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

Meyre, David; Bouatia-Naji, Nabila; Vatin, Vincent; Veslot, J; Samson, Chantal; Tichet, Jean; Marre, Michel; Balkau, Beverley; Froguel, Philippe

doi:10.1007/s00125-007-0787-9

Cited by 44 publications

(32 citation statements)

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“…Residual heterogeneity may be partially explained by an interaction between genotype and BMI. We did not find any evidence that the other two ENPP1 polymorphisms (which, together with K121Q, define a previously reported haplotype [15]) have an individual effect on diabetes risk, a result that is consistent with a recent population study by the same investigators (23).…”

Section: Enpp1 K121q Meta-analysis In Type 2 Diabetessupporting

confidence: 90%

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

McAteer

Prudente

Bacci³

et al. 2008

Diabetes

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,9 for the ENPP1 Consortium* OBJECTIVE-Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes. RESEARCH DESIGN AND METHODS-After a systematicreview of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a randomeffects approach. Our primary analysis consisted of 30 studies comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included BMI as a covariate.RESULTS-We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38 [95% CI 1.10 -1.74], P ϭ 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies (P ϭ 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI , P ϭ 0.50).CONCLUSIONS-The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to be modulated by BMI.

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Section: Enpp1 K121q Meta-analysis In Type 2 Diabetessupporting

confidence: 90%

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

McAteer

Prudente

Bacci³

et al. 2008

Diabetes

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“…10,11,49,50 The question of ENPP1's functional importance in OB etiology is complicated by negative results obtained in other association studies. 12,51 The distribution of association signals across the ENPP1 gene locus observed in this study (see Figure 1b) suggests that associations with OB traits (for example BMI and leptin) may be driven by the 3 0 UTR region, and not necessarily by K121Q polymorphism. This hypothesis is supported by several earlier studies that reported associations of OB-related traits with markers in ENPP1 3 0 UTR.…”

Section: Discussionmentioning

confidence: 65%

“…[6][7][8][9] ENPP1 lies on chromosome 6q22-q23 (OMIM#173335) in a region where several independent studies found a linkage peak to OB phenotypes. [10][11][12][13] ENPP1 is an attractive candidate gene for studying OB, as it was proposed as a key player in the etiology of insulin resistance 14,15 and in a recently suggested mechanism underlying defective adipocyte maturation. 16 The ENPP1 product has also been identified as one of the central regulators of extracellular pyrophosphate (ePPi)/phosphate (Pi) equilibrium levels.…”

Section: Introductionmentioning

confidence: 99%

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

et al. 2010

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Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. Aim: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. Subjects and methods: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. Results: Associations were observed between ENPP1 polymorphisms and BMI (P ¼ 0.0037) and leptin (P ¼ 0.0068). ALPL markers were associated with WHR (P ¼ 0.0026) and EGFR (P ¼ 0.0001). The ANKH gene was associated with all four studied obesity-related traits (Po0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. Conclusion: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

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“…A subsequent cellular transfection experiment showed that the Q allele was several fold more effective than the K allele in reducing insulin stimulation of IR autophosphorylation, IR substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis and cell proliferation. 18 During the last decade, genetic association studies have found a positive association between K121Q and T2D in Caucasians and Indians, [19][20][21] Tunisians, 22,23 African Americans 24 and Dominicans. 25 The Q allele was also observed to increase the risk of obesity in the Caucasian population.…”

Section: Introductionmentioning

confidence: 99%

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes or obesity in the Chinese Han population

et al. 2010

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Type 2 diabetes (T2D) mellitus is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. It has been a worldwide public health problem, which is increasing rapidly, especially in developing countries such as China. The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, also known as plasma cell membrane glycoprotein 1, has been reported by genetic association studies as being associated with T2D and obesity in various populations, such as Caucasian and African American. However, there are also some controversial results in Asian populations. Our study tried to examine the associations between ENPP1 and T2D and obesity. Rs1044498 (K121Q) and rs7754561 were genotyped in 1912 patients and 2041 control subjects through TaqMan technology on the ABI7900 system. They showed no statistical association with T2D, obesity or any metabolic quantitative traits. Our meta-analysis result was consistent with it. Our study did not replicate the positive association found previously and suggested that K121Q of ENPP1 might not have a major role in the susceptibility to T2D or obesity in the Chinese Han population.

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

Cited by 44 publications

References 50 publications

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes or obesity in the Chinese Han population

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