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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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Related in: MedlinePlus

Candidate polymorphisms identified by sequencing of the DIO2 gene.A. The vertical arrows show the five candidate variants in human DIO2 gene identified through sequencing. Black boxes are coding regions. *polymorphisms associated with T2DM/IR/fasting insulin. ESECIS, Selenocysteine Insertion Sequence Element; 3′UTR = 3′-untranslated region. B. The characteristics of the 12 patients with T2DM selected for the screening of the DIO2 gene. These patients had extreme HOMA-IR indexes and were selected from two subgroups according low or high HOMA-IR values.
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pone-0103960-g001: Candidate polymorphisms identified by sequencing of the DIO2 gene.A. The vertical arrows show the five candidate variants in human DIO2 gene identified through sequencing. Black boxes are coding regions. *polymorphisms associated with T2DM/IR/fasting insulin. ESECIS, Selenocysteine Insertion Sequence Element; 3′UTR = 3′-untranslated region. B. The characteristics of the 12 patients with T2DM selected for the screening of the DIO2 gene. These patients had extreme HOMA-IR indexes and were selected from two subgroups according low or high HOMA-IR values.

Mentions: An interim study comprising samples of 12 patients with T2DM was used to search for polymorphisms in the DIO2 gene. This first phase study identified 448 amplicons (data not shown). Although no new mutation was detected in the data set, 5 previously described SNPs were identified (Figure 1). These SNPs included two polymorphisms in the 5′ flanking region (rs199598135, rs12885300), one polymorphism in exon 3 (rs225014 - Thr92Ala), and two in the 3′UTR (rs225015, rs225017).


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)

Candidate polymorphisms identified by sequencing of the DIO2 gene.A. The vertical arrows show the five candidate variants in human DIO2 gene identified through sequencing. Black boxes are coding regions. *polymorphisms associated with T2DM/IR/fasting insulin. ESECIS, Selenocysteine Insertion Sequence Element; 3′UTR = 3′-untranslated region. B. The characteristics of the 12 patients with T2DM selected for the screening of the DIO2 gene. These patients had extreme HOMA-IR indexes and were selected from two subgroups according low or high HOMA-IR values.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103960-g001: Candidate polymorphisms identified by sequencing of the DIO2 gene.A. The vertical arrows show the five candidate variants in human DIO2 gene identified through sequencing. Black boxes are coding regions. *polymorphisms associated with T2DM/IR/fasting insulin. ESECIS, Selenocysteine Insertion Sequence Element; 3′UTR = 3′-untranslated region. B. The characteristics of the 12 patients with T2DM selected for the screening of the DIO2 gene. These patients had extreme HOMA-IR indexes and were selected from two subgroups according low or high HOMA-IR values.
Mentions: An interim study comprising samples of 12 patients with T2DM was used to search for polymorphisms in the DIO2 gene. This first phase study identified 448 amplicons (data not shown). Although no new mutation was detected in the data set, 5 previously described SNPs were identified (Figure 1). These SNPs included two polymorphisms in the 5′ flanking region (rs199598135, rs12885300), one polymorphism in exon 3 (rs225014 - Thr92Ala), and two in the 3′UTR (rs225015, rs225017).

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