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Variation in the AU(AT)-Rich Element within the 3'-Untranslated Region of PPP1R3 Is Associated with Variation in Plasma Glucose in Aboriginal Canadians¹

Robarts Research Institute and Department of Medicine (R.A.H., J.W., H.C.), and the Center for Studies in Family Medicine (S.B.H.), University of Western Ontario, London, Ontario, Canada N6A 5K8; and the Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital (B.Z., A.J.G.H.), and the Department of Genetics, The Hospital for Sick Children, University of Toronto (L.-C.T., S.W.S.), Toronto, Ontario, Canada M5G 1X8

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We are investigating associations between variations in candidate genes on chromosome 7q and diabetes-related phenotypes in Canadian Oji-Cree. One of these genes encodes the skeletal muscle regulatory G subunit of the glycogen-associated form of protein phosphatase 1 (PPPIR3), which may play a key role in muscle glycogen metabolism. There is a common 5-bp insertion-deletion polymorphism in a messenger ribonucleic acid-stabilizing AU(AT)-rich element within the 3'-untranslated region (UTR) of PPPIR3. The D allele had a frequency of 0.30 in the Oji-Cree. We found that this 3'-UTR variation of PPPIR3 was significantly associated with variation in 2-h postprandial glucose in adult Oji-Cree with type 2 diabetes or impaired glucose tolerance (IGT). Specifically, Oji-Cree with diabetes or IGT who were D/D homozygotes had significantly lower 2-h postprandial plasma glucose than subjects with the other genotypes. There was no association of the PPPIR3 genotype either with the presence of type 2 diabetes or IGT or with other quantitative traits in this sample. These findings suggest that common PPPIR3 3'-UTR variation that potentially affects messenger ribonucleic acid stability is associated with variation in glycemia in Oji-Cree subjects with type 2 diabetes.

	Introduction

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ALTHOUGH type 2 diabetes is acknowledged to have a genetic component, the identification of susceptibility genes has proven difficult (1, 2). Various complementary strategies, including both linkage and association analyses, are needed to dissect a genetic component for type 2 diabetes (2). To date, linkage studies have provided several promising leads for causative genes in type 2 diabetes (3, 4). However, type 2 diabetes is genetically heterogeneous, and association analysis might also be useful for identifying susceptibility or modifier genes (2, 5). Furthermore, analysis of the genetic determinants of intermediate traits related to type 2 diabetes, such as fasting plasma glucose, may be useful in the identification of susceptibility genes (2).

Genome-wide scanning to identify susceptibility genes for type 2 diabetes in the Pima Indians found linkages of DNA markers at 7q with quantitative traits related to glucose metabolism (6). Within this region is PPP1R3, which is the gene that encodes RG1, the regulatory subunit of skeletal muscle glycogen-associated type 1 serine-threonine protein phosphatase (PP1G) (7). Activation of PP1G results in net dephosphorylation of rate-limiting enzymes in intermediary metabolism (8). The PPP1R3 gene product is a 124-kDa protein that is present in both heart and skeletal muscles (8). The PPP1R3 gene product regulates the activity of PP1G toward glycogen-bound substrates, thereby affecting the balance between glycogen synthesis and glycogenolysis (8). Defective insulin-mediated activation of muscle glycogen synthase activity is seen in members of some families with type 2 diabetes (9, 10). Variation in the PPP1R3-coding sequence has been shown to be associated with differences in peripheral glycogen synthesis and basal glucose oxidation rate (10, 11). Also, studies in Pima Indians with type 2 diabetes and their relatives have shown a reduced basal and insulin-stimulated activity of PP1G (12, 13). Taken together, these results suggest that variation in PPP1R3 could influence the reduction in insulin-stimulated activation of muscle glycogen synthase that is seen in some insulin-resistant subjects. Thus, the PPP1R3 gene product is an attractive candidate in studies of type 2 diabetes and its related intermediate traits.

PPP1R3 messenger ribonucleic acid (mRNA) abundance in skeletal muscle varies over a wide range in normal individuals (14). One possible mechanism that could affect mRNA abundance is the regulation of mRNA stability through sequence variation within the 3'-untranslated region (3'-UTR) (15). There is a common 5-bp insertion-deletion (I/D) polymorphism within the 3'-UTR of PPP1R3 that affects the distance between two ATTTA pentanucleotides, which are the smallest consensus motifs of mRNA-destabilizing AU(AT)-rich elements (7). We hypothesized that the genomic variation underlying these putative differences in mRNA stability would have an impact on quantitative intermediate phenotypes related to type 2 diabetes. We therefore tested for association between the genotypes of the 5-bp I/D polymorphism within the 3'-UTR of PPP1R3 and quantitative intermediate phenotypes related to type 2 diabetes. We included genotypes of PON2 as a positive control in the analysis because we have previously reported associations between fasting plasma glucose and PON2 codon 148 variation in both adult and adolescent Oji-Cree with type 2 diabetes (16, 17).

	Subjects and Methods

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Study subjects

The community of Sandy Lake, Ontario, is located about 2000 km northwest of Toronto, in the subarctic boreal forest of central Canada. The community is isolated and is accessible only by air during most of the year. The prevalence of type 2 diabetes in this community is one of the highest in the world (18). Historically, the ancestors of the contemporary residents of this region lived a nomadic, hunting-gathering subsistence typical of other Algonkian-speaking peoples of the northeastern subarctic. Since the development of the reservation and residential school systems, the lifestyle has changed radically from physically active to sedentary. The primary source of food has changed from wildlife with supplementation by roots and berries to processed foods high in animal fats. Seven hundred and twenty-eight members (72% of the total population) of this community, aged 10 yr and above, participated in the Sandy Lake Health and Diabetes Project (18). Assessments included a questionnaire to assess medical history, including a previous diagnosis of type 2 diabetes. Body mass index (BMI) was defined as weight (kilograms)/height (meters)². The project was approved by the University of Toronto ethics review committee.

Biochemical analyses

Plasma samples were obtained with informed consent. Exclusion criteria included an inadequate blood sample available for all biochemical and/or genetic determinations. Volunteers gave plasma samples after fasting overnight for 8–12 h. Blood was centrifuged at 2000 rpm for 30 min, and the plasma was stored at -70 C. Concentrations of fasting glucose were determined as previously described (16). Concentrations of fasting plasma insulin were determined by RIA (Pharmacia Biotech, Piscataway, NJ). A standard 75-g oral glucose tolerance test (OGTT) was then administered, and a second blood sample was collected after 120 min for plasma glucose determination. Subjects were excluded from the OGTT if they had physician-diagnosed diabetes, if they were currently receiving treatment with insulin and/or oral hypoglycemic agents, or if they had a fasting blood glucose exceeding 11.1 mmol/L. Subjects who were pregnant at the time of recruitment had their OGTT deferred until 3 months postpartum. Type 2 diabetes (19) and impaired glucose tolerance (IGT) (20) were diagnosed using established criteria.

Genetic analysis

An established method was used to genotype the codon 148 AG change in PON2 (16). Genotypes of the 5-bp I/D polymorphism within the 3'-UTR of PPP1R3 were determined using 500 ng genomic DNA amplified using primers PPP1R3–5' (5'-AAC AGA TAA AAC ATG GAC AAT G-3') and PPP1R3–3' (5'-TTG AAA TAT TTG ATC AAT GAA TCC-3') derived from the published complementary DNA sequence (14). Thirty amplification cycles and an annealing temperature of 55 C were used. The resulting fragment sizes were 113 or 108 bp if the variable 5-bp sequence was present (I) or absent (D), respectively. The fragments were resolved on 10% polyacrylamide gels.

Statistical analysis

SAS (version 6.11) was used for all statistical comparisons (21). Quantitative variables were log transformed and subjected to analysis of normality as previously described (16). ANOVAs were performed using the general linear models procedure to determine the sources of variation for log fasting plasma glucose and insulin and log plasma glucose 2 h after a standard glucose load. F tests were computed from the type III sums of squares (21). This form of sums of squares is applicable to unbalanced study designs and adjusts the level of significance to account for other independent variables included in the model. Independent variables for each ANOVA were sex, age, diabetes status, and log BMI. In addition, the family identification number was included as a covariate to correct for nonindependence of individual samples based upon shared genes and/or environment. The genotypes of PPP1R3 and PON2 codon 148 were also included as independent variables. Based upon our previous observation that the association between plasma glucose and PON2 genotype was related to the type 2 diabetes status of the subject, we also included interaction terms to test for interactions between type 2 diabetes status and genotype. When a new significant genotype-phenotype association was identified, the mean values for the trait were compared between genotypic classes using pairwise comparisons of least squares means (21).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical attributes of sample

Sufficient DNA and phenotypic information were obtained for analysis from 523 subjects, aged 18 yr and older, of whom 298 (57%) were women. The mean ± SD for age and BMI were, respectively, 35.8 ± 14.6 yr and 28.1 ± 5.3 kg/m². Sixty-five subjects were classified as having IGT based upon the OGTT. One hundred and nineteen subjects were classified as having type 2 diabetes; of these, 72 had been previously diagnosed with type 2 diabetes and thus did not undergo the OGTT, and 47 were classified as having newly diagnosed type 2 diabetes based upon the results of the OGTT. Of the subjects with type 2 diabetes, 6 were taking insulin, 30 were taking oral hypoglycemic agents, and the remainder were controlled by diet alone.

Allele and genotype frequencies

The frequencies of PPP1R3 D and PON2 G148 were 0.30 and 0.27, respectively. Genotype frequencies of PPP1R3 and PON2 did not deviate from those predicted by the Hardy-Weinberg law in this study sample (both P > 0.10).

Phenotype-genotype associations

Transformation using the natural logarithm for each variable resulted in a distribution that was not significantly different from normal. A total of three ANOVAs were performed: one each for log fasting plasma glucose, log 2-h postchallenge plasma glucose, and log fasting plasma insulin. There were two significant phenotype-genotype associations and two significant interaction terms for type 2 diabetes status and genotype. First, as we previously showed (16, 17), the PON2 genotype was significantly associated with variation in fasting plasma glucose (Table 1). The significant interaction term indicated that this association was related to type 2 diabetes status. Pairwise testing confirmed that PON2 G148 homozygotes who had type 2 diabetes had significantly higher fasting glucose levels than subjects with the other PON2 genotypes who had type 2 diabetes, as we previously reported (16, 17).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In Oji-Cree from Sandy Lake, we have found associations between plasma glucose and a common 5-bp I/D DNA polymorphism in a mRNA-stabilizing AU(AT)-rich element within the 3'-UTR of PPPIR3. The D allele, which is associated with a lower PPPIR3 mRNA abundance in skeletal muscle (7), had a frequency of 0.30 in the Oji-Cree. We found that homozygosity for the D allele was significantly associated with lower 2-h postchallenge glucose in adult Oji-Cree with type 2 diabetes or IGT. There was no association of the PPPIR3 genotype with type 2 diabetes itself, with IGT, or with other quantitative traits, such as plasma insulin. The findings suggest that the common PPPIR3 3'-UTR variation that potentially affects mRNA stability is associated with variation in glycemia in Oji-Cree subjects with type 2 diabetes and IGT. However, the small number of homozygotes and the modest levels of significance suggest that larger studies are required to determine whether this is a general association.

Insulin-mediated glucose disposal varies widely in normoglycemic subjects (22, 23) and appears to be influenced by a variety of genetic and environmental mechanisms (23). Our findings suggest that common genomic variation in PPP1R3 that affects mRNA stability is a potential regulatory mechanism that would posttranscriptionally modulate the abundance of the transcript, and thus of the gene product. A reduced level of the PPP1R3 gene product may, in turn, result in an impairment of insulin-mediated regulation of glycogen synthesis and nonoxidative glucose metabolism. The existence of such a novel regulatory mechanism may be relevant given that other possible regulatory mechanisms, such as phosphorylation of the PPP1R3 gene product by the mitogen-activated protein kinase pathway, do not appear to affect glycogen synthesis by insulin (24).

We have also confirmed our previously reported association between homozygosity for the PON2 G148 allele and elevated plasma glucose in adult Oji-Cree subjects with type 2 diabetes (16). There was no association of the PON2 genotype with type 2 diabetes itself, with IGT, or with other quantitative traits related to type 2 diabetes in any subset of this sample. The association of homozygosity for PON2 G148 with worsened hyperglycemia in type 2 diabetes suggests that variation in PON2 modulates a quantitative type 2 diabetes-related phenotype, but may not itself predispose to type 2 diabetes. The unique structural aspects and tissue distribution of PON2 (25) taken together with our observed genetic association with hyperglycemia suggest that defining its function would be worthwhile.

At least one genomic scan, performed in Mexican Americans, suggested no linkage between any chromosome 7q marker and type 2 diabetes (3). However, genomic scanning in Pima Indian siblingships with type 2 diabetes (6) has revealed substantial and convincing linkages of D7S527, which is relatively close to both PPP1R3 and PON2, with such quantitative phenotypes as glucose uptake, oxidation, and storage rates at physiological and maximally stimulating insulin concentrations. There were also suggestions of linkages with plasma insulin concentration and with type 2 diabetes itself in the Pima Indians (6). Our findings to date suggest that type 2 diabetes per se is not related to genetic variation in either PPP1R3 or PON2. However, there may be a relationship between variation in this region and complex quantitative phenotypes related to glucose uptake and/or storage. This may become manifest as variations in plasma glucose. The specific associations with plasma glucose and not with insulin in our sample suggests that these intermediate traits are themselves complex and have distinct genetic determinants (2). Our findings also emphasize the arbitrary nature of intermediate quantitative traits and that the ability to identify genetic determinants of such traits is limited.

In summary, we have observed that homozygosity for the PPP1R3 D allele was associated with improved 2-h postchallenge plasma glucose in diabetic Oji-Cree. The PPP1R3 variation was not associated with the presence of type 2 diabetes or IGT, and thus cannot be interpreted as being causative for these qualitative phenotypes. However, PPP1R3 may be a modifier gene for complex quantitative phenotypes that are related to type 2 diabetes. Further studies are required to determine whether this association is more general. If genetic factors can modify clinical phenotypes in type 2 diabetes and thus contribute to the spectrum of disease expression, then determination of such genotypes may have an impact upon diagnosis and treatment in a particular subject even after the onset of type 2 diabetes.

	Acknowledgments

 
We acknowledge the chief and council of the community of Sandy Lake; the Sandy Lake community surveyors; the Sandy Lake nurses; the staff of the University of Toronto Sioux Lookout Program; the Department of Clinical Epidemiology, Samuel Lunenfeld Research Institute; Dr. Alexander Logan; Annette Barnie; Fang Sun; Teresa Lippingwell; Joel Napenas; Stefan Sadikian; and Cheri Tully. Dr. Michal Prochazka provided sequence information for the PPP1R3 amplification primers.

	Footnotes

 
¹ This work was supported by grants from the NIH (DK-44597–01) and the Ontario Ministry of Health (04307), the Canadian Diabetes Association, the Blackburn Group, and a Canadian Genome Analysis and Technology award (to Drs. Tsui and Scherer).

² Career Investigator of the Heart and Stroke Foundation of Ontario.

³ Career Investigator of the Ontario Ministry of Health.

⁴ Supported by Health Canada through a National Health Research and Development Program Research Training Award.

Received April 7, 1998.

Revised May 22, 1998.

Revised July 7, 1998.

Accepted July 14, 1998.

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