Association of Auto-Antigen SLC30A8 Gene Variants with Type 1 Diabetes Mellitus

Afreen Bhatty, Saeeda Baig, Nazish Waris, Zil-e-Rubab, Moazzam Ali Shahid, Asher Fawwad

Abstract

Type 1 Diabetes Mellitus (T1DM), is a genetic disease, the prevalence of which is increasing due to delays in the diagnosis because of the absence of standard antibodies. Therefore, there is a need for a molecular variant that can help in early diagnosis in these patients. The polymorphism in the SLC30A8 gene can identify the people at risk of T1DM. However, there is a controversy in the association of the SLC30A8 gene in the pathogenesis of T1DM and a dearth of data in our part of the world. Therefore, we aimed to determine the most frequent autoantigen SLC30A8 genotype and its association with T1DM in the Pakistani population. This case-control study was carried out at Ziauddin Medical University (ZMU) jointly with Baqai Institute of Diabetology and Endocrinology (Baqai Medical University) from June to October 2019. A total of 50 subjects were enrolled (25 cases and 25 controls) in the study. Cases included 25 diagnosed patients of T1DM meeting American Diabetes Association (ADA) new criteria and controls were their first-degree relatives. Blood was drawn, DNA was extracted and amplified through PCR. The RFLP of PCR product was done using a restriction enzyme, Alu I for genotyping. The most frequently observed genotype was CC among cases as well as controls. The CC genotype of rs13266634 was not found significantly associated with T1DM (p=0.08) but the OR was 2.7; CI=0.86 -9.00. Similarly other genotypes were also not found statistically significant. However, HbA1C and Fasting Blood Sugar (FBS) were found statistically significant (p=0.001, p=0.000) in T1DM patients compared to controls. The autoantigenic variants of SLC30A8 of rs13266634 were not found statistically significant with T1DM. The role of this variant as a susceptibility gene in T1DM development should be further confirmed by carrying out studies with a larger sample size.

 

Keywords: SLC30A8, Zinc transporter 8, Diabetes Mellitus, Type 1, variants.

 

https://doi.org/10.55463/issn.1674-2974.49.3.16

 


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ELMAOĞULLARI S., UÇAKTÜRK S. A., ELBEG Ş., DÖĞER E., TAYFUN M., GÜRBÜZ F., and BIDECI A. Prevalence of ZnT8 antibody in Turkish children and adolescents with new onset type 1 diabetes. Journal of Clinical Research in Pediatric Endocrinology, 2018, 10(2): 108. https://dx.doi.org/10.4274%2Fjcrpe.5020

BHATTY A., BAIG S., and SHAHID M. A. Emerging role of zinc transporter-8 autoantibodies (ZnT8A) in type 1 diabetes mellitus-a review. Journal of Advances in Medicine and Medical Research, 2019, 13: 1-10. https://doi.org/10.9734/jammr/2019/v31i630304

BHATTY A., BAIG S., FAWWAD A., RUBAB Z. E., SHAHID M. A., and WARIS N. Association of Zinc Transporter-8 Autoantibody (ZnT8A) with Type 1 Diabetes Mellitus. Cureus, 2020, 12(3). https://dx.doi.org/10.7759%2Fcureus.7263

MICHELS A., ZHANG L., KHADRA A., KUSHNER J. A., REDONDO M. J., and PIETROPAOLO M. Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention. Pediatric Diabetes, 2015, 16(7): 465-484. https://doi.org/10.1111/pedi.12299

GOMES K. F., SEMZEZEM C., BATISTA R., FUKUI R. T., SANTOS A. S., CORREIA M. R., PASSOS-BUENO M. R., and ROSSI DA SILVA M. E. Importance of zinc transporter 8 autoantibody in the diagnosis of type 1 diabetes in Latin Americans. Scientific Reports, 2017, 7(1): 1-7. https://doi.org/10.1038/s41598-017-00307-4

ABDEL-MONEIM A., EL-SENOUSY W. M., ABDEL-LATIF M., KHALIL R. G., and ARAFA A. A. Increased incidence of Anti-IgG of Coxsackievirus and cytomegalovirus among diabetic children in Egypt. International Journal of Bioassays, 2017, 6(9): 5489-5493. https://doi.org/10.21746/ijbio.2017.9.4

RODRIGUEZ-CALVO T., SABOURI S., ANQUETIL F., and VON HERRATH M. G. The viral paradigm in type 1 diabetes: Who are the main suspects? Autoimmunity Reviews, 2016, 15(10): 964-969. https://doi.org/10.1016/j.autrev.2016.07.019

REGNELL S. E., & LERNMARK Å. Early prediction of autoimmune (type 1) diabetes. Diabetologia, 2017, 60(8): 1370-1381. https://doi.org/10.1007/s00125-017-4308-1

ZAYED H. Genetic epidemiology of type 1 diabetes in the 22 Arab countries. Current Diabetes Reports, 2016, 16(5): 37. https://doi.org/10.1007/s11892-016-0736-4

SHERA A. S., MIYAN Z., BASIT A., MAQSOOD A., AHMADANI M. Y., FAWWAD A., and RIAZ M. Trends of type 1 diabetes in Karachi, Pakistan. Pediatric Diabetes, 2008, 9(42): 401-406. https://doi.org/10.1111/j.1399-5448.2007.00309.x

POCIOT F. Type 1 diabetes genome‐wide association studies: not to be lost in translation. Clinical & Translational Immunology, 2017, 6(12): e162. https://doi.org/10.1038/cti.2017.51

THIRUNAVUKKARASU R., ASIRVATHAM A. J., CHITRA A., and JAYALAKSHMI M. SLC30A8 Gene rs13266634 C/T Polymorphism in Children with Type 1 Diabetes in Tamil Nadu, India. Journal of Clinical Research in Pediatric Endocrinology, 2019, 11(1): 55-60. https://dx.doi.org/10.4274%2Fjcrpe.galenos.2018.2018.0195

KAWASAKI E., UGA M., NAKAMURA K., KURIYA G., SATOH T., FUJISHIMA K., OZAKI M., ABIRU N., YAMASAKI H., WENZLAU J. M., DAVIDSON H. W., HUTTON J. C., and EGUCHI K. Association between anti-ZnT8 autoantibody specificities and SLC30A8 Arg325Trp variant in Japanese patients with type 1 diabetes. Diabetologia, 2008, 51(12): 2299-2302. https://doi.org/10.1007/s00125-008-1165-y

NIELSEN L. B., VAZIRI-SANI F., POERKSEN S., ANDERSEN M.-L. M., SVENSSON J., BERGHOLDT R., POCIOT F., HOUGAARD P., DE BEAUFORT C., CASTAÑO L., MORTENSEN H. B., LERNMARK A., and HANSEN L. Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. Autoimmunity, 2011, 44(8): 616-623. https://doi.org/10.3109/08916934.2011.576724

GOHLKE H., FERRARI U., KOCZWARA K., BONIFACIO E., ILLIG T., and ZIEGLER A.-G. SLC30A8 (ZnT8) polymorphism is associated with young age at type 1 diabetes onset. The Review of Diabetic Studies, 2008, 5(1): 25-27. https://doi.org/10.1900/rds.2008.5.25

DEREKE J., PALMQVIST S., NILSSON C., LANDIN-OLSSON M., and HILLMAN M. The prevalence and predictive value of the SLC30A8 R325W polymorphism and zinc transporter 8 autoantibodies in the development of GDM and postpartum type 1 diabetes. Endocrine, 2016, 53(3): 740-746. https://doi.org/10.1007/s12020-016-0932-7

RUTTER G. A., CHABOSSEAU P., BELLOMO E. A., MARET W., MITCHELL R. K., HODSON D. J., SOLOMOU A., and HU M. Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proceedings of the Nutrition Society, 2016, 75(1): 61-72. https://doi.org/10.1017/s0029665115003237

GU F. H. Genetic, epigenetic and biological effects of zinc transporter (SLC30A8) in type 1 and type 2 diabetes. Current Diabetes Reviews, 2017, 13(2): 132-140. https://doi.org/10.2174/1573399812666151123104540

GARNIER L., MARCHAND L., BENOIT M., NICOLINO M., BENDELAC N., WRIGHT C., MOULIN P., LOMBARD C., THIVOLET C., and FABIEN N. Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort. Clinica Chimica Acta, 2018, 478: 162-165. https://doi.org/10.1016/j.cca.2017.12.043

SKÄRSTRAND H., KRUPINSKA E., HAATAJA T. J., VAZIRI-SANI F., LAGERSTEDT J. O., and LERNMARK Å. Zinc transporter 8 (ZnT8) autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8 R and ZnT8 W autoantibody‐positive type 1 diabetes patients. Clinical & Experimental Immunology, 2015, 179(2): 220-229. https://doi.org/10.1111/cei.12448

DELLI A. J., VAZIRI-SANI F., LINDBLAD B., ELDING-LARSSON H., CARLSSON A., FORSANDER G., IVARSSON S. A., LUDVIGSSON J., KOCKUM I., MARCUS C., SAMUELSSON U., ÖRTQVIST E., GROOP L., BONDINAS G. P., PAPADOPOULOS G. K., and LERNMARK Å. 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, 61(10): 2556-2564. https://doi.org/10.2337/db11-1659

XU K., ZHA M., WU X., YU Z., YU R., XU X., CHEN H., and YANG T. Association between rs13266634 C/T polymorphisms of solute carrier family 30 member 8 (SLC30A8) and type 2 diabetes, impaired glucose tolerance, type 1 diabetes—a meta-analysis. Diabetes Research and Clinical Practice, 2011, 91(2): 195-202. https://doi.org/10.1016/j.diabres.2010.11.012

KAWASAKI E., NAKAMURA K., KURIYA G., SATOH T., KOBAYASHI M., KUWAHARA H., ABIRU N., YAMASAKI H., MATSUURA N., MIURA J., UCHIGATA Y., and EGUCHI K. Differences in the humoral autoreactivity to zinc transporter 8 between childhood-and adult-onset type 1 diabetes in Japanese patients. Clinical Immunology, 2011, 138(2): 146-153. https://doi.org/10.1016/j.clim.2010.10.007

PLENGVIDHYA N., CHANPRASERT C., CHONGJAROEN N., YENCHITSOMANUS P.-T., HOMSANIT M., and TANGJITTIPOKIN W. Impact of KCNQ1, CDKN2A/2B, CDKAL1, HHEX, MTNR1B, SLC30A8, TCF7L2, and UBE2E2 on risk of developing type 2 diabetes in Thai population. BMC Medical Genetics, 2018, 19(1): 93. https://doi.org/10.1186/s12881-018-0614-9


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