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Diabetes 55:1260-1264, 2006
DOI: 10.2337/db05-0620
© 2006 by the American Diabetes Association
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Brief Genetics Reports

Hepatocyte Nuclear Factor-4{alpha} P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Kazuo Hara1,2,3,4, Momoko Horikoshi1, Hiroji Kitazato5, Chikako Ito6, Mitsuhiko Noda7, Jun Ohashi8, Philippe Froguel9, Katsushi Tokunaga8, Kazuyuki Tobe1,3, Ryozo Nagai2,10, and Takashi Kadowaki1,3,4

1 Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2 Department of Clinical Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
3 CREST, Japan Science and Technology Corporation (JST), Tokyo, Japan
4 National Institute of Health and Nutrition, Tokyo, Japan
5 Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
6 Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima, Japan
7 Department of Endocrinology and Metabolism, International Medical Center of Japan, Tokyo, Japan
8 Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
9 CNRS 8090, Institut de Biologie de Lille, Institute Pasteur and CHU Lille, Lille, France
10 Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Dr. Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp

Abbreviations: HNF, hepatocyte nuclear factor; LD, linkage disequilibrium; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism


   ABSTRACT
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 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Hepatocyte nuclear factor (HNF)-4{alpha} is a transcription factor known as a key molecule in the development and functions of the ß-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to ß-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10–4). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10–4 and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

We previously conducted a 10-cM genome-wide scan for regions linked to type 2 diabetes in 224 affected Japanese sibpairs and found one suggestive linked region and seven potentially linked regions, including 20q12-q13 (the logarithm of odds [LOD] in a multipoint analysis was 2.32 [P = 0.00102] at D20S119 in a population subset whose maximum BMI was <30 kg/m2), near the gene for hepatocyte nuclear factor (HNF)-4{alpha} (1). Evidence for a type 2 diabetes locus in chromosome 20q12-q13 (OMIM no. 603694) has also been reported from studies in several Caucasian and Chinese populations (2–5), suggesting that this region may harbor a susceptibility gene for type 2 diabetes common to these ethnic groups. The transcription factor HNF-4{alpha} (HNF4A) gene, the gene for maturity-onset diabetes of the young (MODY) type 1 (6), a dominantly inherited, early-onset type 2 diabetes characterized by defective glucose-dependent insulin secretion (7), is located in this region. The HNF4A has a complex expression pattern, in part due to alternative splicing, and is expressed in many tissues, including the liver and pancreas. Three of the isoforms are transcribed by an alternative P2 promoter, located about 46 kb upstream of the P1 promoter and the coding exons. Transcripts from both the P1 and P2 promoters have been detected in pancreatic ß-cells, but the P2 promoter is suggested to be the major transcription start site in these cells (8–10). Mutations of HNF4A have been identified in families of MODY type 1 diabetic families, in both the coding and the regulatory regions of the gene, including the P2 promoter region (11). In the ß-cells, HNF4A regulates the expression of genes involved in glucose metabolism and insulin secretion (12,13). Therefore, HNF4A is currently one of the most attractive candidates as the type 2 diabetes susceptibility gene. Indeed, significant associations between single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A and type 2 diabetes have been shown in three Caucasian populations (14–16). However, the precise SNPs directly influencing the susceptibility to type 2 diabetes remain to be identified.

In this study, we conducted a haplotype analysis to investigate whether SNPs in the HNF4A gene influence the susceptibility to type 2 diabetes in the Japanese population.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
The inclusion criteria used for diabetic and nondiabetic subjects in this study have been previously described (17). Diabetes was diagnosed according to the criteria of the World Health Organization (WHO) (18). All subjects enrolled in this study were of full Japanese ancestry. SNPs were genotyped in 192 nondiabetic subjects (mean age 69.1 ± 6.93 years and mean BMI 23.9 ± 2.77 kg/m2) and type 2 diabetic subjects (mean age 63.1 ± 4.16 years and mean BMI 24.6 ± 2.78 kg/m2) (first case-control cohort). We confirmed the results derived from our first case-control cohort in a second cohort (384 type 2 diabetic subjects with a mean age of 62.5 ± 9.78 years and a mean BMI of 24.4 ± 3.92 kg/m2 and 384 nondiabetic subjects with a mean age of 68.4 ± 9.80 years and a mean BMI of 23.4 ± 5.87 kg/m2) and a third cohort (192 type 2 diabetic subjects with a mean age of 63.7 ± 8.31 years and mean BMI of 23.8 ± 1.39 kg/m2 and 192 nondiabetic subjects with a mean age of 69.1 ± 8.32 years and a mean BMI of 22.9 ± 2.7 kg/m2). The three cohorts of subjects (first, second, and third cohorts) were recruited during different times (in the order of first, second, and third cohorts). The type 2 diabetic subjects of the first and second cohorts were recruited from the outpatient clinic of University of Tokyo Hospital; they were all residents of the Tokyo metropolitan area. The type 2 diabetic subjects of the third cohort and the nondiabetic subjects of all the three cohorts were recruited from the Hiroshima Atomic Bomb Casualty Council Health Management Center; they were all residents of Hiroshima, a city 500 miles west of Tokyo (note that all of the nondiabetic subjects were recruited from Hiroshima). Informed consent was obtained from all of the subjects enrolled in the study, and the study was approved by the Ethics Committee of the University of Tokyo.

Screening and selection of SNPs in HNF4A.
To establish an SNP map encompassing HNF4A, SNPs were ascertained by both direct sequencing and a search of databases. We conducted a screening for SNPs by direct sequencing at all the exons of HNF4A and their exon-intron boundaries and along a 1,500-bp region 5' upstream of exon D, which has been reported to be a ß-cell–specific promoter region. The conditions and sequences of the primers used in the PCR shall be made available upon request. The SNPs were identified based on the sequences reported in GenBank that contain the HNF4A gene (accession no. NT_086910). From the public database, rs6065723, rs1884612, rs4812822, rs4810424, rs1884613, rs1884614, rs2144908, rs2273618, and rs3818247 were selected and validated in 30 type 2 diabetic subjects. The SNPs were genotyped in type 2 diabetic subjects and nondiabetic subjects by direct sequencing. PCR was performed under standard conditions, and the sequencing reactions were performed using the BigDye terminator kit (Applied Biosystems, Foster City, CA) and resolved using an ABI 3700 automated DNA sequencer (Applied Biosystems). The results were integrated using a Sequencher (Gene Codes Corporation, Ann Arbor, MI) and individual SNPs were manually genotyped. Ambiguous base callings were eliminated from further analysis. There was no genotyping error based on blind replicates for two SNPs in 192 samples.

Statistical analysis.
The characteristics of the populations were described as means ± SD. The proportions of specific genotypes or alleles in subjects with and without type 2 diabetes were compared using the {chi}2 test. The differences among subjects with different SNP genotypes were statistically tested using ANOVA. The statistical analyses, except for the haplotype estimation, were performed using JMP for Windows, Version 4.00 (SAS Institute, Cary, NC).

Haplotype analysis.
The frequencies of each haplotype were estimated, and the differences in the haplotype frequencies between nondiabetic and diabetic subjects were assessed using a software based on the expectation-maximization (EM) algorithm, SNPAlyze (Dynacom, Tokyo, Japan), and PHASE, Version 2 (http://www.stat.washington.edu/stephens/software.html). The differences in the haplotype frequencies were then analyzed using the {chi}2 and permutation tests. The linkage disequilibrium (LD) structure in the HNF4A region was plotted using GOLD software.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Genomic DNAs from 192 unrelated type 2 diabetic and nondiabetic Japanese individuals were genotyped at an average of one SNP every 4.1 kb across an ~78-kb region harboring the HNF4A gene and its alternative upstream promoter, P2. All the genotypic distributions of the SNPs that were identified were in Hardy-Weinberg equilibrium in both the nondiabetic and type 2 diabetic subjects (P > 0.05). Among those identified, SNPs with a minor allele frequency >0.10 were investigated for LD in HNF4A and for their association with type 2 diabetes. As shown in Fig. 1A, SNPs were used to determine the pattern of LD in the chromosomal region of HNF4A. The LD plot illustrates that the chromosomal region beginning with rs6065723, –27 kb upstream of the P2 promoter, and rs6073418, 17kb downstream of the P2 promoter, represents one block of strong LD, which is consistent with previous reports (15,16,20). No difference in the distributions of either the genotypes or the SNPs in HNF4A were observed between the nondiabetic and type 2 diabetic subjects (Table 1). We then tested the association of haplotypes with susceptibility to type 2 diabetes and found very strong evidence of an association between type 2 diabetes and a certain haplotype in the promoter region of the HNF4A gene. This highly significant association was seen with the haplotype consisting of two SNPs, namely rs1884614 and rs2144908, in the P2 promoter region of the HFN4A gene (overall P value = 3.82 x 10–4) (Table 2). In contrast, there was no significant association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region. Indeed, the extent of association between haplotypes and type 2 diabetes decreased with increasing distance from the P2 promoter region (Fig. 1B). This result supports the idea that a type 2 diabetes susceptibility polymorphism might be located in the P2 promoter region but not in any other region of the HNF4A gene. Martin et al. (19) reported that haplotype analysis allowed more accurate mapping of the Alzheimer’s disease susceptibility locus to the APOE gene than analysis of individual SNPs, similar to our findings. The association of type 2 diabetes with the rs1884614-rs2144908 haplotype was replicated in two other case-control cohorts. The second cohort (overall P value = 1.51 x 10–4) consisted of 384 diabetic and 384 nondiabetic subjects. The third cohort (overall P value = 0.019) (Table 2) included both type 2 diabetic and nondiabetic subjects recruited from the same area of Japan to exclude the possibility of false haplotype associations as a result of population stratification between samples enrolled from different areas of Japan (Tokyo and Hiroshima). The T-G rs1884614-rs2144908 haplotype was found consistently more frequently in the type 2 diabetic subjects than in the nondiabetic subjects of the first (0.052 vs. 0.024, haplotype-specific P value = 0.04, odds ratio [OR] 2.23 [95% CI 1.06–5.35]), second (0.042 vs. 0.012, haplotype-specific P value = 3.6 x 10–4, OR 3.50 [95% CI 1.67–7.11]), and third cohorts (0.039 vs. 0.007, haplotype-specific P value = 0.003, OR 5.83 [95% CI 1.69–22.4]) (Table 2).


Figure 1
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  		FIG. 1. Association of a haplotype in the HNF4A region with type 2 diabetes. A: The pairwise marker LD between SNPs in the HNF4A region. The axes are scaled by distance markers (kb). The LD structure in the HNF4A region was plotted using GOLD software. B: –Log10 P values of the differences in haplotype frequencies between the type 2 diabetic and nondiabetic subjects were plotted against the physical distance in the first cohort (192 diabetic and 192 nondiabetic subjects). At the bottom, the two promoters and exons of HNF4A are described. C: The result obtained from the first cohort was confirmed in the second cohort (384 diabetic and 384 nondiabetic subjects). HNF1 refers to the HNF1 binding site, and TATA refers to the TATA box in the P2 promoter region.

 

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  		TABLE 1. Comparison of genotypic and allelic distribution of SNPs in HNF4A between subjects with type 2 diabetes and those without diabetes

 

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  		TABLE 2 Haplotype frequencies consisting of rs1884614 (SNP6) and rs2144908 (SNP7) in the P2 promoter region of HNF4A between subjects with type 2 diabetes and those without diabetes

 
We found no association between individual SNPs in the P2 promoter region and type 2 diabetes, which differs from the results reported by Silander et al. (15) in a Finnish population and by Love-Gregory et al. (16) in Ashkenazi Jews. However, our result was consistent with that reported in two recent articles published by Bagwell et al. (20) and Winckler et al. (21), who reported no evidence of any association of single SNPs with type 2 diabetes in Scandinavians and American Caucasians. These discrepant results among the studies may be attributable to the different genetic backgrounds of the subjects. In contrast, we found significant and consistent association between certain haplotypes and type 2 diabetes, which is consistent with the report of Bagwell et al. in which haplotypes consisting of SNPs in the P2 promoter region, but not any individual SNPs, were significantly associated with type 2 diabetes. The haplotype found to be associated with type 2 diabetes in the present study is relatively uncommon. However, it is noteworthy that the association between this haplotype and type 2 diabetes was observed consistently in all the three cohorts, suggesting the existence of an as-yet-unidentified polymorphism that might be relatively uncommon but associated with susceptibility to type 2 diabetes.

The results of the present study revealed that the P2 region of the HNF4A gene might be a susceptibility region for type 2 diabetes common to different ethnic groups, including the Japanese. Given that specific haplotypes, but not individual SNPs, in the P2 promoter region were significantly associated with type 2 diabetes, there might exist an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene directly influencing the susceptibility to type 2 diabetes. It is also possible that SNPs constituting the haplotype in the P2 promoter region of the HNF4A gene associated with type 2 diabetes may coordinately affect the susceptibility to type 2 diabetes.


   ACKNOWLEDGMENTS
 
This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (to T.K.); Grant-in-Aid for Scientific Research on Priority Areas "Applied Genomics" from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Grant-in-Aid from the 21st Century Program (to R.N.).

We thank Naoko Miyama and Yuko Okada for technical assistance.


   FOOTNOTES
 
K.H. and M.H. contributed equally to this study.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication May 16, 2005 and accepted in revised form November 28, 2005


   REFERENCES
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 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

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