Limits...
Carriers of a novel frame-shift insertion in WNT16a possess elevated pancreatic expression of TCF7L2.

Howard EW, Been LF, Lerner M, Brackett D, Lightfoot S, Bullen EC, Sanghera DK - BMC Genet. (2013)

Bottom Line: Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%).Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway.However, further studies would be needed to mechanistically link the two definitively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

ABSTRACT

Background: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2.

Results: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003).

Conclusions: Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.

Show MeSH

Related in: MedlinePlus

Distributions of serum levels (mean ±SD) of inflammatorycytokines (TNFα and MCP-I) among Wnt16a insertion carriersnon-carriers in SDS subjects. Serum levels of TNFα weresignificantly higher (p=0.008) in insertion carriers, while a similarbut non-significant trend was seen with MCP-1. The statistical analysiswas performed in combined samples (T2D and controls) after adjusting forthe confounding effects of age, BMI, gender, and T2D status.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3675375&req=5

Figure 2: Distributions of serum levels (mean ±SD) of inflammatorycytokines (TNFα and MCP-I) among Wnt16a insertion carriersnon-carriers in SDS subjects. Serum levels of TNFα weresignificantly higher (p=0.008) in insertion carriers, while a similarbut non-significant trend was seen with MCP-1. The statistical analysiswas performed in combined samples (T2D and controls) after adjusting forthe confounding effects of age, BMI, gender, and T2D status.

Mentions: A genetic screening of 2,034 SDS individuals (977 T2D cases and 1,057 controlsT2D cases and 1,057 controls) showed that 33% of T2D cases and 32% non-diabeticcontrols were carriers of a CCCA insertion; the number of carriers of thisinsertion did not differ significantly among cases versus controls (p=0.08).Multiple regression analysis, performed in diabetics and non-diabetic controlsseparately, did not reveal any association of the Wnt16a insertion withobesity (BMI, waist-to-hip ratio [WHR]) (Table 1).However, the insertion carriers showed moderately higher mean (±SD) levelsof total cholesterol compared to non-carriers (173.8±52.9 (mg/dL) vs.179.2±49.9 (mg/dL), p=0.038). Serum mean levels of inflammatory cytokinesTNFα were also significantly higher among insertion carriers compared tonon-carriers (p=0.008) (Figure 2). A similar butnon-significant trend was seen with increased mean levels of MCP-1 amonginsertion carriers compared to non-carriers (p=0.440) (Figure 2). There was a significant difference in the frequency of‘T’ (the at risk allele for T2D) in rs7903146 of TCF7L2among cases and controls (38% cases vs. 28% controls). The age- and sex-adjustedOR showing ‘T’ allele-associated T2D risk was 1.51 (95%CI[1.37-1.66], p=1.53x10-17). However, no association ofTCF7L2 polymorphism was seen with inflammatory cytokines (TNFαor MCP-1) (data not shown).


Carriers of a novel frame-shift insertion in WNT16a possess elevated pancreatic expression of TCF7L2.

Howard EW, Been LF, Lerner M, Brackett D, Lightfoot S, Bullen EC, Sanghera DK - BMC Genet. (2013)

Distributions of serum levels (mean ±SD) of inflammatorycytokines (TNFα and MCP-I) among Wnt16a insertion carriersnon-carriers in SDS subjects. Serum levels of TNFα weresignificantly higher (p=0.008) in insertion carriers, while a similarbut non-significant trend was seen with MCP-1. The statistical analysiswas performed in combined samples (T2D and controls) after adjusting forthe confounding effects of age, BMI, gender, and T2D status.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675375&req=5

Figure 2: Distributions of serum levels (mean ±SD) of inflammatorycytokines (TNFα and MCP-I) among Wnt16a insertion carriersnon-carriers in SDS subjects. Serum levels of TNFα weresignificantly higher (p=0.008) in insertion carriers, while a similarbut non-significant trend was seen with MCP-1. The statistical analysiswas performed in combined samples (T2D and controls) after adjusting forthe confounding effects of age, BMI, gender, and T2D status.
Mentions: A genetic screening of 2,034 SDS individuals (977 T2D cases and 1,057 controlsT2D cases and 1,057 controls) showed that 33% of T2D cases and 32% non-diabeticcontrols were carriers of a CCCA insertion; the number of carriers of thisinsertion did not differ significantly among cases versus controls (p=0.08).Multiple regression analysis, performed in diabetics and non-diabetic controlsseparately, did not reveal any association of the Wnt16a insertion withobesity (BMI, waist-to-hip ratio [WHR]) (Table 1).However, the insertion carriers showed moderately higher mean (±SD) levelsof total cholesterol compared to non-carriers (173.8±52.9 (mg/dL) vs.179.2±49.9 (mg/dL), p=0.038). Serum mean levels of inflammatory cytokinesTNFα were also significantly higher among insertion carriers compared tonon-carriers (p=0.008) (Figure 2). A similar butnon-significant trend was seen with increased mean levels of MCP-1 amonginsertion carriers compared to non-carriers (p=0.440) (Figure 2). There was a significant difference in the frequency of‘T’ (the at risk allele for T2D) in rs7903146 of TCF7L2among cases and controls (38% cases vs. 28% controls). The age- and sex-adjustedOR showing ‘T’ allele-associated T2D risk was 1.51 (95%CI[1.37-1.66], p=1.53x10-17). However, no association ofTCF7L2 polymorphism was seen with inflammatory cytokines (TNFαor MCP-1) (data not shown).

Bottom Line: Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%).Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway.However, further studies would be needed to mechanistically link the two definitively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

ABSTRACT

Background: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2.

Results: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003).

Conclusions: Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.

Show MeSH
Related in: MedlinePlus