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The rs225017 polymorphism in the 3'UTR of the human DIO2 gene is associated with increased insulin resistance.

Leiria LB, Dora JM, Wajner SM, Estivalet AA, Crispim D, Maia AL - PLoS ONE (2014)

Bottom Line: The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal DIO2 expression.Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (/D'/ = 0.811; r2 = 0.365).In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.

View Article: PubMed Central - PubMed

Affiliation: Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

ABSTRACT
The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal DIO2 expression. Thus, we aimed to investigate whether other DIO2 polymorphisms, individually or in combination with the Thr92Ala, may contribute to IR. The entire coding-region of DIO2 gene was sequenced in 12 patients with type 2 diabetes mellitus (T2DM). Potentially informative variants were evaluated in 1077 T2DM patients and 516 nondiabetic subjects. IR was evaluated using the homeostasis model assessment (HOMA-IR) index. DIO2 gene sequencing revealed no new mutation but 5 previously described single nucleotide polymorphisms (SNPs). We observed that all T2DM patients displaying high HOMA-IR index (n = 6) were homozygous for the rs225017 (T/A) polymorphism. Further analysis showed that the median fasting plasma insulin and HOMA-IR of T2DM patients carrying the T/T genotype were higher than in patients carrying the A allele (P = 0.013 and P = 0.002, respectively). These associations were magnified in the presence of the Ala92Ala genotype of the Thr92Ala polymorphism. Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (/D'/ = 0.811; r2 = 0.365). In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.

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Possible interaction between rs225017 and Thr92Ala variants in modulation of insulin resistance.HOMA-IR indexes in T2DM patients according to different genotypes of DIO2 rs225017 (A/T) and rs225014 (Thr92Ala) polymorphisms. Results are expressed as median (percentiles 25% and 75%). Circles represent outlier values. Interaction P value  = 0.010, adjusted for age, sex, BMI, and use of medication for T2DM.
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pone-0103960-g002: Possible interaction between rs225017 and Thr92Ala variants in modulation of insulin resistance.HOMA-IR indexes in T2DM patients according to different genotypes of DIO2 rs225017 (A/T) and rs225014 (Thr92Ala) polymorphisms. Results are expressed as median (percentiles 25% and 75%). Circles represent outlier values. Interaction P value  = 0.010, adjusted for age, sex, BMI, and use of medication for T2DM.

Mentions: Taking these results into account, we tested whether any haplotype constituted by the rs225017 and Thr92Ala polymorphisms might affect fasting plasma insulin levels or HOMA-IR index differently as compared with the effect of each polymorphism analyzed separately. To test this hypothesis, we performed GLM analyses using fasting insulin levels or the HOMA-IR index as the dependent variable, and age, sex, BMI, use of medication for T2DM and the polymorphic combinations of the two DIO2 variants as independent variables. These interaction analyses are shown in Table 2. Patients carrying the Ala/Ala – T/T haplotype showed higher fasting insulin values than patients with other genotype combinations, adjusting for covariables (F = 11.072, P = 0.001). Likewise, patients carrying the Ala/Ala – T/T haplotype showed a higher HOMA-IR index than patients with other genotype combinations (F = 4.740; P = 0.010) (Figure 2).


The rs225017 polymorphism in the 3'UTR of the human DIO2 gene is associated with increased insulin resistance.

Leiria LB, Dora JM, Wajner SM, Estivalet AA, Crispim D, Maia AL - PLoS ONE (2014)

Possible interaction between rs225017 and Thr92Ala variants in modulation of insulin resistance.HOMA-IR indexes in T2DM patients according to different genotypes of DIO2 rs225017 (A/T) and rs225014 (Thr92Ala) polymorphisms. Results are expressed as median (percentiles 25% and 75%). Circles represent outlier values. Interaction P value  = 0.010, adjusted for age, sex, BMI, and use of medication for T2DM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126657&req=5

pone-0103960-g002: Possible interaction between rs225017 and Thr92Ala variants in modulation of insulin resistance.HOMA-IR indexes in T2DM patients according to different genotypes of DIO2 rs225017 (A/T) and rs225014 (Thr92Ala) polymorphisms. Results are expressed as median (percentiles 25% and 75%). Circles represent outlier values. Interaction P value  = 0.010, adjusted for age, sex, BMI, and use of medication for T2DM.
Mentions: Taking these results into account, we tested whether any haplotype constituted by the rs225017 and Thr92Ala polymorphisms might affect fasting plasma insulin levels or HOMA-IR index differently as compared with the effect of each polymorphism analyzed separately. To test this hypothesis, we performed GLM analyses using fasting insulin levels or the HOMA-IR index as the dependent variable, and age, sex, BMI, use of medication for T2DM and the polymorphic combinations of the two DIO2 variants as independent variables. These interaction analyses are shown in Table 2. Patients carrying the Ala/Ala – T/T haplotype showed higher fasting insulin values than patients with other genotype combinations, adjusting for covariables (F = 11.072, P = 0.001). Likewise, patients carrying the Ala/Ala – T/T haplotype showed a higher HOMA-IR index than patients with other genotype combinations (F = 4.740; P = 0.010) (Figure 2).

Bottom Line: The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal DIO2 expression.Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (/D'/ = 0.811; r2 = 0.365).In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.

View Article: PubMed Central - PubMed

Affiliation: Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

ABSTRACT
The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal DIO2 expression. Thus, we aimed to investigate whether other DIO2 polymorphisms, individually or in combination with the Thr92Ala, may contribute to IR. The entire coding-region of DIO2 gene was sequenced in 12 patients with type 2 diabetes mellitus (T2DM). Potentially informative variants were evaluated in 1077 T2DM patients and 516 nondiabetic subjects. IR was evaluated using the homeostasis model assessment (HOMA-IR) index. DIO2 gene sequencing revealed no new mutation but 5 previously described single nucleotide polymorphisms (SNPs). We observed that all T2DM patients displaying high HOMA-IR index (n = 6) were homozygous for the rs225017 (T/A) polymorphism. Further analysis showed that the median fasting plasma insulin and HOMA-IR of T2DM patients carrying the T/T genotype were higher than in patients carrying the A allele (P = 0.013 and P = 0.002, respectively). These associations were magnified in the presence of the Ala92Ala genotype of the Thr92Ala polymorphism. Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (/D'/ = 0.811; r2 = 0.365). In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.

Show MeSH
Related in: MedlinePlus