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A Single Nucleotide Polymorphism in Protein Tyrosine Phosphatase PTP-1B Is Associated with Protection from Diabetes or Impaired Glucose Tolerance in Oji-Cree

John P. Robarts Research Institute (A.M., H.C., R.A.H.), London, Ontario, Canada N6A 5K8; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto (B.Z., A.J.G.H.), Ontario, Canada M5G 1X5; Thames Valley Family Practice Research Unit, University of Western Ontario (S.B.H.), London, Ontario, Canada N6G 4X8; Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research (B.P.K.), Pointe Claire-Dorval, Quebec, Canada H9R 4P8

Address all correspondence and requests for reprints to: Robert A. Hegele, M.D., Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca

Abstract

Several lines of evidence support a role for protein tyrosine phosphatase 1B (PTP-1B) in metabolism, and specifically in insulin sensitivity and obesity. We report the development of reagents for the amplification and sequencing of the PTP-1B gene, which has resulted in the identification of a novel single nucleotide polymorphism (SNP), designated 981C T. We found a significant association between this SNP and the risk of either impaired glucose tolerance (IGT) or type 2 diabetes in the Oji-Cree of Sandy Lake, Ontario, Canada. Six hundred and fifty-three subjects were genotyped using PCR amplification of exon 8, followed by digestion with the restriction enzyme AvaI. Sixty-eight subjects were heterozygotes, and none was a homozygote. Thus, the overall frequencies of the C allele and the T allele were 0.948 and 0.052, respectively. Subjects with the PTP-1B 981T/981C genotype were approximately 40% less likely to have IGT or diabetes as subjects with the 981C/981C genotype (P = 0.040). There was no difference in quantitative traits among subjects grouped according to the PTP-1B 981CT SNP genotype. These very preliminary findings suggest that genomic variation in PTP-1B is associated with a reduced risk of diabetes and are consistent with the idea that this protein is important in metabolism.

PROTEIN TYROSINE phosphatases (PTP; EC 3.1.3.48) play a critical role in cell growth, motility, proliferation, and differentiation (1, 2). The ubiquitously expressed PTP-1B was the first tyrosine phosphatase to be characterized and in vitro dephosphorylates many receptor tyrosine kinases, including the ß-subunit of the insulin receptor (1, 2, 3, 4). A focal role for PTP-1B in metabolism was suggested by the observation that targeted disruption of the gene in mice resulted in enhanced insulin sensitivity and resistance to diet-induced obesity (5). Additional evidence favoring the potential importance of PTP-1B in diabetes mellitus (DM) comes from multiple linkage studies of type 2 DM on chromosome 20q13.1-q13.2 (6, 7, 8, 9), which harbors the PTP-1B gene (10). With the availability of genomic structure and DNA sequence for PTP-1B (11), it has become possible to develop markers for this gene. We report the development of amplification primers for the PTP-1B promoter and exons, and the use of these primers to identify a common single nucleotide polymorphism (SNP) in exon 8.

Subjects and Methods

Subjects

To screen for variants in PTP-1B, we sequenced the genomic DNA from eight unrelated subjects with type 2 DM of various ethnic backgrounds (mean age, 48.5± 5.7 yr; mean duration of type 2 DM, 5.2± 5.5 yr) and from three unrelated, unaffected, normal control subjects.

Association analysis with type 2 DM and related traits was carried out using samples from Oji-Cree subjects from Sandy Lake, Ontario, Canada (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). This community is located about 2000 km northwest of Toronto, in the subarctic boreal forest of central Canada. Seven hundred and twenty-eight members (72% of the total population) of this community, aged 10 yr or more, participated in the Sandy Lake Health and Diabetes Project (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Several complete clinical descriptions of the entire study sample have already been published (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). The project was approved by ethics review panels of the Universities of Western Ontario and Toronto and the Sandy Lake First Nations Band Council.

Biochemical analyses

Plasma samples were obtained with informed consent. Subjects were excluded from the study because of insufficient blood samples. Subjects gave plasma samples after fasting overnight for 12 h. Blood was centrifuged at 2000 rpm for 30 min, and the plasma was stored at -70 C. Concentrations of fasting plasma glucose and insulin were determined as previously described (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). A standard 75-g oral glucose tolerance test (OGTT) was then administered, and a second blood sample was collected 2 h later for plasma glucose determination. Subjects were excluded from the OGTT if they had physician-diagnosed diabetes, if they were receiving treatment with insulin and/or oral hypoglycemic agents, or if they had a fasting blood glucose exceeding 11.1 mmol/liter. Subjects who were pregnant at the time of recruitment had their OGTT deferred until 3 months postpartum. Type 2 DM, impaired glucose tolerance (IGT), and normal glucose tolerance (normoglycemic) were defined using pre-1997 criteria (22, 23).

Genomic DNA amplification and SNP identification

To amplify coding regions and intron-exon boundaries from genomic DNA, a primer set was developed using the genomic sequence for PTP-1B (11). Amplification primer sequences for the PTP-1B promoter exons 1–10, promoter, and 3'-untranslated regions are shown in Table 1. Primers were each designed to anneal at a single temperature, which allowed for use of a single amplification device. Amplification conditions were 94 C for 5 min, followed by 30 cycles comprised of 30 sec each of denaturing at 94 C, annealing at 59 C, and extension at 72 C, then a final extension step at 72 C for 10 min. Each fragment was directly sequenced in both directions (ABI PRISM 377, PE Applied Biosystems, Mississauga, Canada).

PTP-1B 981CT SNP genotyping

Exon 8 was amplified using the primers shown in Table 1 and the conditions defined above. The SNP alters a recognition site for endonuclease AvaI, and this became the basis of a rapid screening assay. After digestion with AvaI, the product amplified from the 981C allele yielded fragments with sizes of 239 and 93 bp, whereas the product amplified from the 981T allele yielded a single fragment of 332 bp. These fragments were resolved in 2% agarose gels (Fig. 1). Genotype scoring was performed with the reader blinded to the individual diagnosis. Known controls were run with each reaction, and all 68 heterozygotes were confirmed by either repeat restriction analysis or direct genomic sequencing. In other samples this genotyping procedure could unequivocally classify 981T/981T homozygotes (five of five), as confirmed by direct genomic DNA sequencing.

View larger version (74K): [in this window] [in a new window]   Figure 1. AvaI restriction digestion of exon 8 of the PTP-1B gene. Two homozygotes for PTP-1B 981C/981C are shown (C/C), each with two digestion fragments of 239 and 93 bp. Two heterozygotes, whose digestion pattern includes an additional fragment of 332 bp, are also shown (C/T). All genotypes were visualized on 2% agarose gels. M, A 100-bp DNA ladder size marker.

² analysis was used to compare differences in proportions between groups, using Fisher’s exact test. Odds ratios and 95% confidence intervals were determined using the Mantel-Haenszel method. Pairwise t tests were used to compare differences in the least squares means of quantitative traits between groups, with Bonferroni adjustment for multiple comparisons. SAS version 6.12 (SAS Institute, Inc., Cary NC) was used for all analyses.

Results

Identification of PTP-1B 981CT SNP

Genomic DNA screening experiments revealed only one silent SNP in the subjects screened, namely in 981CT in exon 8 at the third base of codon 303 in 2 normal subjects. The 981T allele frequency was 0.120 in 100 alleles from 50 normal Caucasians, and the genotype frequencies followed Hardy Weinberg expectations.

Association of PTP-1B 981CT SNP with affected status

There was clinical and biochemical information as well as DNA from 653 study subjects from Sandy Lake. Of these, 107 had type 2 DM, 70 had IGT, and 486 were normoglycemic. Baseline clinical and biochemical attributes are shown in Table 2. Sixty-eight subjects were heterozygotes, and none was a homozygote for the 981T allele. The allele frequency was thus 0.052, with no deviation of observed genotype frequencies from the Hardy-Weinberg expectation.

View this table: [in this window] [in a new window]   Table 2. Clinical and biochemical attributes according to affected status and PTP-1B 981CT SNP genotype (mean ± SE)

Genotype frequencies were compared between subjects grouped according to affected status. There was a significant decrease in risk of being affected with either type 2 DM or IGT among carriers of the 981T allele (Table 3). This was due to the significant decrease in risk of being affected with IGT in carriers of this allele. In contrast, there was no difference in risk of type 2 DM in carriers of this allele. However, there was marked overlap of confidence intervals for all affected subgroups.

View this table: [in this window] [in a new window]   Table 3. PTP-1B 981CT SNP genotype frequency according to affected status

We report the development of reagents for the amplification and sequencing of the PTP-1B gene, which has resulted in the identification of the novel 981CT SNP. In addition, we found a significant association between this SNP and the risk of being affected with either IGT or type 2 diabetes in the Oji-Cree of Sandy Lake. Specifically, subjects with the PTP-1B 981T/981C genotype were 42% less likely to have either IGT or type 2 diabetes than subjects with the 981C/981C genotype (P = 0.040). Subgroup analyses showed that the odds ratio was significantly decreased for subjects with IGT (0.24; 95% confidence interval, 0.06–0.97; P = 0.012), but not diabetes itself. However, there was marked overlap between the confidence intervals for the odds ratio of each subgroup. There was also no difference in quantitative traits among subjects grouped according to the PTP-1B 981CT SNP genotype. The findings suggest that genomic variation in PTP-1B is associated with an altered risk of developing an abnormal metabolic phenotype in Oji-Cree, and that the less common 981T allele was protective.

The results are consistent with the idea that the risk of impaired glycemic control (IGT plus diabetes) is modestly decreased overall in this study sample. Although the odds ratios appeared to be different for IGT and diabetes subgroups, the confidence intervals overlapped significantly. This fluctuation was possibly related to sampling variation rather than to a true difference in allelic association based upon affected status. Furthermore, these results are probably not related to admixture artifact, as previous analyses of allele frequencies in this sample indicated that Caucasian admixture is less than 10% (18, 19). However, it is also possible that there was no real association, and the modest P value represents a type 1 error.

PTP-1B is responsible for negatively regulated insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment (24). Interest in PTP-1B as a potential pharmacological target has intensified recently (1, 2) for several reasons. First, disruption of the murine homolog of PTP-1B was associated with reductions in blood glucose and insulin concentrations and with enhanced insulin sensitivity, as assessed through glucose and insulin tolerance tests (5). Also, the induced mutant mice had increased phosphorylation of the insulin receptor in liver and muscle (5). On a high fat diet, induced mutant mice were resistant to weight gain and remained insulin sensitive, whereas wild-type mice rapidly gained weight and became insulin resistant (5). These results suggested a major role for PTP-1B in modulation of insulin sensitivity and energy metabolism. Although there was no association of the PTP-1B 981CT SNP with static biochemical measures or weight in the Oji-Cree, the association of protection from diabetes in carriers of PTP-1B 981T was analogous to the association of improvement in metabolic indexes seen in the induced mutant mice.

As the PTP-1B 981CT SNP is silent at the amino acid level, the mechanistic basis of the association must be through linkage disequilibrium with an unmeasured functional variant, either within PTP-1B or a flanking regulatory region or within a closely linked gene on chromosome 20q13.1–13.2, whose product plays a role in metabolism. To date, DNA sequencing experiments have found no common promoter variants as much as 650 bp upstream of the transcription start site (data not shown). It would be of interest to determine whether the findings of other studies of linkage of 20q13.1-q13.2 with diabetes were due to functional variation in PTP-1B in those samples (6, 7, 8, 9). The described amplification reagents now make it possible to test this hypothesis. Furthermore, although this part of 20q was neither linked nor associated with type 2 DM or IGT in a genome scan in the Oji-Cree, that study was not powered to detect a protective relationship in fewer than 100 sibling pairs (13). These factors indicate the need for confirmatory studies of the relationship between genomic variation in PTP-1B and metabolic phenotypes.

The association of genetic variation in PTP-1B with a human phenotype is only the second such association for a PTP and the first for a metabolic phenotype. Myoclonic epilepsy of Lafora (OMIM 254780) was shown to result from mutations in laforin, a phosphatase with dual specificity (25). In addition, mutations in PTP receptor C type (CD45, OMIM 151460) have been associated with susceptibility to multiple sclerosis (26) and a form of combined immunodeficiency (27). The heterogeneity of these associated disease phenotypes confirms a broad range of physiological roles for this family of proteins and related molecules.

In summary, we have observed that PTP-1B 981T was associated with a reduced risk of an abnormal metabolic phenotype (IGT plus diabetes) in the Oji-Cree of Sandy Lake. As the SNP is silent at the amino acid level, the findings cannot be interpreted as directly defining a protective role for PTP-1B. Further studies are required to determine whether the association of PTP-1B 981T with IGT is more general and whether other variants explain the association. However, these observations provide support for the concept that the PTP-1B gene product is important in metabolism.

Acknowledgments

The following individuals are acknowledged: the chief and council of the community of Sandy Lake, the Sandy Lake surveyors, the Sandy Lake nurses; the staff of the University of Toronto Sioux Lookout program, and the Department of Clinical Epidemiology of the Samuel Lunenfeld Research Institute.

Footnotes

This work was supported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association (in honor of Rheta Maude Gilbert), the Canadian Genetic Diseases Network, the Blackburn Group, and Merck Frosst Canada.

¹ Career Investigator with the Heart and Stroke Foundation of Ontario and holds a Canada Research Chair (Tier I) in Human Genetics.

Abbreviations: DM, Diabetes mellitus; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PTP, protein tyrosine phosphatase; SNP, single nucleotide polymorphism.

Received June 28, 2001.

Accepted November 8, 2001.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mok, A. Articles by Hegele, R. A. Search for Related Content PubMed PubMed Citation Articles by Mok, A. Articles by Hegele, R. A.