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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2242
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1791-1795
Copyright © 2007 by The Endocrine Society

Insulin Gene/IDDM2 Locus in Japanese Type 1 Diabetes: Contribution of Class I Alleles and Influence of Class I Subdivision in Susceptibility to Type 1 Diabetes

Takuya Awata, Eiji Kawasaki, Hiroshi Ikegami, Tetsuro Kobayashi, Taro Maruyama, Koji Nakanishi, Akira Shimada, Hiroyuki Iizuka, Susumu Kurihara, Masataka Osaki, Miho Uga, Yumiko Kawabata, Shoichiro Tanaka, Yasuhiko Kanazawa, Shigehiro Katayama on behalf of the Japanese Study Group on Type 1 Diabetes Genetics1

Division of Endocrinology and Diabetes, Department of Medicine (T.A., S.Ku., M.O., S.Ka.) and Division of RI Laboratory, Biomedical Research Center (T.A., H.Ii.), Saitama Medical University, Saitama 350-0495, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K., M.U.), Nagasaki University Hospital of Medicine and Dentistry, Nagasaki 852-8501 Japan; Department of Endocrinology, Diabetes and Metabolism (H.Ik., Y.Kaw.), Kinki University School of Medicine, Osaka 589-8511, Japan; Third Department of Internal Medicine (T.K., S.T.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan; Department of Internal Medicine (T.M.), Saitama Social Insurance Hospital, Saitama 330-0074, Japan; Department of Endocrinology and Metabolism (K.N.), Toranomon Hospital, Tokyo 160-8582, Japan; and Department of Internal Medicine (A.S., Y.Kan.), Keio University School of Medicine, Tokyo 160-8582, Japan

Address all correspondence and requests for reprints to: Takuya Awata, Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan. E-mail: awata{at}saitama-med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: It is suggested that insulin autoimmunity plays an important role in the development of type 1 diabetes in humans. However, the association between insulin gene (INS) region (IDDM2) and type 1 diabetes has been uncertain in Asians.

Objective: A multicenter collaboration study was conducted to clarify the role of the IDDM2 region in Japan.

Subjects and Methods: In total, 661 patients with type 1 diabetes and 706 control subjects were enrolled. The INS variable number of tandem repeat (VNTR) class I/class III status was estimated by genotyping the –23 HphI single nucleotide polymorphism. From surrounding polymorphisms across the insulin gene, we also inferred haplotypes bearing INS VNTR lineages.

Results: The frequency of the class I allele was 99.3% in patients and 96.7% in controls (P < 10–5), and the class I/III or III/III genotype was found in 1.4% of patients and in 6.4% of controls [odds ratio (OR) 0.20, P < 10–5]. The class I subdivision revealed IC to increase significantly in patients with type 1 diabetes (P = 0.002), whereas ID did not; the distribution of IC and ID was significantly different between patients and controls (P = 0.014).

Conclusion: The present study certainly shows that the IDDM2 region is also a susceptibility locus in the Japanese population. Furthermore, it was revealed that IC may be more susceptible to type 1 diabetes than ID, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ASSOCIATION BETWEEN the HLA class II (DRB1 and DQB1) genes (IDDM1) and type 1 diabetes has been observed in all ethnic groups, including Asians (1, 2). The insulin gene (INS) region is another established susceptibility locus to type 1 diabetes (IDDM2) in Caucasians; the shortest (class I) variable number of tandem repeat (VNTR) alleles were found to increase, whereas the longest (class III) alleles were observed to decrease in the patients in comparison to the controls (3, 4). The INS VNTR is composed of 14- to 15-bp variant repeats with the consensus sequence 5'-ACAGGGGTGTGGGG-3' (5, 6). It was reported that most class III alleles are associated with higher levels of INS transcription than class I alleles in the thymus (7, 8). The higher INS expression may more efficiently induce tolerance to insulin. Recently, Nakayama et al. (9) demonstrated that insulin itself is a primary autoantigen that initiates the immune response leading to diabetes in nonobese diabetic mice. Although heterogeneity exists in the etiology of human type 1 diabetes, several lines of evidence suggest that insulin also plays an important role in the development of type 1 diabetes in humans (10, 11, 12).

Therefore, in Asians, clarifying the role of the IDDM2 region in the susceptibility to type 1 diabetes is considered to be an essential issue. However, the association between the INS VNTR and type 1 diabetes in Asians has been still uncertain (2, 13, 14, 15), largely because of the predominance of class I over class III alleles and the small sample size of the previous studies. To overcome this, a multicenter collaboration study in Japan, subsequent to the previous studies (16, 17), was thus conducted to analyze the IDDM2 locus. Furthermore, the heterogeneity of class I or class III alleles and the surrounding polymorphisms, which so far have been scarcely analyzed in Asians, were also determined.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 1367 Japanese subjects, including 661 patients with type 1 diabetes and 706 control subjects were studied. An ethics committee from each institute approved the study, and informed consent was obtained from all subjects. The patients with type 1 diabetes consisted of 363 females and 298 males with a mean (±SD) age-at-onset of 29.1 (±17.1) yr. Control subjects consisted of 408 females and 298 males with mean (±SD) age of 36.6 (±13.4) yr. The diagnosis of type 1 diabetes was made by diabetologists according to the criteria of the National Diabetes Data Group (18).

–23HphI single nucleotide polymorphism (SNP) and surrounding polymorphisms

More than 50 SNPs were identified in a 7.8-kb region flanking the insulin gene (19). Among them, we identified the –23HphI SNP and nine common SNPs within the 4.1-kb region in which type 1 susceptibility was mapped (20), and a 5-bp insertion/deletion polymorphism at +2336. The –23HphI SNP was typed by PCR-restriction fragment length polymorphism using primers as described previously (21). The SNPs at positions –2733, –2221, +805, +862, +1127, +1140, +1355, +1404, and +1428 were determined by direct sequencing of PCR products, and the insertion/deletion polymorphism at +2336 was determined by PCR and 4% agarose gel electrophoresis. Frequencies of INS haplotypes of each group were inferred using the SNPAlyze V5.1 software (Dynacom, Yokohama, Japan), which applies expectation-maximization (EM) algorithm (22) for haplotype inference.

INS VNTR polymorphism

We determined the exact length of class I alleles in part of the subjects (109 patients and 86 control subjects), and then we checked its correlation with the present subdivision (IC and ID) as defined by haplotype analysis. The exact class I allele lengths were determined by fluorescence-labeled PCR using primers 5FP1 (labeled with 6-carboxyfluorescein) and 5FP2 (23), and capillary electrophoresis. Genomic DNA was subjected to PCR amplification (4 min at 94 C, 1 cycle; 1 min at 94 C, then 10 min at 68 C, 18 cycles; 1 min at 94 C, then 10 min + 15 sec increments per cycle at 68 C, 12 cycles; 10 min at 72 C) using Tbr EXT DNA polymerase (Finzymes Oy, Espoo, Finland). A mixture of PCR products and an internal size standard (GeneScan 1000) were run on ABI PRISM genetic analyzer and size analysis was determined with the GeneScan software (Applied Biosystems Japan Ltd., Tokyo, Japan).

Statistics

The differences in genotype and allele frequencies were assessed by either Fisher’s exact test or {chi}2 test. The OR and its 95% confidence interval (95% CI) were calculated using Woolf’s method. The differences in frequencies of each haplotype were assessed by permutation tests (24) using the SNPAlyze V5.1 software (Dynacom, Chiba, Japan). Continuous clinical data were compared using unpaired Student’s t test, and the categorical clinical data were compared using Fisher’s exact test. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
INS VNTR genotypes and alleles

First, we determined the frequencies of INS VNTR class I/class III genotypes and alleles. We found the complete linkage disequilibrium between –23HphI SNP and INS VNTR genotypes in 138 Japanese subjects, whose INS VNTR genotype status was previously determined by Southern blot analysis (13). Furthermore, Stead et al. provided data on their home page (http://www.le.ac.uk/ge/ajj/insulin) showing the linkage disequilibrium between INS VNTR and the –23HphI SNP to be complete in 59 Japanese subjects. Based on the very tight linkage disequilibrium between INS VNTR class I/class III alleles and the –23HphI A/T alleles, respectively, in the Japanese population, we estimated the INS VNTR genotype status by the –23HphI SNP genotype. As shown in Table 1Go, the frequency of the INS VNTR class I allele was 99.3% in the patients and 96.7% in the controls (P < 10–5), and the class I/III or III/III genotype was found in 1.4% of the patients and in 6.4% of the controls (OR 0.20, P < 10–5).


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  		TABLE 1. Frequencies of INS genotypes and alleles

 
Surrounding polymorphisms and INS haplotypes

We next estimated haplotype frequencies for the SNPs flanking the INS VNTR and the insertion/deletion polymorphism at +2336. Table 2Go shows the estimated INS haplotype frequencies by EM algorithm from the polymorphism data. Stead et al. (19) reported inferred haplotypes in non-Africans, including 59 Japanese subjects (http://www.le.ac.uk/ge/ajj/insulin/haplotypes.html). Following the report, the inferred haplotypes in the present study were named according to bearing INS VNTR lineage. In the present study, we observed an unusual haplotype, which was deduced from a patient with type 1 diabetes, in which only the +2336 variation is different from the IIIAa haplotype; thus that was named IIIAa' (Table 2Go). The frequencies of the other inferred haplotypes were all very rare (<10–7) in each group, and were not shown in Table 2Go. Permutation tests were used to assess the statistical significance of the haplotype frequency differences (24).


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  		TABLE 2. INS haplotype frequency estimates in Japanese

 
From the haplotype analysis, class I alleles were divided into two lineages (IC and ID) and class III into two lineages (IIIA and IIIB). As shown in Table 2Go, the haplotype carrying the VNTR IC was found to significantly increase in patients with type 1 diabetes (P = 0.002), whereas the ID did not. In the young-onset (i.e. an onset age of less than 20 yr) patients; IC was significantly associated with type 1 diabetes, whereas ID was significantly negatively associated with type 1 diabetes. Distribution of class I subdivision was significantly different between patients with type 1 diabetes and control subjects ({chi}2 = 6.0, P = 0.014), and between young-onset patients and controls ({chi}2 = 14.4, P = 0.0001). As for the class III subdivision, the class IIIA (IIIAa, IIIAa', or IIIAb) was predominant over class IIIB in the controls, and only IIIAa and IIIAb haplotypes significantly decreased in the patients in comparison to the controls, although the difference in the class III subset distribution failed to reach statistical significance ({chi}2 = 3.9, P = 0.144).

INS genotypes with class I subdivision

Diplotypes of each individual were assigned using maximum-likelihood estimation by EM algorithm, and were named as genotypes of bearing INS VNTR lineages. Table 3Go shows the frequencies of the INS genotypes with the class I subdivision. Among the class I/I subjects, only the IC/IC genotype was significantly increased in the patients (OR 1.38). In young-onset patients, the frequencies of the IC/IC and IC/ID genotypes significantly increased, whereas the ID/ID genotype was significantly decreased in type 1 diabetes compared with control subjects. According to the findings of a contingency table analysis, global distribution of the class I/I genotypes with the subdivision was significantly different between young-onset patients and controls ({chi}2 = 16.0, P = 0.0003), although that was not significant between whole patients and controls ({chi}2 = 5.6, P = 0.060).


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  		TABLE 3. Frequencies of INS genotypes with class I subdivision

 
Correlation between class I subdivision and exact length in number of repeats

Previously, INS VNTR class I alleles in the Japanese population were subdivided into 1S (25–38 repeats), 1M (39–41 repeats), and 1L (42–44 repeats) based on the repeat number (15). According to the web site by Stead et al. (http://www.le.ac.uk/ge/ajj/insulin), it appears that IC corresponds to 1S and ID to 1M or 1L. Therefore, regarding the genotype, IC/IC, IC/ID, ID/ID, IC/III, and ID/III correspond to 1S/1S; 1S/1M or 1S/1L; 1M/1M, 1M/1L, or 1L/1L; 1S/III; and 1M/III or 1L/III, respectively. In the present study, among 195 Japanese subjects (109 patients and 86 controls; 187 class I/I and eight class I/III), 185 genotypes (94.9%) follow this correspondence.

Clinical characteristics of patients and INS genotypes

Sex, mode of onset (acute, fulminant, or slow), glutamic acid decarboxylase antibody positivity, IA-2 antibody positivity, and coexistence of autoimmune thyroid disease, defined as Graves’ disease, Hashimoto’s thyroiditis, or positivity for antibodies against thyroid peroxidase and/or thyroglobulin, were similar among the INS VNTR genotype groups (IC/IC, IC/ID, ID/ID, or I/III) and they were not significantly different (data not shown). However, the age at onset was significantly older in ID/ID patients than both IC/IC and IC/ID (P = 0.028 and 0.0034, respectively).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, INS VNTR class I alleles were found to be significantly associated with susceptibility to type 1 diabetes and class III alleles were found to be protective in the Japanese population (P < 10–5). Because of the predominance of the class I alleles, previous studies in the Japanese population failed to show any firm association of INS VNTR with type 1 diabetes (13, 14, 15). Using a larger sample size than that of earlier studies, we could certainly show that the insulin gene locus contributes to the disease risk in the Japanese population, for the first time in non-Caucasian populations.

We further assessed the heterogeneity of class I and class III alleles in relation to disease susceptibility. Nevertheless, because of the limited number of class III alleles in the present study, it was difficult to assess the heterogeneity in class III-associated protection. We observed that the protection of the class IIIA (particularly IIIAa) was stronger than that of class IIIB in terms of the significance level (Table 2Go), although the difference in the class III subset distribution was not significant. Therefore, in line with the recent report on Caucasians (25), we could not confirm that the class IIIB-bearing haplotype, previously called very protective haplotype, was more protective than the class IIIA-bearing haplotype, called protective haplotype (26). However, further accumulation of subjects with sufficient number of class III alleles is necessary to clarify the heterogeneity in class III-associated protection in the Japanese population.

Regarding the class I subdivision, we found some evidence that the IC haplotype is more susceptible to type 1 diabetes than the ID (Tables 2Go and 3Go). Because these IC and ID haplotypes are identical at the 4.1-kb IDDM2-encoded susceptibility region (20, 27) except for the VNTR, the variability of the class I alleles (http://www.le.ac.uk/ge/ajj/insulin/classI.html) may thus modulate the susceptibility to type 1 diabetes. In a previous study in the Japanese population (15), class I alleles were divided into 1S (25–38 repeats), 1M (39–41 repeats), and 1L (42–44 repeats), and the 1S allele and the 1S/1S genotype were found to be both significantly increased in 152 patients, in comparison to the 167 control subjects. Because a close correlation was observed between IC and 1S, and between ID and 1M or 1L, the present collaboration study principally confirms the findings of the previous study (15); note that only 86 control subjects (no patients) from the previous study were included in the present study, and the significant differences between IC and ID remained after removing the overlapping 86 control subjects (data not shown).

Heterogeneity in class I-associated susceptibility to type 1 diabetes has also been analyzed in Caucasians. Bennett et al. (26, 28) reported that the most common 814 allele (42 repeats, ID) was not significantly transmitted from class I/III heterozygous fathers. Similarly, analyzing a subset of the same families, Stead et al. (29) found that the ID– alleles, which include the 814 allele, showed a protective effect when transmitted from ID–/III heterozygous fathers. However, the anomalous behavior of a specific size of class I allele was not confirmed by McGinnis and Spielman (30). Recently, Barratt et al. (25) reported that, with a large sample, they failed to replicate any inhomogeneity in susceptibility to type 1 diabetes within class I or class III allele groups (25), which definitely ruled out any difference between IC and ID. In the present study, in contrast, we provide evidence, albeit weak, for a difference of susceptibility to type 1 diabetes between IC and ID in the Japanese population. A lower impact of HLA class II (DRB1, DQB1)-associated susceptibility to type 1 diabetes in the Japanese population (31, 32) may have facilitated the evaluation of non-HLA, minor susceptibility genes to type 1 diabetes. However, the case-control studies used in this study tend to involve population stratification. Family-based studies and further transracial studies, including Asian and African populations, are necessary to replicate our findings and help elucidate the role of VNTR variability in disease susceptibility.

In the present study, the age at onset was found to be significantly older in ID/ID patients than both IC/IC and IC/ID, and consequently, the association of the class I subdivision with type 1 diabetes was more evident in the young-onset patients as shown in Tables 2Go and 3Go, which may indicate that INS VNTR could affect the disease progression, or alternatively, adult-onset type 1 diabetes may be etiologically more heterogeneous in terms of autoimmunity to insulin. However, age-dependent influences of INS VNTR, which appear to be unclear in previous studies, need to be proven in independent studies.

In conclusion, the present study strongly shows the IDDM2 region to also be a susceptibility locus in the Japanese population, thus suggesting that insulin is an important autoantigen across different ethnic groups. Furthermore, the subdivision of class I alleles revealed that IC may be more susceptible to type 1 diabetes than ID in the Japanese population, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes, although further confirmation studies are necessary.


   Acknowledgments
 
We thank Ritsuko Doki for her valuable technical assistance.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online March 6, 2007

1 Members of the Japanese Study Group on Type 1 Diabetes Genetics are: Takuya Awata, Hiroshi Ikegami, Eiji Kawasaki, Tetsuro Kobayashi, Taro Maruyama, Koji Nakanishi, Akira Shimada, and Kazuma Takahashi. Back

Abbreviations: CI, Confidence interval; EM, expectation-maximization; OR, odds ratio; SNP, single nucleotide polymorphism; VNTR, variable number of tandem repeats.

Received October 13, 2006.

Accepted February 22, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Jenkins D, Mijovic C, Fletcher J, Jacobs KH, Bradwell AR, Barnett AH 1990 Identification of susceptibility loci for type 1 (insulin-dependent) diabetes by trans-racial gene mapping. Diabetologia 33:387–395[CrossRef][Medline]
  2. Park Y, Eisenbarth GS 2001 Genetic susceptibility factors of type 1 diabetes in Asians. Diabetes Metab Res Rev 17:2–11[CrossRef][Medline]
  3. Bell GI, Horita S, Karam JH 1984 A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183[Abstract]
  4. Pugliese A, Miceli D 2002 The insulin gene in diabetes. Diabetes Metab Res Rev 18:13–25[CrossRef][Medline]
  5. Bell GI, Selby MJ, Rutter WJ 1982 The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295:31–35[CrossRef][Medline]
  6. Stead JD, Jeffreys AJ 2000 Allele diversity and germline mutation at the insulin minisatellite. Hum Mol Genet 9:713–723[Abstract/Free Full Text]
  7. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C 1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15:289–292[CrossRef][Medline]
  8. Pugliese A, Zeller M, Fernandez Jr A, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD 1997 The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297[CrossRef][Medline]
  9. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS 2005 Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220–223[CrossRef][Medline]
  10. Lee KH, Wucherpfennig KW, Wiley DC 2001 Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2:501–507[CrossRef][Medline]
  11. Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, Roep BO, Peakman M 2004 Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 113:451–463[CrossRef][Medline]
  12. Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA 2005 Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435:224–228[CrossRef][Medline]
  13. Matsumoto C, Awata T, Iwamoto Y, Kuzuya T, Saito T, Kanazawa Y 1994 Lack of association of the insulin gene region with type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 37:210–213[CrossRef][Medline]
  14. Kawaguchi Y, Ikegami H, Shen GQ, Nakagawa Y, Fujisawa T, Hamada Y, Ueda H, Fu J, Uchigata Y, Kitagawa Y, Omori Y, Shima K, Ogihara T 1997 Insulin gene region contributes to genetic susceptibility to, but may not to low incidence of, insulin-dependent diabetes mellitus in Japanese. Biochem Biophys Res Commun 233:283–287[CrossRef][Medline]
  15. Awata T, Kurihara S, Kikuchi C, Takei S, Inoue I, Ishii C, Takahashi K, Negishi K, Yoshida Y, Hagura R, Kanazawa Y, Katayama S 1997 Evidence for association between the class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population. Diabetes 46:1637–1642[Abstract]
  16. Ikegami H, Awata T, Kawasaki E, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Amemiya S, Kawabata Y, Kurihara S, Tanaka S, Kanazawa Y, Mochizuki M, Ogihara T 2006 The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan. J Clin Endocrinol Metab 91:1087–1092[Abstract/Free Full Text]
  17. Kawasaki E, Awata T, Ikegami H, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Uga M, Kurihara S, Kawabata Y, Tanaka S, Kanazawa Y, Lee I, Eguchi K 2006 Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. Am J Med Genet A 140:586–593[Medline]
  18. National Diabetes Data Group 1979 Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057.[Medline]
  19. Stead JD, Hurles ME, Jeffreys AJ 2003 Global haplotype diversity in the human insulin gene region. Genome Res 13:2101–2111[Abstract/Free Full Text]
  20. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, Bell JI 1993 Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet 4:305–310[CrossRef][Medline]
  21. Julier C, Hyer RN, Davies J, Merlin F, Soularue P, Briant L, Cathelineau G, Deschamps I, Rotter JI, Froguel P, Boitard C, Bell JI, Lathrop GM 1991 Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354:155–159[CrossRef][Medline]
  22. Excoffier L, Slatkin M 1995 Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927[Abstract]
  23. McGinnis RE, Spielman RS 1995 Insulin gene 5' flanking polymorphism. Length of class 1 alleles in number of repeat units. Diabetes 44:1296–1302[Abstract]
  24. Fallin D, Cohen A, Essioux L, Chumakov I, Blumenfeld M, Cohen D, Schork NJ 2001 Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer’s disease. Genome Res 11:143–151[Abstract/Free Full Text]
  25. Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC, Harold D, Concannon P, Gharani N, McCarthy MI, Olavesen MG, McCormack R, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Gillespie KM, Tuomilehto-Wolf E, Tuomilehto J, Bennett ST, Clayton DG, Cordell HJ, Todd JA 2004 Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53:1884–1889[Abstract/Free Full Text]
  26. Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, Nerup J, Bouzekri N, Cambon-Thomsen A, Rønningen KS, Barnett AH, Bain SC, Todd JA 1995 Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284–292[CrossRef][Medline]
  27. Bennett ST, Todd JA 1996 Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–370[CrossRef][Medline]
  28. Bennett ST, Wilson AJ, Esposito L, Bouzekri N, Undlien DE, Cucca F, Nistico L, Buzzetti R, Bosi E, Pociot F, Nerup J, Cambon-Thomsen A, Pugliese A, Shield JP, McKinney PA, Bain SC, Polychronakos C, Todd JA 1997 Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group. Nat Genet 17:350–352[CrossRef][Medline]
  29. Stead JD, Buard J, Todd JA, Jeffreys AJ 2000 Influence of allele lineage on the role of the insulin minisatellite in susceptibility to type 1 diabetes. Hum Mol Genet 9:2929–2935[Abstract/Free Full Text]
  30. McGinnis RE, Spielman RS 1995 Insulin expression: is VNTR allele 698 really anomalous. Nat Genet 10:378–380[CrossRef][Medline]
  31. Abiru N, Kawasaki E, Eguch K 2002 Current knowledge of Japanese type 1 diabetic syndrome. Diabetes Metab Res Rev 18:357–366[CrossRef][Medline]
  32. Kawasaki E, Matsuura N, Eguchi K 2006 Type 1 diabetes in Japan. Diabetologia 49:828–836[CrossRef][Medline]



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