The K121Q Polymorphism of the <i>ENPP1/PC-1</i> Gene Is Associated With Insulin Resistance/Atherogenic Phenotypes, Including Earlier Onset of Type 2 Diabetes and Myocardial Infarction

Bacci, Simonetta; Ludovico, Ornella; Prudente, Sabrina; Zhang, Xu Dong; Paola, Rosa Di; Mangiacotti, Davide; Rauseo, Anna; Nolan, D.; Duffy, Jill; Fini, G.; Salvemini, Lucia; Amico, Cesare; Vigna, Carlo; Pellegrini, Fabio; Menzaghi, Claudia; Doria, Alessandro; Trischitta, Vincenzo

doi:10.2337/diabetes.54.10.3021

Cited by 109 publications

(115 citation statements)

References 24 publications

(17 reference statements)

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“…We believe that studies that are adequately powered, as was the study described in the present report, are required; among the published association studies of the K121Q variant, ours is the largest so far. Thus, on the basis of the previous reports of the presumed effect of the K121Q genotype [20,29] we estimate the statistical power at a significance level of 0.05 in the present study to detect an association with type 2 diabetes and obesity (depending on BMI strata) to be 85-98% and 90-99%, respectively.…”

Section: Discussionmentioning

confidence: 82%

“…No evidence of an impact of the variant on measures of insulin sensitivity indices [39][40][41] was observed. In fact, the impact of the gene variant on insulin resistance has been ambiguous, yielding association in some but not all populations studied [16,[19][20][21][22]42]. Finally, we were unable to relate the K121Q variant to the presence of type 2 diabetes or associated quantitative metabolic traits in the Danish sample.…”

Section: Discussionmentioning

confidence: 90%

“…Hence, initial findings indicating association of the Q allele with insulin resistance [16,19,20] were not confirmed in all subsequent studies [21,22]. 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].…”

mentioning

confidence: 99%

“…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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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: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

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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“…Another polymorphism has been described in the ENPP1 (encoding ectonucleotide pyrophosphatase 1) gene. ENPP1 is an inhibitor for an inhibitor of insulin secretion associated with insulin resistance, development of diabetes before the age of 65 and myocardial infarction before the age of 50 [72]. Recently, a TNF-induced protein 3 (TNFAIP3, a negative regulator of NFκB) polymorphism was identified to modulate the risk for coronary artery disease in type 2 diabetics [73].…”

Section: Genes Associated With Diabetes and Atherosclerosismentioning

confidence: 99%

Mechanisms by which diabetes increases cardiovascular disease

Gleissner

Galkina

Nadler

et al. 2007

Drug Discovery Today: Disease Mechanisms

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Diabetes mellitus is one of the major risk factors for cardiovascular disease which is the leading cause of death in the U.S. Increasing prevalence of diabetes and diabetic atherosclerosis makes identification of molecular mechanisms by which diabetes promotes atherogenesis an important task. Targeting common pathways may ameliorate both diseases. This review focuses on well known as well as newly discovered mechanisms which may represent promising therapeutic targets.

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Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

Doria

Wójcik

et al. 2008

JAMA

118

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Context A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. Objective To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. Design, Setting, and Participants 1. Case-control study of 734 type 2 diabetic patients (322 with angiographically-diagnosed CAD and 412 with no evidence of CAD) who were recruited in 2001–2006 at the Joslin Clinic/Beth Israel Deaconess Medical Center, 2. Independent cohort study of 475 type 2 diabetic patients from the Joslin Clinic whose survival status was monitored from their recruitment in 1993–1996 until December 31, 2004. Study subjects were genotyped for a representative SNP at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A1c (HbA1c) measurements taken in the years before study entry. Main Outcome Measures Case-control study: association between SNP rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof. Cohort study: cumulative 10-year mortality. Results Individuals homozygous for the risk allele were significantly more frequent in case than control subjects (42.3 vs. 28.9%, p=0.0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted p for interaction = 0.048) in the presence of poor glycemic control (worst tertile of the distribution of HbA1c at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD risk for subjects having two risk alleles but not poor glycemic control was increased two-fold (OR=1.99, 1.17–3.41), whereas the risk for study subjects with the same genotype and with poor glycemic control was increased four-fold (OR=4.27, 2.26–8.01). The interaction was stronger (adjusted p=0.005) when a measure of long-term glycemic control (7-year average rather than most recent HbA1c) was used, with ORs of 7.83 (3.49–17.6) for subjects having two risk alleles and a history of poor glycemia and 1.54 (0.72–3.30) for subjects with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with two risk alleles and poor glycemic control, 23.1% in those with only the two risk alleles, 30.0% in those with only poor glycemic control, and 31.6% in those with neither factor, p for interaction=0.036). Conclusions In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.

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The K121Q Polymorphism of the ENPP1/PC-1 Gene Is Associated With Insulin Resistance/Atherogenic Phenotypes, Including Earlier Onset of Type 2 Diabetes and Myocardial Infarction

Cited by 109 publications

References 24 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

Mechanisms by which diabetes increases cardiovascular disease

Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

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