Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes.

Laukkanen, Olli; Pihlajamäki, Jussi; Lindström, Jaana; Eriksson, Johan G.; Valle, Timo T.; Hämäläinen, Helena; Ilanne‐Parikka, Pirjo; Keinänen‐Kiukaanniemi, Sirkka; Tuomilehto, Jaakko; Uusitupa, Matti; Laakso, Markku

doi:10.1007/s00125-004-1395-6

Cited by 55 publications

(36 citation statements)

References 41 publications

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“…In Sicilians and South Asians, subjects carrying the Q121 allele were reported to have significantly higher glucose and insulin levels during oral glucose tolerance tests (OGTT) and lower insulin sensitivity during glucose clamp studies (Pizzuti et al 1999;. Controversial results on the association between K121Q genotype frequency and the risk for T2D have also been reported (Rasmussen et al 2000;Gonza´lez-Sa´nchez et al 2003;Laukkanen et al 2004), though a recent meta-analysis confirmed a modest but significant association with T2D (Bacci et al 2005). In addition, Meyre et al (2005) conducted a large study involving 6,147 subjects and found the variant to correlate strongly with childhood obesity, morbid or moderate obesity in adults and T2D.…”

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confidence: 99%

No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population

et al. 2006

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Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, also known as PC-1) inhibits insulin signal transduction pathway(s). Previous studies have demonstrated the K121Q variant of the ENPP1 gene to have a significant functional role in determining susceptibility to insulin resistance and type 2 diabetes (T2D). To assess whether the K121Q variant has any impact on T2D in Japanese, we undertook an extensive case-control association study using a total of 911 unrelated Japanese T2D patients and 876 control subjects. No significant difference was observed in either genotype distribution (P=0.95) or allele frequency (P=0.83) between T2D and control groups. Notably, the frequency of the ancestral Q121 allele, which is also present in other primates, was quite high in AfricanAmericans, and showed a marked ethnic variation (77.3% in African-Americans, 16.7% in European Americans, 10.5% in Japanese and 4.2% in Han Chinese). Consequently, the pairwise F ST value (a classic measure of genetic distance between pairs of population) showed highly significant differentiations between African-American and non-African-American populations (F ST >0.3). Our results indicated that the K121Q variant of the ENPP1 gene has very little, if any, impact on T2D susceptibility in Japanese, but may play a role in the inter-ethnic variability in insulin resistance and T2D.

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Section: Introductionmentioning

confidence: 99%

No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population

et al. 2006

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“…The association between the ENPP1 three-allele risk haplotype and childhood obesity was recently confirmed in a German population [24], whereas the association with the at-risk haplotype for adult obesity and type 2 diabetes was not replicated in other well powered studies [25,26]. Some other reports on the K121Q single nucleotide polymorphism (SNP) have shown inconsistent allelic associations with BMI [27] and obesity [28] or even no association with insulin resistance or type 2 diabetes [20,[29][30][31][32][33][34]. The effects of ENPP1 SNPs have not been investigated yet in the context of a prospective cohort study, said to be the 'gold standard' in genetic epidemiology [35].…”

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ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study

et al. 2007

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Aims/hypothesis We assessed the predictive value of ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) SNPs with regard to the risk of developing obesity and/or type 2 diabetes in a large French general population. Methods We genotyped the ENPP1 SNPs K121Q (rs1044498), IVS20delT-11 (rs1799774) and A/G+1044TGA (rs7754561) in 5,153 middle-aged participants of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. Results At baseline, the K121Q polymorphism was not associated either with BMI (p=0.98) or with class I obesity (odds ratio [OR] 0.99, p=0.81), but showed a borderline association with class II obesity (OR 1.65, p=0.02). The K121Q variant was not associated with any trait during the 9-year follow-up. Pooled analyses both at baseline and at follow-up failed to show any association with hyperglycaemia (OR 1.08, p=0.28) or type 2 diabetes (OR 1.15, p=0.38). However, we did show an association of the Q121 allele with the risk of hyperglycaemia (OR 1.45, p= 0.001; n=265) and type 2 diabetes (OR 1.65, p=0.01; n= 103) in participants reporting a family history of type 2 diabetes. These results did not remain significant after a Bonferroni correction. The IVS20delT-11 and A/G+1044TGA polymorphisms and the three-allele risk haplotype (K121Q, IVS20delT-11 and A→G+1044TGA [QdelTG]) were not associated with any trait, either at baseline or at follow-up. Conclusions/interpretation In a general French population we did not find an association of the QdelTG risk haplotype with adult obesity and type 2 diabetes. We detected nominal evidence of association between the K121Q polymorphism and both severe adult obesity at baseline and the risk of hyperglycaemia or type 2 diabetes in participants with a family history of type 2 diabetes in pooled analyses both at baseline and follow-up.Keywords Ectonucleotide pyrophosphatase/ phosphodiesterase 1 . ENPP1 . Familial background of type 2 diabetes . Genetic epidemiology . Hyperglycaemia .

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“…Some studies have been able to relate the Q allele to type 2 diabetes [23,24] whereas others failed to do so [19,21,[25][26][27]. Likewise, a large intervention study failed to show evidence of an impact of the K121Q variant on the conversion from IGT to overt type 2 diabetes or weight change during 3 years of follow-up [28], whereas another prospective investigation found the Q allele to be associated with deterioration in an atherogenic risk profile as well as an earlier onset of type 2 diabetes [20]. Recently, evidence for an association of the K121Q variant and a risk haplotype defined by three single-nucleotide polymorphisms (SNPs) in ENPP1, including the K121Q variant, with different subtypes of obesity and type 2 diabetes was demonstrated in a sample of about 6,000 subjects of French and Austrian Caucasian origin [29].…”

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Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

et al. 2006

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Aims/hypothesis Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor α subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes. Subjects and methods The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.Results No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10-1.25], p=1×10 −6 ). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m 2 ; odds ratio 1.63 [95% CI 1.09-2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait. Conclusions/interpretation In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.

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Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes.

Cited by 55 publications

References 41 publications

No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population

No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population

ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

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