The presence of the 299Gly/399Ile haplotype in the toll-like receptor 4 (TLR4) gene is associated with protection to type 2 diabetes mellitus (T2DM) in Brazilian population

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 796-817-Diabetes Genetics & Epidemiology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-802
Tais Silveira Assmann*1, Natalia Emerim Lemos2, Letícia de Almeida Brondani1, Luis Henrique Canani3 and Daisy Crispim4
1Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, 2Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil, 3Hosp de Clinicas - Porto Alegre, Porto Alegre, Brazil, 4Clinical Hospital from Porto Alegre, Porto Alegre, Brazil
Introduction: It was recently hypothesized that a defect in the innate immune system underlies the pathophysiology of obesity, insulin resistance (IR) and, consequently, type 2 diabetes mellitus (T2DM). Thus, polymorphisms in genes encoding proteins of the innate immune system, such as the toll-like receptor 4 (TLR4), could affect the development of T2DM. TLR4 is a key receptor of the innate immunity for the recognition of lipopolysaccharide (LPS), a component of gram-negative bacteria. The ligation of LPS to the TLR4 results in the secretion of proinflammatory cytokines and induction of innate and adaptive immune responses. It is well known that proinflammatory cytokines are associated with the development of IR. Two TLR4 polymorphisms [Thr399Ile (C/T; rs4986791) and Asp299Gly (A/G; rs4986790)] have been associated with T2DM in some populations.

Objective: To investigate the association of the Asp299Gly and Thr399Ile polymorphisms, individually or in combination, with susceptibility to T2DM in a white Southeast Brazilian population.

Methods: We analyzed 748 patients with T2DM and 472 non-diabetic subjects. The local ethic committee approved the study, and all subjects signed an informed consent form. Polymorphisms were genotype by Real-Time PCR using TaqMan MGB probes (Life Technologies). Haplotypes constructed from the combination of Thr399Ile and Asp299Gly polymorphisms were inferred using Phase 2.1 program, which implements a Bayesian statistical method. 

Results: Genotypes of both polymorphisms were in Hardy-Weinberg equilibrium. The frequency of the 399Ile (T) allele was higher in non-diabetic subjects as compared to T2DM patients (7% vs. 4%; OR=0.636, CI 95% 0.433-0.935). Moreover, T2DM patients carrying the T allele of this polymorphism had lower levels of fasting plasma glucose (FPG) than patients with the C/C genotype (152.0 ± 36.0 vs. 162.5 ± 64 mg/dl; P=0.031). The Asp299Gly (A/G) polymorphism was not significantly associated with T2DM (P=0.06); however, T2DM patients with the G/G genotype showed lower levels of FPG as compared to patients carrying the A allele (108.0 ± 28.2 vs. 173.1 ± 73.0 mg/dl; P=0.04). The 299Gly (G) /399Ile (T) haplotype was also associated with protection for T2DM (Permutation P=0.021) and with lower levels of FPG (P=0.026).

Conclusion: In our population, the TLR4 399Ile (T) allele and the 299Gly (G) /399Ile (T) haplotype are associated with a significant protection for T2DM as well as with lower FPG in T2DM patients.

Nothing to Disclose: TSA, NEL, LDAB, LHC, DC

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Sources of Research Support: CNPq, FAPERGS, FIPE-HCPA, CAPES