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Diabetes 53:S31-S35, 2004
© 2004 by the American Diabetes Association, Inc.

Section I: Genetic Factors in Type 2 Diabetes -- In Search of New Links

Single Nucleotide Polymorphisms in the Proximal Promoter Region of the Adiponectin (APM1) Gene Are Associated With Type 2 Diabetes in Swedish Caucasians

Harvest F. Gu1, Adili Abulaiti1, Claes-Göran Östenson1, Keith Humphreys2, Claes Wahlestedt3, Anthony J. Brookes3, and Suad Efendic1

1 Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
2 Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden
3 Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adiponectin (APM1) is an adipocyte-derived peptide. The APM1 gene is located on chromosome 3q27 and linked to type 2 diabetes. In patients with type 2 diabetes, the adiponectin level in plasma is decreased in comparison to healthy subjects. To identify genetic defects of the APM1 gene that contribute to the development of type 2 diabetes, we genotyped 13 single nucleotide polymorphisms (SNPs) in 106 patients with type 2 diabetes, 325 patients with impaired glucose tolerance (IGT), and 497 nondiabetic control subjects in Swedish Caucasians by using dynamic allele-specific hybridization (DASH). We found that SNPs -11426(A/G) and -11377(G/C) in the proximal promoter region had significant differences of allele frequencies between type 2 diabetic patients and nondiabetic control subjects (P = 0.02 and P = 0.04, respectively). SNP-11426(A/G) was significantly associated with fasting plasma glucose in type 2 diabetic patients (P = 0.02) and in IGT subjects (P = 0.04), while the patients carrying CC and CG genotypes for SNP-11377(G/C) had a higher BMI than the patients with the GG genotype (P = 0.03). Haplotype analysis of 13 SNPs in the APM1 gene showed that estimates of haplotype frequencies in Swedish Caucasians are similar to those estimated in French Caucasians. However, no significant association of haplotypes with type 2 diabetes and IGT was detected in our study. The present study provides additional evidence that SNPs in the proximal promoter region of the APM1 gene contribute to the development of type 2 diabetes.

Adiponectin (APM1, also known as ACRP30, GBP28, or AdipoQ) is secreted from adipose tissue and regulates insulin sensitivity (1,2). The APM1 gene has been identified and is located on chromosome 3q27 (3–5). In this chromosome region, genome-wide scans have revealed a susceptibility locus for type 2 diabetes (6), coronary heart disease (7), and measures of adiposity (8). Several studies have demonstrated that the adiponectin level in plasma is decreased in patients with type 2 diabetes or obesity in comparison to healthy subjects (9,10). Thus, adiponectin may play a role in the pathogenesis of type 2 diabetes and insulin resistance. Recently, mutation screening of the APM1 gene in Japanese and French populations was performed, and 13 single nucleotide polymorphisms (SNPs) were found in the APM1 gene (11,12). SNPs +45T/G and +276G/T in exon 2 and intron 2, respectively, of the APM1 gene were found to be significantly associated with type 2 diabetes in Japanese patients with normal body weight (BMI <24 kg/m2) mainly due to decreased insulin sensitivity (11). Stumvoll et al. (13) demonstrated that SNP +45T/G in the APM1 gene increases the risk for obesity and secondarily for insulin resistance in nondiabetic Caucasians of German ancestry. Furthermore, in another group of nondiabetic Caucasians, a haplotype defined by SNPs +45T/G and +276G/T was strongly associated with many components of the insulin resistance syndrome (14).

A recent report from French Caucasians predicted no association of SNPs +45T/G and +276G/T with type 2 diabetes. The haplotype including SNPs -11391G/A and -11377C/G in the proximal promoter region of the APM1 gene was strongly associated with adiponectin levels in the plasma and type 2 diabetes. However, the authors failed to detect association with insulin resistance indexes (12). In the present study, we performed a genetic association study for 13 SNPs in the APM1 gene in patients with type 2 diabetes, subjects with impaired glucose tolerance (IGT), and nondiabetic healthy individuals of Swedish ancestry. This may provide further evidence to evaluate the contribution of genetic variation of the APM1 gene in the development of type 2 diabetes.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects.
We studied 106 (50 women and 56 men) type 2 diabetic patients and 325 (158 women and 167 men) IGT subjects randomly selected from each family and 497 (250/249) unrelated nondiabetic control subjects. All were Swedes selected from the Stockholm Diabetes Prevention Program and were sex- and age-matched between case subjects (type 2 diabetic patients and IGT subjects) and nondiabetic control subjects. Type 2 diabetic patients and IGT subjects were diagnosed according to the 1985 World Health Organization criteria. The nondiabetic control subjects had normal birth weight, normal BMI (<25 kg/m2), and no relatives with type 2 diabetes. Concentrations of plasma glucose, plasma insulin, and other clinical characteristics were measured as previously described. Clinical characteristics of the type 2 diabetic patients, IGT subjects, and nondiabetic control subjects are summarized in Table 1. Informed consent was obtained from all subjects, and the study was approved by the local ethics committees. Genomic DNA was extracted from peripheral blood using a Puregene DNA purification kit (Gentra).


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  		TABLE 1 Clinical characteristics of Swedish type 2 diabetic patients, IGT subjects, and nondiabetic control subjects

 
Insulin resistance index measurements.
Insulin resistance was assessed by homeostasis model assessment (HOMA) (15). The HOMA index for insulin resistance (HOMA-IR) was then calculated in the present study by using the following formula: fasting plasma glucose (mmol/l) x fasting plasma insulin (mU/ml)/22.5.

SNP identification numbers of APM1 in HGVbase.
All SNPs found by mutation screening of a French population (12) are recorded in the SNP database called HGVbase. The SNP identification numbers and detailed sequence information (25 bp in each direction around SNP) are publicly available in this database (http://hgvbase.cgb.ki.SE).

PCR-dynamic allele-specific hybridization (DASH) assay design and genotyping.
We have used a high throughput SNP scoring technique called dynamic allele-specific hybridization (DASH) (16). PCR-DASH assay design and SNP genotyping protocol were used as described previously (17). (The sequences of primers and probes designed for PCR-DASH and optimized PCR conditions are available in the supplemental data [Table 1]).

Statistical analyses.
The distribution of the alleles of each SNP was tested for the Hardy-Weinberg equilibrium. Logistic regression was used to test for differences in allele frequencies and clinical features between case subjects (type 2 diabetic patients and IGT subjects) and nondiabetic control subjects. We obtained estimates of pairwise linkage disequilibrium values |D'| (18) using the software 2LD. The haplotype estimation was carried out using the Estimation Haplotype program (EH-plus) (ftp://linkage.rockefeller.edu/software/eh) (19,20). Differences in clinical and metabolic variables between individuals with different genotypes were tested by Student’s t tests and ANOVA using the BMDP statistical software version 1.12 (Los Angeles, CA).


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We have performed genotyping for 13 SNPs of the APM1 gene in 106 Swedish patients with type 2 diabetes, 325 subjects with IGT, and 497 nondiabetic control subjects. All participants were selected from the Stockholm Diabetes Prevention Program and were clinically well characterized. The 13 SNPs in the APM1 gene were reported previously in Japanese and French populations (11,12). Genotype distributions for the 13 SNPs studied in our population were in the Hardy-Weinberg equilibrium. The allele frequencies of SNPs in the APM1 gene in type 2 diabetic patients, IGT subjects, and nondiabetic control subjects are summarized in Table 2.


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  		TABLE 2 Allele frequencies of 13 SNPs of the APM1 gene in Swedish type 2 diabetic patients, IGT subjects, and nondiabetic control subjects

 
The proximal promoter region of the APM1 gene includes 5'-untranslated region (UTR), exon 1, and intron 1. In this region, five SNPs including -11426(A/G), -11391(G/A), -11377(G/C), -4041(A/C), and -3971(A/G) were genotyped. For SNP -11426 (A/G), which is located in the 5'-UTR, type 2 diabetic patients had a significantly higher G allele frequency in comparison to nondiabetic control subjects (0.184/0.816 vs. 0.087/0.913, P = 0.02). Table 3 shows the clinical characteristics of patients with type 2 diabetes, subjects with IGT, and nondiabetic control subjects according to genotypes of SNP -11426(A/G). The diabetic patients with AG and GG genotypes had significantly higher fasting plasma glucose levels in comparison to those patients carrying the AA genotype (9.1 ± 5.1 and 10.2 ± 6.7 vs. 7.5 ± 2.5 mmol/l, P = 0.02). Similarly, the carriers of AG and GG genotypes in IGT subjects had a statistically significantly higher fasting plasma glucose level than the carriers of the AA genotype (5.5 ± 0.7 and 5.4 ± 0.5 vs. 5.3 ± 0.7 mmol/l, P = 0.04). For SNP -11377(G/C), which is also located on the 5'-UTR, a significant difference of allele frequencies between type 2 diabetic patients (0.745/0.255) and nondiabetic control subjects (0.674/0.326, P = 0.04) was found. Table 3 also summarizes the clinical features of type 2 diabetic patients, IGT subjects, and nondiabetic control subjects with the genotypes of SNP -11377(G/C). The results indicated that type 2 diabetic patients with CC and CG genotypes had a statistically significantly higher BMI than the patients with the GG genotype (31.2 ± 6.4 and 29.9 ± 5.2 vs. 27.3 ± 3.6 kg/m2, P = 0.03).


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  		TABLE 3 Clinical characteristics of type 2 diabetic patients, IGT subjects, and nondiabetic control subjects according to the genotypes of SNP -11426(A/G) and SNP -11377(G/C)

 
There are three nonsynonymous SNPs [G84R(G/C), G90S(G/A), and Y111H(T/C)] in exon 3 of the APM1 gene. We found that these three SNPs had low allele frequencies and were not associated with type 2 diabetes or IGT.

We have carried out a haplotype analysis for the 13 genotyped SNPs of the APM1 gene. There is a strong linkage disequilibrium across the gene (see the supplemental data, Table 2), as was reported for the French Caucasians study (12). Furthermore, estimates of haplotype frequencies for our samples are similar to those estimated for French Caucasians (comparison of haplotype frequencies between French and Swedish Caucasians is shown in the supplemental data, Table 3). To see if we could obtain statistically significant estimates of association with diagnosis compared with those obtained by SNP analysis, we tested for haplotype association in all 2-SNP haplotypes and comparatively analyzed the significances between case subjects (the patients with type 2 diabetes and the subjects with IGT together or separated in each group) and nondiabetic control subjects. However, we found no statistically significant associations.


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The purpose of the present study was to examine the contribution of the APM1 gene in the development of type 2 diabetes in Swedish Caucasians. We have genotyped 13 SNPs in the APM1 gene, which have been reported in a Japanese population and in French Caucasians. Additional mutations (i.e., R112C, I1164T, R221S, and H241P) that were subsequently reported in a Japanese population (21) were not detected in the present study. We found that SNP -11426(A/G) is strongly associated with increased fasting plasma glucose levels in type 2 diabetes and IGT. In another SNP -11377(G/C), the C allele may contribute a genetic risk for increasing body weight in type 2 diabetes. The present study indicated that these two SNPs in the proximal promoter region of the APM1 gene are associated with type 2 diabetes in Swedish Caucasians.

In addition to the present study, other studies have reported that SNPs in the APM1 gene had a strong association with type 2 diabetes in the Japanese population, as well as in German, French, and American Caucasians (11–14). Figure 1 represents localization of SNPs in the APM1 gene and genetic association with type 2 diabetes and/or insulin resistance in five populations. SNPs +45G15G and +276(G/T) had a strong association with insulin resistance in Japanese type 2 diabetic patients (11). The SNP +45G15G, either independently or as a haplotype together with SNP +276(G/T), was associated with obesity and insulin resistance in German and American Caucasians (13,14). However, the association of these two SNPs with type 2 diabetes and insulin resistance was not seen in French Caucasians (12) as well as in the present study. Instead, a haplotype including SNPs -11391(G/A) and -11377(G/C) in the proximal promoter region was found to be associated with adiponectin levels and with type 2 diabetes in French Caucasians (12). In the present study, we detected that SNP -11377(G/C) may contribute to the genetic risk for BMI in type 2 diabetes. Furthermore, we have found that another SNP [-11426(A/G)] in the proximal promoter region is associated with fasting plasma glucose in type 2 diabetes in Swedish Caucasians. Thus, our study is mainly consistent with the recent report from French Caucasians (12) and provides further evidence that SNPs in the proximal promoter region of the APM1 gene are associated with type 2 diabetes.



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  		FIG. 1. Localization of SNPs in the APM1 gene and genetic association with type 2 diabetes and/or insulin resistance in five populations.

 
Type 2 diabetes is a complex disease. The pathogenesis of type 2 diabetes and the metabolic syndrome are not fully clarified, but the interaction between genetic factors and environmental triggers is important. Genetic association between the SNPs of candidate genes and type 2 diabetes may not be fully explained by a single population study. The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-{gamma} gene is found to associate with a decreased risk for type 2 diabetes (22). In different populations, however, the association for other genes, such as calpain 10, have been replicated in some but not all studies (23). This may be due to differences in geographic and haplotype structures of candidate type 2 diabetes susceptibility variants in this gene (24). Variants in the APM1 gene have been associated with type 2 diabetes and/or insulin resistance in five different populations, including a Japanese population and German, French, American, and Swedish Caucasians. However, the susceptibility SNPs of this gene for type 2 diabetes and/or insulin resistance are different in different populations. This may reveal that the genetic defects of SNPs in the APM1 gene are influenced by genetic backgrounds and environmental factors in different ethnic populations.


   ACKNOWLEDGMENTS
 
The work was supported by the Novo Nordic Consortium, the Swedish Research Council, the Vetenskapligt Arbete Inom Diabetologi Foundation, the Loo and Hans Osterman Foundation, and the Swedish Diabetes Association.

The authors thank all subjects for participating in the present study, Drs. Philippe Froguel and Francis Vasseur for SNP information, Dr. Yudi Pawitan for valuable discussion in statistical analysis, and Yvonne Strömberg for excellent assistance.


   FOOTNOTES
 
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier.

Address correspondence and reprint requests to Harvest F. Gu, Department of Molecular Medicine, Karolinska Hospital, Stockholm, 171 76 Sweden. E-mail: harvest.gu{at}molmed.ki.se

Received for publication March 10, 2003 and accepted in revised form May 27, 2003

Key Words: DASH, dynamic allele-specific hybridization • HOMA, homeostasis model assessment • HOMA-IR, HOMA index for insulin resistance • IGT, impaired glucose tolerance • SNP, single nucleotide polymorphism • UTR, untranslated region


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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