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

Abstract

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.

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

“…To identify the populations to be included in this study, we initially selected all of the relevant case/control studies reported in previous meta-analyses of ENPP1 that assessed association results with type 2 diabetes (13,14,16,17), the largest consisting of 7,318 case and 13,726 control subjects (17). We complemented this approach with a systematic review of the PubMed database for articles that included "ENPP1" as a keyword, last accessed in August 2007.…”

“…A French and Austrian study, consisting of 1,255 case and 1,314 control subjects, examined several polymorphisms in ENPP1 and found evidence that a three-marker haplotype (comprised by K121Q as well as (18). Partial meta-analyses reported by the first two publications (16,17) yielded a nominal association of the Q allele with type 2 diabetes, but they continued to show significant heterogeneity and did not include results from each other or from our own extensive dataset. Similar limitations are present in a recent review (19).…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…One ENPP1 haplotype is associated with childhood and morbid obesity, T2DM, as well as circulating levels of ENPP1. [144][145][146] Expression of a long ENPP1 mRNA isoform, which includes one of the SNPs defining the risk haplotype, is specific for pancreatic islet beta cells, adipocytes and liver. 144 In addition, one ENPP1 SNP may impair insulin binding to the insulin receptor.…”

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

“…26 However, contrary results were also reported between K121Q and T2D in the Asian and Caucasian population. [27][28][29][30][31][32][33] In addition, recent genome-wide association studies have revealed a series of predisposing SNPs of T2D, which are mostly related to insulin secretion rather than to insulin resistance, 34 in large-scale samples and gene pool, but no evidence of association, except one, 21 between ENPP1 and T2D has been reported. [3][4][5] In our study, we examined two representative SNPs of ENPP1, rs1044498 (K121Q) and rs7754561, and investigated the possible association between them and T2D and obesity in a Chinese case-control population, which had been the largest sample investigated in China so far.…”