An Intron Variant of SLC2A9 Increases the Risk for Type 2 Diabetes Mellitus Complicated with Hyperuricemia in Chinese Male Population
AbstractBackground: The aim of this study was to explore the associations of haplotypes of the glucose transporter 9 (SLC2A9) genes with type 2 diabetes mellitus (T2DM) complicated with hyperuricemia (HUA).Methods: Overall, 608 Chinese males, enrolled from the Affiliated Hospital of Medical College of Qingdao University in 2009-2012, were genotyped. The subjects included 167 withT2DM (average age of onset (58.07±11.82 yr), 198 with HUA subjects (average age of onset (39.20±9.73) yr), 115 with T2DM complicated with HUA (average age of onset (51.24±10.09) yr), and 128 control subjects (average age (41.92±10.01) yr). Patients genotypes of the SNPs; including rs734553 was determined by PCR method. Each genotype was regressed assuming the co-dominant, dominant and the recessive models of inheritance with covariates of duration of total glucose, uric acid, urea nitrogen, triglyceride, cholesterol, and creatinine levels.Results: Chi-square test revealed that rs734553polymorphism was both significantly associated with HUA as well as T2DM complicated HUA, but not with pure T2DM. After adjustment for age and gender, analysis showed that people with C allele had higher risk of HUA andT2DMcomplicated HUA than those without C allele. And none of the subjects had the homozygous genotype for SLC2A9 (CC).Conclusion: The SLC2A9 mutation increases the risk for T2DM complicated HUA in Chinese population, which suggested that intron variants between two relatively conserved exons could also be associated with diseases. In patients of T2DM complicated with HUA, the diagnosis and detection of SLC2A9 gene variants should be caused enough attention.
Al-Quwaidhi AJ, Pearce MS, Sobngwi E et al (2014). Comparison of type 2 diabetes prevalence estimates in Saudi Arabia from a validated Markov model against the International Diabetes Federation and other modeling studies. Diabetes Res Clin Pract, 103(3):496-503.
Roddy E, Choi HK (2014). Epidemiology of gout. Rheum Dis Clin North Am, 40(2):155-175.
Wang J, Chen RP, Lei L et al (2013). Prevalence and determinants of hyperuricemia in type 2 diabetes mellitus patients with central obesity in Guangdong Province in China. Asia Pac J Clin Nutr, 22(4):590-8.
Li S, Sanna S, Maschio A et al (2007). The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet, 3(11):e194.
Doring A, Gieger C, Mehta D et al (2008). SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet, 40(4):430-6.
Vitart V, Rudan I, Hayward C et al (2008). SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet, 40(4):437-442.
Wallace C, Newhouse SJ, Braund P et al (2008). Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet, 82(1):139-149.
Stark K, Reinhard W, Neureuther K et al (2008). Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PloS one, 3(4):e1948.
Xing S-C, Wang X-F, Miao Z-M et al (2015). Association of an Exon SNP of SLC2A9 Gene with Hyperuricemia Complicated with Type 2 Diabetes Mellitus in the Chinese Male Han Population. Cell Biochem Biophys, 71(3):1335-1339.
Salas-Burgos A, Iserovich P, Zuniga F et al (2004). Predicting the three-dimensional structure of the human facilitative glucose transporter glut1 by a novel evolutionary homology strategy: insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules. Biophys J, 87(5):2990-9.
Kolz M, Johnson T, Sanna S et al (2009). Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet, 5(6):e1000504.
Gonzalez-Aramburu I, Sanchez-Juan P, Jesus S et al (2013). Genetic variability related to serum uric acid concentration and risk of Parkinson's disease. Mov Disord, 28(12):1737-40.
Testa A, Mallamaci F, Leonardis D et al (2015). Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression. Nutr Metab Cardiovasc Dis, 25(2):167-72.
Testa A, Mallamaci F, Spoto B et al (2014). Association of a polymorphism in a gene encoding a urate transporter with CKD progression. Clin J Am Soc Nephrol, 9(6):1059-65.
Wallace SL, Robinson H, Masi AT et al (1977). Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum, 20(3):895-900.
Miao Z, Yan S, Wang J et al (2009). Insulin resistance acts as an independent risk factor exacerbating high-purine diet induced renal injury and knee joint gouty lesions. Inflamm Res, 58(10):659-68.
Guariguata L, Whiting DR, Hambleton I et al (2014). Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract, 103(2):137-49.
Chang YH, Lei CC, Lin KC et al (2015). Serum uric acid level as an indicator for CKD regression and progression in patients with type 2 diabetes mellitus-a 4.6-year cohort study. Diabetes Metab Res Rev, 32(6):557-64.
Zhuang L, Su J-b, Zhang X-l et al (2016). Serum Amylase Levels in Relation to Islet β Cell Function in Patients with Early Type 2 Diabetes. PloS one, 11(9):e0162204.
Wang Y, Yan S, Li C et al (2013). Risk factors for gout developed from hyperuricemia in China: a five-year prospective cohort study. Rheumatol Int, 33(3):705-10.
Windpessl M, Ritelli M, Wallner M et al (2016). A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia. Am J Nephro, 43(4):245-250.
Mancikova A, Krylov V, Hurba O et al (2016). Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol, 20(4):578-584.
Sull JW, Park EJ, Lee M et al (2013). Effects of SLC2A9 variants on uric acid levels in a Korean population. Rheumatol Int, 33(1):19-23.
Charles BA, Shriner D, Doumatey A et al (2011). A genome-wide association study of serum uric acid in African Americans. BMC medical genomics, 4;4:17.
Wei F, Chang B, Yang X et al (2016). Serum Uric Acid Levels were Dynamically Coupled with Hemoglobin A1c in the Development of Type 2 Diabetes. Sci Rep, 6: 28549.
Ware EB, Riehle E, Smith JA et al (2015). SLC2A9 Genotype Is Associated with SLC2A9 Gene Expression and Urinary Uric Acid Concentration. PLoS One, 10(7):e0128593.
Voruganti VS, Laston S, Haack K et al (2015). Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study. Am J Clin Nutr, 101(4):725-32.
Giri AK, Banerjee P, Chakraborty S et al (2016). Genome wide association study of uric acid in Indian population and interaction of identified variants with Type 2 diabetes. Sci Rep, 6:21440.
Long W, Panwar P, Witkowska K et al (2015). Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport. J Biol Chem, 290(24):15292-303.
Mallamaci F, Testa A, Leonardis D et al (2014). A polymorphism in the major gene regulating serum uric acid associates with clinic SBP and the white-coat effect in a family-based study. J Hypertens, 32(8):1621-8; discussion 1628.
Mallamaci F, Testa A, Leonardis D et al (2015). A genetic marker of uric acid level, carotid atherosclerosis, and arterial stiffness: a family-based study. Am J Kidney Dis, 65(2):294-302.
Abbasian M, Ebrahimi H, Delvarianzadeh M et al (2016). Association between serum uric acid (SUA) levels and metabolic syndrome (MetS) components in personnel of Shahroud University of Medical Sciences. Diabetes Metab Syndr, 10(3):132-6.
Chen D, Zhang H, Gao Y et al (2015). Cross-sectional and longitudinal associations between serum uric acid and metabolic syndrome: Results from Fangchenggang Area Male Health and Examination Survey in China. Clin Chim Acta, 446:226-30.
Wei CY, Sun CC, Wei JC et al (2015). Association between Hyperuricemia and Metabolic Syndrome: An Epidemiological Study of a Labor Force Population in Taiwan. Biomed Res Int, 2015:369179.
Vaya A, Rivera L, Hernandez-Mijares A et al (2015). Association of metabolic syndrome and its components with hyperuricemia in a Mediterranean population. Clin Hemorheol Microcirc, 60(3):327-34.
Janghorbani M, Amini M (2016). Utility of Continuous Metabolic Syndrome Score in Assessing Risk of Type 2 Diabetes: The Isfahan Diabetes Prevention Study. Ann Nutr Metab, 68(1):19-25.
Liu WC, Hung CC, Chen SC et al (2011). The rs1014290 polymorphism of the SLC2A9 gene is associated with type 2 diabetes mellitus in Han Chinese. Exp Diabetes Res, 2011:527520.
Urano W, Taniguchi A, Anzai N et al (2010). Association between GLUT9 and gout in Japanese men. Ann Rheum Dis, 69(5):932-3.
Karns R, Zhang G, Sun G et al (2012). Genome-wide association of serum uric acid concentration: replication of sequence variants in an island population of the Adriatic coast of Croatia. Ann Hum Genet, 76(2):121-7.
Dehghan A, Kottgen A, Yang Q et al (2008). Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet, 372(9654):1953-61.
Stiburkova B, Pavlikova M, Sokolova J et al (2014). Metabolic syndrome, alcohol consumption and genetic factors are associated with serum uric acid concentration. PLoS One, 9(5):e97646.
Evans SA, Doblado M, Chi MM et al (2009). Facilitative glucose transporter 9 expression affects glucose sensing in pancreatic beta-cells. Endocrinology, 150(12):5302-10.
Kimura T, Takahashi M, Yan K et al (2014). Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells. PLoS One, 9(1):e84996.