876]
• Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) [PMID 20571754]
• the SLC30A8, is more likely to represent the genuine signals of T2DM in the Tunisian population [PMID 21510814]
• ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes. [PMID 21244337]
• SLC30A8 rs13266634 polymorphism is among most replicated genetic markers of type 2 diabetes in Europeans and East Asians; risk C-allele does not affect ex-vivo insulin secretion and SLC30A8 expression, which correlates with that of insulin and glucagon [PMID 20138556]
• ZnT-8 may be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta-cells. [PMID 15331542]
• insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 may have a role in rapid progression of type 1 diabetes [PMID 20091020]
• increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin [PMID 21779873]
• Meta-analysis and HuGE review of gene-disease association. (HuGE Navigator) [PMID 19602701]
• Type 2 diabetes susceptibility of SLC30A8 was confirmed in Japanese. [PMID 19033397]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 21036910]
• Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20879858]
• A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes. [PMID 18400535]
• Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 19401414]
• Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism of SLC30A8. [PMID 18324385]
• SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion. [PMID 18628523]
• For the first time, the expression of hZnT-8 is shown in peripheral blood lymphocytes. It varied strongly between individuals. [PMID 17971500]
• ZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes. [PMID 19808923]
• A SNP, rs62510556, in the conserved intron 2 enhancer of SLC30A8 is shown to affect the binding of an unknown transcription factor and thereby modulate enhancer activity. [PMID 21798992]
• Little evidence of association was observed between SNPs in SLC30A8 and type 2 diabetes in African Americans. [PMID 18443202]
• ZnT8A, GADA and IA-2A are autoantibodies that may have a role in successful pancreas graft survival [PMID 21792090]
• findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well[review] [PMID 19655390]
• Studies indicate that T1DM can be detected by determining four autoantibodies, namely those antibodies against insulin, glutamic acid decarboxylase 65, insulinoma antigen (IA)-2 (ICA512) and the zinc transporter ZnT8. [PMID 21073664]
• Meta-analysis results revealed the significant association between rs13266634 C/T polymorphism and T2DM and IGT, but did not support the association between this polymorphism and T1DM. [PMID 21131091]
• No statistically significant differences in genotype and allele frequencies of single nucleotide polymorphism (SNP) rs13266634 in gene SLC30A8 were found between patients with polycystic ovary syndrome (PCOS) and healthy controls. [PMID 19108828]
• ZnT8 autoantibodies determination may be useful measure of therapeutic efficacy in the context of immune-based clinical interventions for type 1 diabetes. [PMID 20610599]
• SLC30A8 provides an important additional and independent predictive marker for T1 diabetes mellitus. [PMID 19120307]
• Children who carry homozygous SLC30A8 single-nucleoetide polymorphism progress to diabetes faster than heterozygote carriers. [PMID 19590848]
• Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [PMID 20802253]
• HHEX, IDE and SLC30A8 showed strongest tissue-specific mRNA expression bias and are associated with increased risk of type 2 diabete. [PMID 20703447]
• Observational study of gene-disease association, gene-gene interaction, and gene-environment interaction. (HuGE Navigator) [PMID 20889853]
• The zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset Type 1 diabetes (T1D) compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. [PMID 17942684]
• Abs recognizing MAP3865c epitopes cross-react with ZnT8, possibly underlying a molecular mimicry mechanism, which may precipitate type 1 diabetes in Mycobacterium avium paratuberculosis-infected individuals. [PMID 22046415]
• Data show that a common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. [PMID 18591387]
• The associations between SNPs of TCF7L2, CDKAL1, SLC30A8 and HHEX and the development of DR and DN. [PMID 22487833]
• Study show that polymorphisms in SLC30A8 were associated with type 2 diabetes risk in the studied population. [PMID 18694974]
• Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and genetic testing. (HuGE Navigator) [PMID 20075150]
• variant residue at amino acid 325 is a key determinant of humoral autoreactivity to ZnT8 and that the SLC30A8 genotype is an important determinant of autoantibody specificity [PMID 18850084]
• This transporter represents an exciting therapeutic target for intervention in type 2 diabetes. [PMID 21099294]
• SLC30A8 (rs13266634) C allele carriers could elevate the risk of type 2 diabetes, especially in Europeans and Asians. [PMID 20167458]
• Meta-analysis of gene-disease association. (HuGE Navigator) [PMID 20167458]
• rs12255372 and rs13266634 markers are independent genetic type 2 diabetes risk factors in a Russian population. [PMID 20873210]
• Rare mutaations are unlikely to be responsible for maturity onset diabetes of the young or other forms of early onset type 2 diabetes. [PMID 17657472]
• REVIEW: role in the autoimmune disease process of type 1 diabetes [PMID 19323954]
• The C-terminal domain of human ZnT8 contains at least two discrete epitopes, one of which is critically dependent upon the arginine residue at position 325. [PMID 19120306]
• Meta-analysis and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 17463249]
• The SLC30A8 variant was associated with the efficacy of insulin sensitizer monotherapy on insulin secretion in patients with newly diagnosed type 2 diabetes mellitus in Shanghai, China. [PMID 22424623]
• ZnT-8 is a pancreatic beta-cell-specific zinc transporter [review] [PMID 16158222]
• Impaired insulin secretion is specifically present in impaired proinsulin conversion is specifically present in a variant of SLC30A8. [PMID 18264689]
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population [PMID 19862325]
• Data show that SNPs in SLC30A8 did not confer a significant risk for type 2 diabetes in Pima Indians. [PMID 19008344]
• Report a chimeric assay providing an efficient and economical technique to screen for islet autoantibodies reacting with IA-2 and ZnT8 in type 1 diabetes mellitus. [PMID 20035758]
• Data show that SNPs from MADD, PROX1, and SLC30A8 were associated with type 2 diabetes. [PMID 21103350]
• Data confirmed the associations of single nucleotide polymorphisms in SLC30A8 with risk for type 2 diabetes in Asians. [PMID 18469204]
• identified the full-length sequences of SLC30A8, extending the SLC30 family to ten members; used an expressed sequence tag (EST) data mining strategy to determine the pattern of ZnT genes expression in tissues [PMID 15154973]
• The results indicate that in Chinese Hans, common variants in SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction. [PMID 18633108]
• Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20809084]
• Single nucleotide polymorphism in SLC30A8 is associated with type 2 diabetes. [PMID 18991055]
• Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [PMID 20490451]
• The C allele of the SLC30A8 gene is associated with preserved beta-cell function in type 1 diabetes patients. [PMID 21604969]
• SLC30A8 rs13266634 gene variation is associated with protection from the development of posttransplantation diabetes mellitus in renal allograft recipients. [PMID 18162509]
• The association of 6 loci with type 2 diabetes risk in Japanese patients is reported. [PMID 18162508]
• ZnT8 is required for normal insulin crystallization and insulin release in vivo but not, remarkably, in vitro [PMID 19542200]

PubMed Articles

Recent articles:

• Perry JR et al. “Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.” PLoS Genet. 2012 May;8(5):e1002741. PMID 22693455
• Fu LL et al. “[Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus].” Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012 Apr;29(2):194-9. PMID 22487833
• Jiang F et al. “Association of a SLC30A8 genetic variant with monotherapy of repaglinide and rosiglitazone effect in newly diagnosed type 2 diabetes patients in China.” Biomed Environ Sci. 2012 Feb;25(1):23-9. PMID 22424623
• Pound LD et al. “Characterization of the human SLC30A8 promoter and intronic enhancer.” J Mol Endocrinol. 2011 Dec;47(3):251-9. PMID 21798992
• Nielsen LB et al. “Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes.” Autoimmunity. 2011 Dec;44(8):616-23. PMID 21604969
• Masala S et al. “Antibodies recognizing Mycobacterium avium paratuberculosis epitopes cross-react with the beta-cell antigen ZnT8 in Sardinian type 1 diabetic patients.” PLoS One. 2011;6(10):e26931. PMID 22046415
• Strawbridge RJ et al. “Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.” Diabetes. 2011 Oct;60(10):2624-34. PMID 21873549
• Majithia AR et al. “Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program.” Diabetologia. 2011 Oct;54(10):2570-4. PMID 21779873
• Occhipinti M et al. “Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant.” Transplantation. 2011 Sep 27;92(6):674-7. PMID 21792090
• Noguchi E et al. “Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.” PLoS Genet. 2011 Jul;7(7):e1002170. PMID 21814517

Top Pubmed articles linked to gene SLC30A8 matching any search term:

• Iwata M et al. “Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals.” Diabetes Care. 2012 Aug;35(8):1763-70. PMID 22688542
• Pound LD et al. “The physiological effects of deleting the mouse slc30a8 gene encoding zinc transporter-8 are influenced by gender and genetic background.” PLoS One. 2012;7(7):e40972. PMID 22829903
• Delli AJ et al. “Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study.” Diabetes. 2012 Jul 10;. PMID 22787139
• Zhang X et al. “No association between the type 2 diabetes mellitus susceptibility gene, SLC30A8 and schizophrenia in a Chinese population.” Hum Psychopharmacol. 2012 Jul;27(4):392-6. PMID 22778022
• Linder K et al. “Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.” PLoS One. 2012;7(6):e38224. PMID 22768041
• Mtiraoui N et al. “Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL, PPARγ, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs.” Diabetes Metab. 2012 Jun 27;. PMID 22749234
• Andersen ML et al. “Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes.” Pediatr Diabetes. 2012 Jun 12;. PMID 22686132
• Xu J et al. “SLC30A8 (ZnT8) variations and type 2 diabetes in the Chinese Han population.” Genet Mol Res. 2012 May 24;11(2):1592-8. PMID 22653633
• Moosavi M et al. “The effect of type 2 diabetes risk Loci on insulin requirements in type 1 diabetes.” Horm Res Paediatr. 2012;77(5):305-8. PMID 22584884
• Ekelund M et al. “Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus.” Diabetes Res Clin Pract. 2012 May 14;. PMID 22591707
• Majithia AR et al. “Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program.” Diabetologia. 2011 Oct;54(10):2570-4. PMID 21779873
• Andersson C et al. “The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.” Autoimmunity. 2011 Aug;44(5):394-405. PMID 21244337
• Rasmussen-Torvik LJ et al. “Association of a fasting glucose genetic risk score with subclinical atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) study.” Diabetes. 2011 Jan;60(1):331-5. PMID 21036910
• Rotger M et al. “Impact of single nucleotide polymorphisms and of clinical risk factors on new‐onset diabetes mellitus in HIV‐infected individuals.” Clin Infect Dis. 2010 Nov 1;51(9):1090-8. PMID 20879858
• Fontaine-Bisson B et al. “Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population.” Diabetologia. 2010 Oct;53(10):2155-62. PMID 20571754
• Stuebe AM et al. “Obesity and diabetes genetic variants associated with gestational weight gain.” Am J Obstet Gynecol. 2010 Sep;203(3):283.e1-17. PMID 20816152
• Pechlivanis S et al. “Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort.” Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1867-72. PMID 20616309
• Voight BF et al. “Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.” Nat Genet. 2010 Jul;42(7):579-89. PMID 20581827
• Cauchi S et al. “Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets.” Mol Genet Metab. 2010 May;100(1):77-82. PMID 20138556
• De Grijse J et al. “Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials.” Diabetologia. 2010 Mar;53(3):517-24. PMID 20091020