Interaction of single nucleotide polymorphisms in ADRB2, ADRB3, TNF, IL6, IGF1R, LIPC, LEPR, and GHRL with physical activity on the risk of type 2 diabetes mellitus and changes in characteristics of the metabolic syndrome: The Finnish Diabetes Prevention Study

Kilpeläinen, Tuomas O.; Lakka, Timo A.; Laaksonen, David E.; Mager, Ursula; Salopuro, Titta; Kubaszek, Agata; Todorova, Boryana; Laukkanen, Olli; Lindström, Jaana; Eriksson, Johan G.; Hämäläinen, Helena; Aunola, Sirkka; Ilanne‐Parikka, Pirjo; Keinänen‐Kiukaanniemi, Sirkka; Tuomilehto, Jaakko; Laakso, Markku; Uusitupa, Matti

doi:10.1016/j.metabol.2007.10.022

Cited by 40 publications

(24 citation statements)

References 56 publications

(83 reference statements)

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“…Furthermore, the second SNP investigated in the present study, rs5404 in SLC2A2, has been evaluated in association with T2D (19–22); however, the obtained results were contradictory. In certain studies (20,21) a significant risk was observed among homozygotes, which was similar to the present results, while in another study (19) the minor allele was found to be associated with increased disease risk and with reduced postprandial glucose levels. To the best of our knowledge, the present study is the first to provide a comprehensive concurrent analysis of two SNPs (rs3749166 and rs5404) under investigation, which appear to be critical for the splicing of genes involved in complementary glucose transport systems.…”

Section: Discussionsupporting

confidence: 91%

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

et al. 2016

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Coding synonymous single nucleotide polymorphisms (SNPs) have attracted little attention until recently. However, such SNPs located in epigenetic, CpG sites modifying exonic splicing enhancers (ESEs) can be informative with regards to the recently verified association of intragenic methylation and splicing. The present study describes the association of type 2 diabetes (T2D) with the exonic, synonymous, epigenetic SNPs, rs3749166 in calpain 10 (CAPN10) glucose transporter (GLUT4) translocator and rs5404 in solute carrier family 2, member 2 (SLC2A2), also termed GLUT2, which, according to prior bioinformatic analysis, strongly modify the splicing potential of glucose transport-associated genes. Previous association studies reveal that only rs5404 exhibits a strong negative T2D association, while data on the CAPN10 polymorphism are contradictory. In the present study DNA from blood samples of 99 Greek non-diabetic control subjects and 71 T2D patients was analyzed. In addition, relevant publicly available cases (40) resulting from examination of 110 Personal Genome Project data files were analyzed. The frequency of the rs3749166 A allele, was similar in the patients and non-diabetic control subjects. However, AG heterozygotes were more frequent among patients (73.24% for Greek patients and 54.55% for corresponding non-diabetic control subjects; P=0.0262; total cases, 52.99 and 75.00%, respectively; P=0.0039). The rs5404 T allele was only observed in CT heterozygotes (Greek non-diabetic control subjects, 39.39% and Greek patients, 22.54%; P=0.0205; total cases, 34.69 and 21.28%, respectively; P=0.0258). Notably, only one genotype, heterozygous AG/CC, was T2D-associated (Greek non-diabetic control subjects, 29.29% and Greek patients, 56.33%; P=0.004; total cases, 32.84 and 56.58%, respectively; P=0.0008). Furthermore, AG/CC was strongly associated with very high (≥8.5%) glycosylated plasma hemoglobin levels among patients (P=0.0002 for all cases). These results reveal the complex heterozygotic SNP association with T2D, and indicate possible synergies of these epigenetic, splicing-regulatory, synonymous SNPs, which modify the splicing potential of two alternative glucose transport-associated genes.

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Section: Discussionsupporting

confidence: 91%

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

et al. 2016

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“…However, this variant was marginally associated with hypertension in a sample of obese women 22 and has been shown to interact with dietary fat intake to modulate waist circumference and triglyceride concentrations 23 and to modify the effect of physical activity on changes in weight and waist circumference. 24 Although two studies failed to show any effect of this variant on plasma ghrelin concentrations, 25,26 it cannot be ruled out that its effects, if any, can only be observed under specific environmental conditions. This could also explain why Mager et al 10 have observed an association between rs27647, rs26802, rs696217, rs4684677 and blood pressure levels in a population of overweight Finnish subjects with impaired glucose tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Such a phenomenon may be an explanation for the discrepancy between results showing that this polymorphism is not associated with ghrelin levels 25 but is associated with high-density lipoprotein cholesterol concentrations. 24 According to the HapMap database, the studied SNPs cover about 75% of the haplotypic variability of the coding regions and proximal promoter of the GHRL gene. Further investigations and further genotyping would be required to completely characterize the genetic variability of the promoter region.…”

Section: Discussionmentioning

confidence: 99%

Influence of ghrelin gene polymorphisms on hypertension and atherosclerotic disease

et al. 2009

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Ghrelin is involved in several metabolic and cardiovascular processes. Recent evidence suggests its involvement in blood pressure regulation and hypertension. The aim of the study was to determine associations of single-nucleotide polymorphisms (SNPs) and haplotypes of the ghrelin gene (GHRL) with hypertension and atherosclerotic disease. Six GHRL SNPs (rs27647, rs26802, rs34911341, rs696217, rs4684677 and a -473G/A (with no assigned rsID)) were investigated in a sample of 1143 hypertensive subjects and 1489 controls of Caucasian origin. Both single-locus and haplotype association analyses were performed. In single-locus analyses, only the non-synonymous rs34911341 was associated with hypertension (odds ratio (OR)¼1.95 (95% confidence interval (CI): 1.26-3.02), P¼0.003). Six common haplotypes with frequency 41% were inferred from the studied GHRL SNPs, and their frequency distribution was significantly different between hypertensive subjects and controls (v 2 ¼12.96 with 5 d.f. (degree of freedom), P¼0.024). The effect of rs26802 was found to be significantly (P¼0.017) modulated by other GHRL SNPs, as its C allele conferred either an increased risk (OR¼1.30 (1.08-1.57), P¼0.005) or a decreased risk (OR¼0.50 (0.23-1.06), P¼0.07) of hypertension according to the two different haplotypes on which it can be found. No association of GHRL SNPs or haplotypes with atherosclerotic disease was observed. In conclusion, we observed statistical evidence for association between GHRL SNPs and risk of hypertension.

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“…Genomewide association studies have been widely applied to analyze the correlation between variants of genes and the components of MetS in recent years [3][4][5][6][7]. Based on the "thrifty phenotype" hypothesis proposed earlier [8,9], it is suggested that variants of the genes that regulate physiologic responses in the liver and adipose tissues may affect the metabolism of glucose and lipoprotein.…”

Section: Introductionmentioning

confidence: 99%

Variants in the insulin-degrading enzyme gene are associated with metabolic syndrome in Chinese elders

Huang

Liu

et al. 2009

Metabolism

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Interaction of single nucleotide polymorphisms in ADRB2, ADRB3, TNF, IL6, IGF1R, LIPC, LEPR, and GHRL with physical activity on the risk of type 2 diabetes mellitus and changes in characteristics of the metabolic syndrome: The Finnish Diabetes Prevention Study

Cited by 40 publications

References 56 publications

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

Influence of ghrelin gene polymorphisms on hypertension and atherosclerotic disease

Variants in the insulin-degrading enzyme gene are associated with metabolic syndrome in Chinese elders

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