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Prevalence of Variants in Candidate Genes for Type 2 Diabetes Mellitus in The Netherlands: The Rotterdam Study and the Hoorn Study¹

Department of Molecular Cell Biology, Leiden University Medical Center (L.M.’t H., J.A.M.), 2333 AL Leiden; the Department of Epidemiology and Biostatistics, Erasmus University (R.P.S., D.E.G.), 3000 DR Rotterdam; the Julius Center for Patient Orientated Research, Utrecht University (R.P.S., D.E.G.), 3508 GA Utrecht; and the Institute for Research in Extramural Medicine, Vrije Universiteit Amsterdam (J.M.D., G.N., R.J.H.), 1081 BT Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. Antonie Maassen, Department of Molecular Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. E-mail: maassen{at}rullf2.medfac.leidenuniv.nl

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations.

No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epi-static interactions between these gene variants. A significant difference in the frequency of the Arg⁹⁷² allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor Met⁹⁸⁵ variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06–3.29; P = 0.03).

We conclude that the association between the Met⁹⁸⁵ variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg⁹⁷² allele of IRS-1 gene makes genetic association studies of this gene less reliable.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
TYPE 2 diabetes mellitus (DM) is a heterogeneous disorder. The disease is characterized by glucose intolerance, which seems to result from the combined effects of insulin resistance and a failure of the ß-cells to compensate for the increased demand of insulin (1).

Several genes have been proposed to contribute to the pathogenesis of common late-onset type 2 DM (2, 3). Remarkably, associations found in a particular population were often not confirmed in other populations, suggesting regional differences in the contribution of certain diabetes susceptibility genes or an artifactual association (4, 5). The replication of an association in an independent second population strengthens the significance of such an association. The possibility should also be considered that multiple gene variants in combination with epistatic effects and environmental factors contribute to the pathogenesis of diabetes. The observation that transgenic animals with combinations of heterozygous null alleles of the insulin receptor, insulin receptor substrate-1 (IRS-1), and/or the glucokinase genes develop manifest diabetes with a high frequency corroborates this possibility (6, 7).

We previously reported the association of a Met⁹⁸⁵ variant in the insulin receptor gene with type 2 DM (8). We have now extended our previous study in a second population-based study in The Netherlands, the Hoorn study (9). We estimated the common odds ratio for four published studies on the Met⁹⁸⁵ variant. In addition, we have tested whether known variants in other genes, previously reported to be associated with type 2 DM in other populations, also associated with type 2 diabetes in The Netherlands (10, 11, 12), and the occurrence of epistatic effects between gene variants was analyzed.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Subjects participating in this study were randomly selected from two population-based studies in The Netherlands, the Rotterdam study and the Hoorn study. The Rotterdam study is a population-based cohort study of determinants for chronic disabling diseases in the elderly (age, >55 yr; n = 7983) (13). The Hoorn study, also a population-based study, examines potential determinants for glucose intolerance and related disorders (9). The initial cohort of 2484 subjects, aged 50–75 yr, was extended with additional subjects of the same age category with known type 2 DM to obtain sufficient diabetic participants for this study. They were recruited via general practitioners. The characteristics of both study populations are shown in Table 1. All subjects participating in the study gave informed consent, and the studies were approved by the appropriate medical ethics committees. We used randomly selected samples of subjects from both studies.

DNA was extracted from peripheral blood samples according to standard procedures and was stored at -30 C. We previously described a detection method for the Met⁹⁸⁵ mutation in the insulin receptor gene; however, to facilitate detection of the Met⁹⁸⁵ variant in larger numbers of DNA samples we used the method described by Hansen et al. (8, 14).

The prevalences of the gene variants in the amylin (Ser²⁰-Gly), coagulation factor V (Leiden mutation, Arg⁵⁰⁶-Gln), and IRS-1 (Gly⁹⁷²-Arg) genes were examined by PCR-restriction fragment length polymorphism-based methods, as described previously (10, 11, 12).

Meta analysis of the association of the insulin receptor Met⁹⁸⁵ variant

Other published studies describing the prevalence of the Met⁹⁸⁵ variant have been reviewed for their suitability to be included in a meta analysis (8, 14, 15, 16, 17). Two studies were excluded because of the absence of the mutation in the diabetic group studied (16) or the small sample size (15).

Statistical analysis

Genotypic or allelic frequencies were compared between diabetic and control subjects. Results were analyzed by Fisher’s exact test. Association of gene variants with diabetes-related parameters was tested by t test or Mann-Whitney U test when appropriate. Common odds ratios for the studies were estimated after testing the homogeneity of the population-specific odds ratios revealed no significant differences using the Mantel-Haenszel test. The statistical software packages SPSS 7.0 and StatXact3.1 were used (SPSS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The characteristics of participants from the Hoorn and Rotterdam studies are shown in Table 1. Subjects in the Hoorn study were slightly younger, and diabetic subjects had higher body mass indexes (BMIs) compared to subjects in the Rotterdam study. Diabetic subjects from the Rotterdam study had higher fasting glucose levels compared to those in the Hoorn study, which may be explained by the larger fraction of diabetic subjects in the Hoorn study who received glucose-lowering medication (data not shown).

Insulin receptor Val⁹⁸⁵-Met mutation

The prevalence of the Met⁹⁸⁵ allele was tested in diabetic and control groups from the Hoorn study. Carrier frequencies in both groups were 3.7% and 2.7%, respectively (Table 2; by exact test, P = 0.34). The previously reported carrier frequencies in the Rotterdam study (5.6% and 1.3%, respectively) are also shown in Table 2 (8). The Zelen statistic for homogeneity of the two studies was 0.07 (P > 0.1). The Mantel-Haenszel common odds ratio was subsequently estimated to be 2.34 [P < 0.02; 95% confidence interval (CI), 1.15–4.74]. No associations were found with diabetes-related parameters, such as fasting, and postload glucose and insulin levels, age of onset, lipids, hypertension, BMI, and waist/hip ratio.

Amylin Ser²⁰-Gly mutation

This mutation was not detected in 141 individuals with type 2 DM from the Rotterdam study (Table 2).

Coagulation factor V, Leiden mutation

We tested normoglycemic and diabetic subjects from the Rotterdam study for the prevalence of the Gln⁵⁰⁶ mutation. Equal allele frequencies of this variant were detected in the Dutch control and type 2 DM groups (Table 2). Homozygotic carriers were not detected.

IRS-1 Gly⁹⁷²-Arg mutation

We tested the prevalence of this mutation in type 2 diabetic and normoglycemic subjects from the Hoorn and Rotterdam studies. The genotypic frequencies are presented in Table 2. The two studies showed opposite trends in the prevalence of the Arg⁹⁷² allele in the control groups, but none of them showed a significant difference from their corresponding diabetic group. Diabetic cohorts had equal prevalences of the Arg⁹⁷² allele. However, the difference between the two control groups was significant (P < 0.05). We also tested whether the Arg⁹⁷² variant associates with obesity in our cohorts. This association was not observed (Table 3). To examine the possible association of the Arg⁹⁷² variant with insulin resistance, we examined the frequency of the Arg⁹⁷² mutation in a cohort of 142 normoglycemic, hyperinsulinemic individuals from the Rotterdam study. A carrier frequency (11%) similar to that in the type 2 DM group was found (P > 0.3), but it was significantly lower than that in the control group (P < 0.05). No significant differences were seen in fasting and postload insulin levels between carriers and noncarriers in both the control and diabetic groups, nor was an association seen with other diabetes-related parameters, such as age of onset, BMI, fasting and postload glucose levels, or waist/hip ratio.

We tested whether certain combinations of gene variants show epistasis in the association with type 2 DM or related parameters. For this part of the study we also included two single nucleotide polymorphisms in the sulfonylurea receptor gene: 1) the intron 16 -3t allele, which is associated with type 2 DM in The Netherlands (allele frequency, 48% and 41% in type 2 DM and controls groups, respectively; P < 0.02; ‘t Hart et al., submitted) and secondly the silent exon 18 Thr⁷⁵⁹ variant (CT; allele frequency, 5% in both groups) not associated with type 2 DM in The Netherlands, but which shows association in other populations (18). All combinations were found in both type 2 diabetic and normoglycemic subjects at similar frequencies (data not shown). An analysis of diabetes-related parameters, such as fasting and 2-h glucose and insulin levels or BMI revealed no obvious association with any of the combinations. Because of the low frequencies of most combinations, a reliable statistical evaluation was not always possible.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We examined whether known candidate gene variants are associated with diabetes in two populations in The Netherlands. The analysis of two separate populations, approximately 150 km apart, allows us to examine the magnitude of regional differences in the prevalence of gene variants. Regional differences complicate the interpretation of genetic association data, as has been shown for the glucagon receptor Gly⁴⁰Ser variant, for example (4). Genetic admixture, due to inclusion of genetically distinct subpopulations, may also lead to artifactual associations (5). We described previously an amino acid substitution at position 985 in the insulin receptor gene that was associated with type 2 DM in one of the population studies (8). We have now extended our previous results with additional subjects from another Dutch population-based study. In the Hoorn study, an excess of the Met⁹⁸⁵ variant is seen among diabetic subjects, but this does not reach statistical significance. We observed no significant differences in the frequency of the Met⁹⁸⁵ allele between the Rotterdam and Hoorn studies, suggesting that at least in The Netherlands, no regional differences in the frequency of this allele exist. Combined analysis of the Hoorn and the Rotterdam data corroborate the association between the Met variant and diabetes in The Netherlands. The common Mantel-Haenszel odds ratio was 2.34 (95% CI, 1.15–4.74; P < 0.02). A study by Hansen et al. in Danish Caucasians (14) did not show a significant association between the Met⁹⁸⁵ variant and diabetes, although a trend to higher frequency in the diabetic group was present [2.0% vs. 1.6% carrier frequency in type 2 DM (n = 254) and normal glucose tolerance (n = 243), respectively]. A recent study in Tamil Indians also found a slightly increased frequency of the Met⁹⁸⁵ allele in diabetics compared to control subjects (10% vs. 8%). However, the population size in this study was too small to have the statistical power to detect significant differences at the given prevalences (n = 99) (17). The Mantel-Haenszel summary odds ratio across all four studies was 1.87 (P = 0.03; 95% CI, 1.06–3.29), suggesting a slight, but significant, effect of this variant on the risk of developing type 2 diabetes in different populations (8, 14, 17). In vitro studies overexpressing this mutant receptor have suggested that there might be slight changes in signal transduction properties of the mutant compared to those of the wild-type insulin receptor (19). Further studies are needed to examine to what extent the Met⁹⁸⁵ variant enhances the risk for diabetes in the context of different genetic backgrounds.

The mutation in the Amylin gene, reported by Sakagashira et al. to occur at high frequency in Japanese individuals with type 2 DM, was not detected in our cohorts. Recently, another study in Caucasians with type 2 DM also failed to detect this mutation (20). Also, data obtained in a Taiwanese population did not show an association of this mutation with type 2 diabetes (21). Thus, it is unlikely that this mutation plays a significant role in the pathogenesis of type 2 DM.

A high prevalence of thrombosis and other cardiovascular complications occurs in type 2 diabetic patients. This finding triggered a search for the association of thrombogenic factors with diabetes. It was previously shown that the Gln⁵⁰⁶ variant in the coagulation factor V gene associates with thrombosis in different ethnic populations (22, 23). A study among Italians showed an association of the same mutation with type 2 DM (12). We were unable to demonstrate such an association with type 2 diabetes in The Netherlands. Other studies also found no evidence for the association of this mutation with diabetes (24, 25). Taken together, these results suggests that the association of this mutation with diabetes might be regional or artifactual.

Several reports have indicated an association of the 972 variant in the IRS-1 gene with type 2 DM, although the associations with diabetes generally are weak or absent (26, 27). In addition, a higher prevalence of this mutation in obese subjects was seen (26, 28). Furthermore, it was shown that this mutation was associated with insulin resistance in some populations (27, 29). Transfection studies showed clear changes in the signal transduction properties of the mutant IRS-1 protein (30). Our data do not show an association of the IRS-1 mutant with diabetes, BMI, or hyperinsulinemia. We do see a significant difference in the prevalence of the Arg⁹⁷² allele between the control cohorts in Rotterdam and Hoorn, indicating that regional differences in the distribution of this genotype occurs. Such a situation complicates the interpretation of association studies of this variant. There was no evidence for a selection bias in the control group of the Rotterdam study or any other group in our study. Also, the equal distribution of several other (nondiabetic) variants in the Rotterdam and Hoorn studies argues against a selection bias or genetic admixture in our groups (data not shown).

We also searched for possible epistatic effects between the gene variants. We additionally included in the analysis variants in the sulfonylurea receptor gene, which have been shown to be associated with type 2 DM and reduced ß-cell function in several populations (18, 31, 32) (‘t Hart et al., submitted). In cases where combinations occurred with a frequency to allow statistical testing, no evidence for epistatic effects was detected. All combinations were found at equal frequencies in subjects with NGT or type 2 diabetes mellitus, arguing against a contribution of epistatic effects between those gene variants. Furthermore, the other combinations occurring at low frequencies also did not suggest an enhanced association with type 2 diabetes.

We conclude that the Met⁹⁸⁵ variant in the insulin receptor gene is significantly associated with type 2 DM and represents a risk factor for the development of type 2 DM. Variants in the genes for amylin, IRS-1, and coagulation factor V do not seem to be associated with type 2 DM in The Netherlands, either alone or by epistatic interaction with each other.

	Acknowledgments

 
The authors thank the participants of the study for their cooperation.

	Footnotes

 
¹ This work was supported by grants from the Diabetes Fonds Nederland and the European Economic Committee (Grant BMH4-CT98–3084).

Received October 8, 1998.

Revised December 9, 1998.

Accepted December 14, 1998.

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