Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population

Imamura, Minako; Iwata, Minoru; Maegawa, Hiroshi; Watada, Hirotaka; Hara, Hiroshi; Tanaka, Yasushi; Tobe, Kazuyuki; Kaku, Kohei; Kashiwagi, Atsunori; Kawamori, R; Nakamura, Yusuke; Maeda, Shiro

doi:10.1007/s00125-011-2293-3

Cited by 35 publications

(21 citation statements)

References 22 publications

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“…Genetic variants at the SPRY2 locus have been associated with body fat distribution and susceptibility to type 2 diabetes [12,13,14]. We showed associations of placental SPRY2 with increased C-peptide and post-load glucose and decreased HMW adiponectin in normal human pregnancy.…”

Section: Discussionmentioning

confidence: 61%

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Placental Sprouty 2 (SPRY2): Relation to Placental Growth and Maternal Metabolic Status

et al. 2014

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Background:SPROUTY2 (SPRY2) is a membrane-associated protein expressed by placental macrophages with regulatory roles in tissue growth and development. The SPRY2 locus was shown to be associated with body fat distribution and susceptibility to type 2 diabetes. Objectives: We assessed whether SPRY2 mRNA levels are related with maternal metabolic status and with placental weight. We also studied the association of placental mRNA of SPRY2 with macrophage-derived inflammatory genes. Methods: A maternal metabolic profile [C-peptide, post-load glucose and high-molecular-weight (HMW) adiponectin] was assessed between 24 and 28 weeks of gestation in 200 control women delivering adequate-for-gestational-age (AGA) infants. Placentas and newborns were weighed at delivery. Placental mRNA levels of SPRY2 and of macrophage-derived inflammatory genes MMP2, TNFα and CD163 were quantified by real-time PCR. Women delivering small-for-gestational-age infants (SGA, n = 25) and women with gestational diabetes (GDM, n = 25) were also studied as validation groups for placental growth. Results: In control women delivering AGA infants, placental SPRY2 mRNA levels showed positive associations with a more adverse maternal metabolic status (higher maternal C-peptide and post-load glucose and lower HMW adiponectin), with more placental weight and with a more placental inflammatory phenotype (higher placental mRNA levels of MMP2,TNFα and CD163) (all p < 0.05 to p = 0.001). Compared to AGA infants, placental weight and placental SPRY2 mRNA levels were lower in placentas from SGA infants and higher in placentas from women with GDM (all p < 0.0001). Conclusions: Our results suggest a link between placental SPRY2 mRNA levels and placental growth, which may be modulated by maternal metabolic status and placental inflammation.

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Section: Discussionmentioning

confidence: 61%

“…SPRY2 was also recently shown to be involved in body fat distribution and susceptibility to type 2 diabetes [12,13,14]. A physiological state of insulin resistance is required to preferentially direct maternal nutrients toward the fetoplacental unit, allowing adequate growth of the fetus.…”

Section: Introductionmentioning

confidence: 99%

Placental Sprouty 2 (SPRY2): Relation to Placental Growth and Maternal Metabolic Status

et al. 2014

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“…We identified novel regulators of insulin production including a type 2 diabetes locus, Spry2 (5–7). Spry2 is known to negatively regulate growth factor signaling, but its link to diabetes is not clear.…”

Section: Introductionmentioning

confidence: 99%

A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response

et al. 2017

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Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2—a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed that Spry2 is a novel UPR target and its upregulation is dependent on PERK. Knockdown of Spry2 resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR. Spry2 deletion in the adult mouse β-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel β-cell link between Spry2 and human diabetes.

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“…Single nucleotide polymorphisms (SNPs) in CAMK1D have been found to be associated with the susceptibility of developing T2D in an east Asian population (14). However, no significant association between the CAMK1D SNP and T2D was found in a study based on European populations (15).…”

Section: Introductionmentioning

confidence: 99%

Investigation into the promoter DNA methylation of three genes (CAMK1D, CRY2 and CALM2) in the peripheral blood of patients with type 2 diabetes

Cheng

Tang

et al. 2014

Experimental and Therapeutic Medicine

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Promoter DNA methylation may reflect the interaction between genetic backgrounds and environmental factors in the development of metabolic disorders, including type 2 diabetes (T2D). Calcium/calmodulin-dependent protein kinase 1D (CAMK1D), cryptochrome 2 (CRY2) and calmodulin 2 (CALM2) genes have been identified to be associated with a risk of T2D. Therefore, the aim of the present study was to investigate the contribution of promoter DNA methylation of these genes to the risk of T2D. Using bisulfite pyrosequencing technology, the DNA methylation levels of the CpG dinucleotides within the CAMK1D, CRY2 and CALM2 gene promoters were measured in 48 patients with T2D and 48 age- and gender-matched healthy controls. The results demonstrated that the promoters of these three genes were hypomethylated in the peripheral blood of all the subjects, and DNA methylation of these three genes did not contribute to the risk of T2D.

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Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population

Cited by 35 publications

References 22 publications

Placental Sprouty 2 <b><i>(SPRY2)</i></b>: Relation to Placental Growth and Maternal Metabolic Status

Placental Sprouty 2 <b><i>(SPRY2)</i></b>: Relation to Placental Growth and Maternal Metabolic Status

A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response

Investigation into the promoter DNA methylation of three genes (CAMK1D, CRY2 and CALM2) in the peripheral blood of patients with type 2 diabetes

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