Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults

Matsuoka, Naoki; Patki, Amit; Tiwari, Hemant K.; Allison, David B.; Johnson, Steven B.; Gregersen, Peter K.; Rl, Leibel; Wk, Chung

doi:10.1038/sj.ijo.0803132

Cited by 60 publications

(57 citation statements)

References 22 publications

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“…Besides, we did not examine the full three-SNP haplotype, a fact that confines comparisons between the two studies somewhat, since it is possible, as indicated by the French study [29], that more than one variant in ENPP1 modulates the risk of type 2 diabetes and obesity. A few other smaller (of the order of 400 to 1,100 participants) and probably statistically underpowered studies found either no association [19,22,37,42], association of the rare Q allele [26] or association of the common K allele with obesity [38]. The reason for the apparent discrepancies between the studies, including ours, that have evaluated the pathogenic impact of the K121Q variant is far from obvious.…”

Section: Discussioncontrasting

confidence: 60%

“…Similar results were obtained when adjusting for the effects of age and sex (data not shown). To try to replicate previous findings of an influence of the ENPP1 gene on more extreme forms of obesity [29,38], we compared the K121Q genotypes of the subjects above the 90th percentile of the BMI distribution (n=586, mean±SD BMI, 35.7±3.8 kg/m 2 ) with the genotypes of subjects with BMI between the 10th and 20th percentiles (n=583, mean± SD BMI, 21.9±0.4 kg/m 2 ). No differences in allele frequencies or genotype distributions were found between these groups (p=0.6 for the codominant model; p=0.4 for the dominant model for the Q allele; p=0.6 for the recessive model for the Q allele).…”

Section: Resultsmentioning

confidence: 99%

“…It is possible that the susceptibility induced by the polymorphism is modulated by interactions with other ethnicspecific genetic or environmental factors and that the phenotypic expression of the variant will therefore be different in various ethnic populations. In this regard it is emphasised that the frequency of the K121Q polymorphism varies considerably between different ethnic groups [24,38,42,43]. It is also recognised that many case-control studies of multifactorial diseases with inheritance as complex as that of type 2 diabetes and obesity are often statistically underpowered in order to yield conclusive results, and random spurious positive associations due to multiple testing often cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Having established the association between ENPP1 K121Q and hyperglycemia, we explored the interaction between K121Q and BMI because of preliminary evidence that the effect of the Q allele on glycemic traits is mediated by an increase in adiposity (3,5,7,13,30) and suggestions that this variant may also contribute to obesity traits (5,6,(31)(32)(33). Although we observed no association of ENPP1 K121Q with BMI or waist circumference, our interaction analysis supports the observation that a higher BMI strengthens the association of this particular polymorphism with elevated insulin resistance and glucose levels.…”

Section: Discussionmentioning

confidence: 99%

Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study

et al. 2008

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OBJECTIVE-A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K3 Q missense single nucleotide polymorphism (SNP) at position 121 with type 2 diabetes. We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it.RESEARCH DESIGN AND METHODS-We characterized the haplotype structure of ENPP1 and selected 39 tag SNPs that captured 96% of common variation in the region (minor allele frequency Ն5%) with an r 2 value Ն0.80. We genotyped the SNPs in 2,511 Framingham Heart Study participants and used age-and sex-adjusted linear mixed effects (LME) models to test for association with quantitative metabolic traits. We also examined whether interaction between K121Q and BMI affected glycemic trait levels. RESULTS-The Q allele of K121Q (rs1044498) was associated with increased fasting plasma glucose (FPG), A1C, fasting insulin, and insulin resistance by homeostasis model assessment (HOMA-IR; all P ϭ 0.01-0.006). Two noncoding SNPs (rs7775386 and rs7773477) demonstrated similar associations, but LME models indicated that their effects were not independent from K121Q. We found no association of K121Q with obesity, but interaction models suggested that the effect of the Q allele on FPG and HOMA-IR was stronger in those with a higher BMI (P ϭ 0.008 and 0.01 for interaction, respectively).CONCLUSIONS-The Q allele of ENPP1 K121Q is associated with hyperglycemia and insulin resistance in whites. We found an adiposity-SNP interaction, with a stronger association of K121Q with diabetes-related quantitative traits in people with a higher BMI. Diabetes 57: [1971][1972][1973][1974][1975][1976][1977] 2008 E ctonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), is a transmembrane glycoprotein that down-regulates insulin signaling in cells by inhibiting the tyrosine kinase activity of the insulin receptor, perhaps by interaction with its ␣-subunit (1). Within the coding region of ENPP1, a K3 Q missense single nucleotide polymorphism (SNP) at position 121 (K121Q; rs1044498) has been previously associated with insulin resistance and related abnormalities in some studies (2-7). The molecular mechanism thought to be responsible for the role of the Q121 variant is a "gain of function" of the ENPP1 protein inhibitory activity on the insulin receptor (8). It has also been reported that insulin receptor autophosphorylation in fibroblasts is decreased in Q allele carriers compared with KK homozygotes (2). Thus, the ENPP1 gene is considered to be a likely candidate gene for insulin resistance and type 2 diabetes (9).Multiple studies have shown both positive and negative evidence of association between variants in ENPP1 and obesity, type 2 diabetes, and related traits. Most recently, Meyre et al. (5) found that a haplotype formed by three SNPs ...

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“…Where we encountered a large source of heterogeneity, we addressed it in a sequential manner: first, due to the large allele frequency differences in K121Q across populations (12% Q allele in HapMap CEU, 93% Q allele in HapMap YRI), we restricted the studies to be included in the final metaanalysis to those performed in the ethnic group with the largest number of samples (self-reported European descent); and second, given the suggestions that ENPP1 plays a role in obesity (15,(31)(32)(33) and that obesity may modulate the effect of ENPP1 K121Q on diabetes risk (15,21,22,32-34), we included BMI as a covariate in meta-regression and adjusted the meta-analysis accordingly. Egger's test was used to address publication bias.…”

Section: Methodsmentioning

confidence: 99%

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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Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults

Cited by 60 publications

References 22 publications

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

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

Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study

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

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