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Glutamine to Arginine Substitution at Amino Acid 84 of Mammalian Tribbles Homolog TRIB3 and CKD in Whites With Type 2 Diabetes

2007; Elsevier BV; Volume: 50; Issue: 4 Linguagem: Inglês

10.1053/j.ajkd.2007.06.023

1523-6838

Salvatore De Cosmo, Sabrina Prudente, Francesco Andreozzi, Eleonora Morini, Anna Rauseo, Daniela Scarpelli, Yuanyuan Zhang, Rui‐Hua Xu, Francesco Perticone, Bruno Dallapiccola, Giorgio Sesti, Alessandro Doria, Vincenzo Trischitta,

Pancreatic function and diabetes

Insulin resistance is associated with chronic kidney disease (CKD; defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2) in patients with type 2 diabetes.1De Cosmo S. Minenna A. Ludovico O. et al.Increased urinary albumin excretion, insulin resistance, and related cardiovascular risk factors in patients with type 2 diabetes: Evidence of a sex-specific association.Diabetes Care. 2005; 28: 910-915Crossref PubMed Scopus (82) Google Scholar The substitution of glutamine by arginine at amino acid 84 of TRIB3 (the p.Q84R polymorphism) is associated with insulin resistance.2Prudente S. Hribal M.L. Flex E. et al.The functional Q84R polymorphism of mammalian Tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy.Diabetes. 2005; 54: 2807-2811Crossref PubMed Scopus (91) Google Scholar We tested by means of restriction fragment length polymorphism whether TRIB3 p.Q84R is associated with CKD in a sample of patients with type 2 diabetes from Italy (529 men, 483 women; age 61.5 ± 10 years). Sex, age, diabetes duration, body mass index, hemoglobin A1c level, proportions of microalbuminuria and macroalbuminuria, arterial hypertension, and dyslipidemia were not different across genotypes (data not shown). As listed in Table 1, according to a recessive model of inheritance, individuals carrying 2 copies of the allele coding for p.R84 had a greater risk of CKD. A second study was performed in patients with type 2 diabetes from the Boston area (362 men, 221 women; age 64.7 ± 6.9 years). In this case, individuals with at least 1 copy of the allele coding for p.R84 tended to have a greater risk of CKD (P = 0.07), suggesting a dominant model of inheritance. Thus, results did not replicate the first study in terms of either statistical level of significance reached or genetic model of inheritance. Lack of replication in genotype-phenotype associations is not uncommon in complex disorders3Ioannidis J.P. Ntzani E.E. Trikalinos T.A. Contopoulos-Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-309Crossref PubMed Scopus (1604) Google Scholar, 4He W. Rose D.W. Olefsky J.M. Gustafson T.A. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains.J Biol Chem. 1998; 273: 6860-6867Crossref PubMed Scopus (128) Google Scholar, 5Redden D.T. Allison D.B. Non replication in genetic association studies of obesity and diabetes research.J Nutr. 2003; 133: 3323-3326PubMed Google Scholar and can be caused by population stratification or insufficient power. In our original study, the population was homogeneous and the P value was robust, making population stratification unlikely. In addition, the second study had 90% power to replicate results from the first study, suggesting that lack of replication was caused by genetic and/or environmental differences between the populations studied. Our data indicate that the TRIB3 R84 variant might be associated with CKD in patients with type 2 diabetes. Additional studies are needed to confirm this finding and investigate gene-gene/environment interactions in different populations.Table 1TRIB3 Q84R Genotype Distribution in Patients With Diabetes With or Without CKDWholeQQQRRROR (95% CI) for Additive ModelOR (95% CI) for Recessive ModelOR (95% CI) for Dominant ModelSample from Italy No CKD855602 (70)233 (27)20 (3)1.30 (0.89-1.90)4.74 (1.77-12.7)1.08 (0.68-1.74) CKD157112 (71)35 (22)10 (7)P = 0.17P = 0.002P = 0.74Sample from Boston No CKD403285 (71)105 (26)13 (3)1.03 (0.94-1.13)1.15 (0.41-3.24)1.44 (0.97-2.15) CKD180115 (64)59 (33)6 (3)P = 0.50P = 0.79P = 0.07Note: Values expressed as number (percent) after adjusting for age, sex, hemoglobin A1c level, and the presence/absence of arterial hypertension. Genotypes were in Hardy-Weinberg equilibrium in both samples.Abbreviations: CKD, chronic kidney disease (indicated by estimated glomerular filtration rate < 60 mL/min/1.73 m2); QQ, patients carrying the Q84/Q84 genotype; QR, patients carrying the Q84/R84 genotype; RR, patients carrying the R84/R84 genotype; OR, odds ratio; CI, confidence interval. Open table in a new tab Note: Values expressed as number (percent) after adjusting for age, sex, hemoglobin A1c level, and the presence/absence of arterial hypertension. Genotypes were in Hardy-Weinberg equilibrium in both samples. Abbreviations: CKD, chronic kidney disease (indicated by estimated glomerular filtration rate < 60 mL/min/1.73 m2); QQ, patients carrying the Q84/Q84 genotype; QR, patients carrying the Q84/R84 genotype; RR, patients carrying the R84/R84 genotype; OR, odds ratio; CI, confidence interval. Letters to the Editor may be in response to an article that appeared in AJKD no more than 6 months previously, or may concern a topic of interest to current nephrology. The body of the letter should be as concise as possible and in general should not exceed 250 words. Up to 10 references and 1 figure or table may be included. There is no guarantee that letters will be published. Letters are subject to editing and abridgment without notice.Letters should be submitted via AJKD’s online manuscript handling site, www.editorialmanager.com/ajkd. More information, including details about how to contact the editorial staff for assistance, is available in the journal’s Information for Authors. Letters to the Editor may be in response to an article that appeared in AJKD no more than 6 months previously, or may concern a topic of interest to current nephrology. The body of the letter should be as concise as possible and in general should not exceed 250 words. Up to 10 references and 1 figure or table may be included. There is no guarantee that letters will be published. Letters are subject to editing and abridgment without notice. Letters should be submitted via AJKD’s online manuscript handling site, www.editorialmanager.com/ajkd. More information, including details about how to contact the editorial staff for assistance, is available in the journal’s Information for Authors. S.D.C. and S.P. contributed equally to this work. Support: This work was supported in part by the Italian Ministry of Health (R.C. 2005 to S.P) and NIH Grant HL73168. Financial Disclosure: None.