Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Brief Genetics Reports

Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene

The Absence of Evidence for the Association of Three Frequent Single Nucleotide Polymorphisms and Four Common Haplotypes With Japanese Type 2 Diabetes

  1. Haruhiko Osawa1,
  2. Hiroshi Onuma1,
  3. Akiko Murakami1,
  4. Masaaki Ochi1,
  5. Tatsuya Nishimiya1,
  6. Kenichi Kato2,
  7. Ikki Shimizu2,
  8. Yasuhisa Fujii2,
  9. Jun Ohashi3 and
  10. Hideichi Makino1
  1. 1Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan
  2. 2Ehime Prefectural Hospital, Ehime, Japan
  3. 3Department of Human Genetics, School of International Health, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
    Diabetes 2003 Feb; 52(2): 562-567. https://doi.org/10.2337/diabetes.52.2.562
    PreviousNext
    • Article
    • Figures & Tables
    • Info & Metrics
    • PDF
    Loading

    The Absence of Evidence for the Association of Three Frequent Single Nucleotide Polymorphisms and Four Common Haplotypes With Japanese Type 2 Diabetes

    Abstract

    FOXC2, a forkhead/winged helix transcription factor, represents a promising candidate gene for type 2 diabetes since transgenic mice that specifically overexpress this gene in adipocytes are lean and insulin sensitive. To determine whether there are single nucleotide polymorphisms (SNPs) in this gene that are associated with type 2 diabetes, sequences of the coding and ∼1 kb of 5′ flanking regions in 24 Japanese type 2 diabetic subjects were initially analyzed using PCR direct sequencing, and the regions containing the identified polymorphisms were then examined. In 200 control subjects, three frequent SNPs were found (g. −512C>T [32.3%] and −350G>T [13.0%] in the 5′ flanking region and +1548C>T [10.0%] in the 3′ flanking region). Linkage disequilibria were found between all three pairs of these SNPs. Of the eight possible haplotypes defined by these SNPs, only four were found. When the frequencies of these SNPs and the four common haplotypes between 195 type 2 diabetic and 200 control subjects were compared, no association was evident. The +898C>T (Pro300Ser), +907C>A (Leu303Met), 1167_1169delCCA (389delHis), and +1251C>A (Ala417Ala) identified in the coding region were rare, although +907C>A could be higher in type 2 diabetic subjects (1.5%) than in control subjects (0.3%). Thus, the SNPs identified in the FOXC2 gene are unlikely to have major effects on susceptibility to Japanese type 2 diabetes.

    Type 2 diabetes is characterized by insulin resistance in insulin target tissues and an impaired insulin secretion from pancreatic β-cells (1). The gene mutations identified thus far account for specific types of diabetes as single genetic factors and constitute only a small proportion of all type 2 diabetic cases (2). Common type 2 diabetes is thought to be a polygenic disease, and its major genetic factors remain to be elucidated (3). It has recently been reported that single nucleotide polymorphisms (SNPs) in calpain-10, peroxisome proliferator-activated receptor γ (PPARγ), and adiponectin are associated with type 2 diabetes (4–6).

    FOXC2, a forkhead/winged helix transcription factor, has been identified as a key regulator of adipocyte metabolism (7). Transgenic mice that specifically overexpress the FOXC2 gene in white and brown adipocytes show a lean and insulin-sensitive phenotype. In these mice, intra-abdominal white adipose tissue (WAT) deposition is reduced with a change to brown fat-like histology, whereas interscapular brown adipose tissue (BAT) is hypertrophic. Serum triglycerides, free fatty acids, glucose, and insulin levels are all lowered. The enhanced expression of BAT-specific genes such as uncoupling protein-1 (UCP-1) and PPARγ coactivator-1 (PGC-1), and genes involved in the insulin signaling pathway in WAT, such as the insulin receptor and insulin receptor substrate-1 (IRS-1) could account for this improvement. Since an enhanced FOXC2 gene expression appears to counteract insulin resistance and obesity, this represents a promising candidate for a type 2 diabetes susceptibility gene.

    In view of this, we initiated a systematic search for SNPs in the FOXC2 gene of Japanese subjects. The FOXC2 gene has only one exon based on the human draft sequence for the FOXC2 gene on chromosome 16 (GenBank accession no. NT_024788) and the human FOXC2 cDNA sequence (no. NM_005251). We initially examined this exon 1 that encodes the entire molecule and the ∼1 kb of 5′ flanking region in 24 type 2 diabetic patients using PCR direct sequencing. This screening of 24 subjects permits the detection of an allele whose frequency in patients is 3.3% with a power of 80%, and 4.7% with a power 90%. Since we found that the human draft sequence of FOXC2 contained one extra C at 1061 (NT_024788), resulting in a frameshift mutation, we used the one base shorter number beyond +1060 as the correct reference numbers of this gene. This sequence matched with the human FOXC2 cDNA sequence (no. NM_005251). The sequencing of both strands revealed the presence of two SNPs, −512C>T and −350G>T, in the 5′ flanking sequence; one synonymous SNP, +1251C>A (Ala417Ala) and one missense SNP, +907C>A (Leu303Met) in the coding region; and +1548C>T in the 3′ untranslated region. When the regions that included these identified SNPs were sequenced in a total of 195 type 2 diabetic subjects and 200 control subjects, the other two rare mutations, namely +898C>T (Pro300Ser) and a deletion of CCA between 1167 and 1169 (1167_1169delCCA, 389delHis), were also found as described below.

    We determined the sequences of the regions containing these six SNPs and 1167_1169delCCA in 200 control subjects (See Table 1 for clinical features). The frequencies of these polymorphisms were determined to be −512C>T (32.3%), −350G>T (13.0%), +898C>T (0%), +907C>A (0.3%), 1167_1169delCCA (0.5%), +1251C>A (0%), and +1548C>T (10.0%) (Table 2). The frequencies of the genotypes in each of the SNPs with >5% frequencies, namely −512C>T, −350G>T, and +1548C>T, are also shown (Table 3). We then examined the linkage disequilibrium between any two of these three frequent SNPs. Linkage disequilibrium was found between all of the three pairs (Table 4). The estimated frequencies of haplotypes defined by −512C>T and +1548C>T were f(C-C) = 0.577, f(C-T) = 0.100, f(T-C) = 0.323, and f(T-T) = 0.000. The estimated frequencies of haplotypes defined by −512C>T and −350G>T were f(C-G) = 0.547, f(C-T) = 0.130, f(T-G) = 0.323, and f(T-T) = 0.000. The estimated frequencies of haplotypes defined by −350G>T and +1548C>T were f(G-C) = 0.771, f(G-T) = 0.099, f(T-C) = 0.129, and f(T-T) = 0.001. We then determined the estimated haplotype frequencies defined by these three SNPs, and only four of the eight possible haplotypes were detected (Table 5). The estimated haplotype frequencies defined by −512C>T, −350G>T, and +1548C>T were f(C-G-C) = 0.447, f(T-G-C) = 0.323, f(C-T-C) = 0.130, and f(C-G-T) = 0.100.

    Next we sequenced the regions containing the identified polymorphisms in 171 additional type 2 diabetic subjects, and compared the allele frequencies of these polymorphisms between a total of 195 type 2 diabetic patients and 200 nondiabetic control subjects (see Table 1 for clinical features). No significant differences in the allele frequencies of −512C>T, −350G>T, +898C>T, +907C>A, 1167_1169delCCA, +1251C>A, and +1548C>T were detected between type 2 diabetic and control subjects (Table 2). The +907C>A (Leu303Met) was found in 6 of 390 alleles in type 2 diabetic subjects, but in only 1 of 400 alleles in the control subjects, suggesting that this missense mutation could be higher in type 2 diabetes, but it should be noted that the allele frequency was quite low. Genotype frequencies of the SNPs with >5% frequencies, namely −512C>T, −350G>T, and +1548C>T, are not significantly different between type 2 diabetic and control subjects (Table 3).

    The estimated haplotype frequencies were then determined for type 2 diabetes. In the 195 type 2 diabetic subjects, significant linkage disequilibria were found to be the same as for the control subjects, and the estimated haplotype frequencies were also similar to those in control subjects. The estimated frequencies of haplotypes defined by −512C>T and +1548C>T were f(C-C) = 0.592, f(C-T) = 0.105, f(T-C) = 0.303, and f(T-T) = 0.000. The estimated frequencies of haplotypes defined by −512C>T and −350G>T were f(C-G) = 0.561, f(C-T) = 0.136, f(T-G) = 0.303, and f(T-T) = 0.000. The estimated frequencies of haplotypes defined by −350G>T and +1548C>T were f(G-C) = 0.759, f(G-T) = 0.105, f(T-C) = 0.136, and f(T-T) = 0.000. The estimated haplotype frequencies defined by the three SNPs were f(C-G-C) = 0.456, f(T-G-C) = 0.303, f(C-T-C) = 0.136, and f(C-G-T) = 0.105 (Table 5).

    We detected three frequent SNPs with >5% allele frequencies, namely g −512C>T, −350G>T, and +1548C>T. Linkage disequilibria were found between all three pairs of these SNPs. None of these three SNPs or the four common haplotypes defined by them were associated with type 2 diabetes, suggesting that it is unlikely that these SNPs of the FOXC2 gene have major effects on susceptibility to Japanese type 2 diabetes. It should be noted that a small effect of these polymorphisms on susceptibility cannot be excluded, since the sample size was limited in the present study.

    Our findings show that Japanese subjects had four major haplotypes determined by the three SNPs located in the region in linkage disequilibrium, namely, g. −512C>T, −350G>T, and +1548C>T. These three SNPs would be useful as haplotype tag SNPs in searching for an association with specific phenotypes in type 2 diabetes, especially in cases where a large number of samples are involved. Most recently, Gabriel et al. (8) reported that only three to five common haplotypes in each haplotype block, in which historical recombination is rare, generally capture 90% of the chromosomes. These common haplotypes represent potentially attractive markers for association studies.

    We identified six novel SNPs and a deletion, namely −512C>T, −350G>T, +898C>T, +907C>A, 1167_1169delCCA, +1251C>A, and +1548C>T in the FOXC2 gene. These have not been found in either the J-SNP (http://snp.ims.u-tokyo.ac.jp) or the NCBI databases (http://www.ncbi.nlm.nih.gov/). Of these, two SNPs, −512C>T and −350G>T, were found in the 5′ flanking region. When the sequences around these two SNPs were assessed using the TFSEARCH computer program (http//www.cbrc.jp/research/db/TFSEARCH.html), the results indicated that −350G>T might affect a putative binding site for MyoD, whereas no significant DNA elements were found around −512.

    Two missense mutations, +898C>T (Pro300Ser) and +907C>A (Leu303Met), and a deletion, 1167_1169delCCA(389delHis), in the coding region of the FOXC2 gene were found in the present study. Since these mutations were rare, a structural defect in this gene is not a major determinant of susceptibility to type 2 diabetes. Whether these mutations may affect type 2 diabetes susceptibility in a small number of subjects merits further investigation, especially including an analysis of their family members. In these mutations, the +907C>A (Leu303Met) is most promising since this missense mutation was found in 6 of 390 alleles in type 2 diabetic subjects, but in only 1 of 400 alleles in control subjects. Interestingly, mutations in the coding region of the FOXC2 gene are known to cause lymphoedema-distichiasis, an autosomal dominant form of primary lymphoedema with onset of lower-limb swelling at puberty or later. Small insertions or deletions and nonsense mutations in the coding region of this gene have been occasionally reported (9–11).

    In summary, we report here a systematic search for SNPs in the FOXC2 gene and the identification of three frequent SNPs in linkage disequilibrium, in addition to four major haplotypes defined by these SNPs. No association of these SNPs or haplotypes with type 2 diabetes was evident. The issue of how these SNPs affect FOXC2 gene expression in adipocytes and whether SNPs in this gene are associated with type 2 diabetes in other ethnic groups remains unclear. Further study will be required to clarify these points.

    RESEARCH DESIGN AND METHODS

    This study involved an initial screening of 24 unrelated type 2 diabetic outpatients from the Ehime University Hospital and the Ehime Prefectural Hospital. The subjects were selected based on the fact that they showed the typical characteristics of type 2 diabetes, such as age of onset between 40 and 60 years, treatment with diet alone or oral hypoglycemic agents, and the presence of first-degree relatives with type 2 diabetes. Diabetes was diagnosed based on the American Diabetes Association criteria as reported in 1998 (12). The entire FOXC2 gene was initially sequenced in these 24 diabetic patients. For the association study, the regions containing the SNPs identified were sequenced in 171 additional unrelated type 2 diabetic subjects and 200 nondiabetic subjects. The 200 nondiabetic control subjects did not have a history of diabetes or first-degree relatives with diabetes, and they had a normal glucose tolerance as evidenced by a 75-g oral glucose tolerance test. All patients and control subjects were informed of the purpose of the study and their consent was obtained. The study was approved by the ethics committee of the Ehime University Hospital and Ehime Prefectural Hospital. The clinical characteristics of the 195 type 2 diabetic subjects and the 200 control subjects are summarized in Table 1. The age of the control subjects was comparable to the age of onset of the type 2 diabetic subjects.

    PCR direct sequencing was performed as described previously with the following modifications (13,14). Genomic DNA was extracted from leukocytes using a DNA Isolation Kit for Mammalian Blood (Boehringer Mannheim, Indianapolis, IN). The 5′ flanking region and exon 1 of the FOXC2 gene were individually amplified using primers, as described in Tables 6 and 7. The 5′ flanking region was amplified using the Advantage GC genomic polymerase mix by following the manufacturer’s protocol (Clontech Laboratories, Palo Alto, CA). Genomic DNA (100 ng) was amplified in a 50-μl reaction mixture, which included 1 μl of Advantage GC polymerase mix, 10 pmol of each primer, and 10 nmol of each dNTP. After the first denaturing for 1 min at 95°C, PCR was carried out for 35 cycles with denaturing at 94°C for 30 s, annealing and extension at 68°C for 3 min, with a final extension period of 3 min. The coding region (exon 1) was amplified by touchdown PCR. Genomic DNA (50 ng) was amplified in a 25-μl reaction mixture, which included 0.625 units of thermus aquaticus (Taq) or EXTaq DNA polymerase (Takara Shuzo Biomedical Group, Shiga, Japan), 5 pmol of each primer, 5 nmol of each dNTP, and 5% DMSO. When this condition was not applicable, a PCR Optimizer kit (Invitrogen) was used. The PCR mixture was the same as above except for the buffers indicated in Table 2. After the first denaturing for 3 min at 94°C, the touchdown PCR was carried out for 15 cycles with denaturing at 94°C for 1 min, annealing at 65–51°C for 2 min by reducing 1°C each cycle, and extension at 72°C for 3 min. An additional 25 cycles were done with denaturing at 94°C for 1 min, annealing at 50°C for 2 min, and extension at 72°C for 3 min, with a final extension period of 7 min. The amplified PCR products were electrophoresed on a 1.5–2% agarose gel and then stained with Cyber Green I (BioWhittaker Molecular Application, Rockland, ME) to confirm the size of each molecule.

    These PCR products were sequenced using forward and/or reverse primers, after purification using a Multiscreen PCR filter (Millipore, Bedford, MA). The sequencing reaction was carried out using Taq Dye Deoxy and ABI Prism terminator cycle sequencing kits (PE Applied Biosystems, Foster City, CA). The products were then purified using an Autoseq G-50 column (Amersham Pharmacia Biotech, Piscataway, NJ). These products were then electrophoresed on an ABI Gene analyzer 3100 system (PE Applied Biosystems). Both strands of the entire FOXC2 gene were sequenced for the initial screening of the 24 type 2 diabetic subjects to detect any unknown SNPs. Sequences of plus strands where the identified SNPs were located were then checked for the association study, since these strands permit a more precise identification of these SNPs. The other strand was also sequenced, when required.

    The χ2 test was used for statistical analysis unless otherwise indicated. Haplotype frequencies between two and three SNPs were estimated based on the EH program (15), and the Arlequin program (16), respectively. The relative linkage disequilibrium value (D’) for two polymorphisms was defined as the ratio of the linkage disequilibrium parameter (D) to the possible maximum linkage disequilibrium parameter (17). To examine deviations from linkage equilibrium between the two polymorphisms, a χ2 test was performed as described by Imanishi et al. (18). The linkage disequilibrium among three SNPs was analyzed using the likelihood ratio test in EH program (15).

    View this table:
    • View inline
    • View popup
    TABLE 1

    Clinical features of the control and type 2 diabetic subjects

    View this table:
    • View inline
    • View popup
    TABLE 2

    Allele frequency of SNPs in the FOXC2 gene for control and type 2 diabetic subjects

    View this table:
    • View inline
    • View popup
    TABLE 3

    Genotype frequencies of each SNP with a >5% frequency in the FOXC2 gene for control and type 2 diabetic subjects

    View this table:
    • View inline
    • View popup
    TABLE 4

    Linkage disequilibrium between two of the three SNPs in the FOXC2 gene and haplotype frequencies in control subjects

    View this table:
    • View inline
    • View popup
    TABLE 5

    Estimated haplotype frequencies defined by the three frequent SNPs in the FOXC2 gene

    View this table:
    • View inline
    • View popup
    TABLE 6

    Primers used for PCR and sequencing of 5′ flanking region of the FOXC2 gene promoter

    View this table:
    • View inline
    • View popup
    TABLE 7

    Primers used for PCR and sequencing of the coding region of the FOX 2 gene

    Acknowledgments

    This work was mainly supported by a Grant-in-Aid for Scientific Research on Priority Areas “Medical Genome Science” (no. 12204007), and a Grant-in-Aid for Scientific Research (no. 14571097) from the Ministry of Education, Culture, Science, Sports and Technology of Japan. We thank F. Tanabe and M. Murase for technical assistance and suggestions.

    Footnotes

    • Address correspondence and reprint requests to Dr. H. Osawa, Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan. E-mail: harosawa{at}m.ehime-u.ac.jp.

      Received for publication 25 August 2002 and accepted in revised form 29 October 2002.

      BAT, brown adipose tissue; IRS-1, insulin receptor substrate-1; PPARγ, peroxisome proliferator-activated receptor γ; SNP, single nucleotide polymorphism; Taq, thermus aquaticus; UCP-1, uncoupling protein-1; WAT, white adipose tissue.

    • DIABETES

    REFERENCES

    1. ↵
      DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: a balanced overview. Diabetes Care15 :318 –368,1992
      OpenUrlAbstract/FREE Full Text
    2. ↵
      McCarthy MI, Hattersley AT: Molecular diagnostics in monogenic and multifactorial forms of type 2 diabetes. Expert Rev Mol Diagn1 :403 –412,2001
      OpenUrlCrossRefPubMed
    3. ↵
      McCarthy MI, Froguel P: Genetic approaches to the molecular understanding of type 2 diabetes. Am J Physiol Endocrinol Metab283 :E217 –E225,2002
      OpenUrlAbstract/FREE Full Text
    4. ↵
      Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet26 :163 –175,2000
      OpenUrlCrossRefPubMedWeb of Science
    5. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet26 :76 –80,2000
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Tomita M, Kimura S, Ito C, Froguel P, Kadowaki T: Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes51 :536 –540,2002
      OpenUrlAbstract/FREE Full Text
    7. ↵
      Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S: FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell106 :563 –573,2001
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science296 :2225 –2229,2002
      OpenUrlAbstract/FREE Full Text
    9. ↵
      Bell R, Brice G, Child AH, Murday VA, Mansour S, Sandy CJ, Collin JR, Brady AF, Callen DF, Burnand K, Mortimer P, Jeffery S: Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene. Hum Genet108 :546 –551,2001
      OpenUrlCrossRefPubMedWeb of Science
    10. Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet67 :1382 –1388,2000
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      Finegold DN, Kimak MA, Lawrence EC, Levinson KL, Cherniske EM, Pober BR, Dunlap JW, Ferrell RE: Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet10 :1185 –1189,2001
      OpenUrlAbstract/FREE Full Text
    12. ↵
      The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care23 (Suppl. 1) :S4 –S19,2000
    13. ↵
      Osawa H, Onuma H, Murakami A, Ochi M, Nishimiya T, Kato K, Shimizu I, Fujii Y, Ohashi J, Makino H: Systematic search for single nucleotide polymorphisms in the insulin gene: evidence for a high frequency of −23T>A in Japanese subjects. Biochem Biophys Res Commun286 :451 –455,2001
      OpenUrlPubMed
    14. ↵
      Osawa H, Onuma H, Murakami A, Ochi M, Nishimiya T, Kato K, Shimizu I, Fujii Y, Ohashi J, Makino H: Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes. Diabetes51 :863 –866,2002
      OpenUrlAbstract/FREE Full Text
    15. ↵
      Terwillinger J, Otto J: Handbook of Human Linkage Analysis. Baltimore, MD, Johns Hopkins University Press,1994
    16. ↵
      Schneider S, Roessli D, Excoffier L: Arlequin Ver: 2000: A Software for Population Genetics Data Analysis. Geneva, Genetics and Biometry Laboratory, University of Geneva,2000
    17. ↵
      Lewontin R: The interaction of selection and linkage. I. General considerations, heterotic models. Genetics49 :49 –67,1964
      OpenUrlFREE Full Text
    18. ↵
      Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojobori T: Estimation of allele and haplotype frequencies for HLA and complement loci. In HLA 1991. Tsuji K, Aizawa M, Sasazuki T, Eds. Oxford, U.K., Oxford University Press,1992 , p.76 –79
    PreviousNext
    Back to top

    In this Issue

    February 2003, 52(2)
    • Table of Contents
    • Index by Author
    Sign up to receive current issue alerts
    View Selected Citations (0)
    Print
    Download PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for your interest in spreading the word about Diabetes.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene
    (Your Name) has forwarded a page to you from Diabetes
    (Your Name) thought you would like to see this page from the Diabetes web site.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Citation Tools
    Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene
    Haruhiko Osawa, Hiroshi Onuma, Akiko Murakami, Masaaki Ochi, Tatsuya Nishimiya, Kenichi Kato, Ikki Shimizu, Yasuhisa Fujii, Jun Ohashi, Hideichi Makino
    Diabetes Feb 2003, 52 (2) 562-567; DOI: 10.2337/diabetes.52.2.562

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Add to Selected Citations
    Share

    Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene
    Haruhiko Osawa, Hiroshi Onuma, Akiko Murakami, Masaaki Ochi, Tatsuya Nishimiya, Kenichi Kato, Ikki Shimizu, Yasuhisa Fujii, Jun Ohashi, Hideichi Makino
    Diabetes Feb 2003, 52 (2) 562-567; DOI: 10.2337/diabetes.52.2.562
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Abstract
      • RESEARCH DESIGN AND METHODS
      • Acknowledgments
      • Footnotes
      • REFERENCES
    • Figures & Tables
    • Info & Metrics
    • PDF

    Related Articles

    Cited By...

    More in this TOC Section

    • The Krüppel-Like Factor 11 (KLF11) Q62R Polymorphism Is Not Associated With Type 2 Diabetes in 8,676 People
    • CHRM3 Gene Variation Is Associated With Decreased Acute Insulin Secretion and Increased Risk for Early-Onset Type 2 Diabetes in Pima Indians
    • Polymorphism in the Transcription Factor 7-Like 2 (TCF7L2) Gene Is Associated With Reduced Insulin Secretion in Nondiabetic Women
    Show more Brief Genetics Reports

    Similar Articles

    Navigate

    • Current Issue
    • Online Ahead of Print
    • Scientific Sessions Abstracts
    • Collections
    • Archives
    • Submit
    • Subscribe
    • Email Alerts
    • RSS Feeds

    More Information

    • About the Journal
    • Instructions for Authors
    • Journal Policies
    • Reprints and Permissions
    • Advertising
    • Privacy Policy: ADA Journals
    • Copyright Notice/Public Access Policy
    • Contact Us

    Other ADA Resources

    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • Scientific Sessions Abstracts
    • Standards of Medical Care in Diabetes
    • BMJ Open - Diabetes Research & Care
    • Professional Books
    • Diabetes Forecast

     

    • DiabetesJournals.org
    • Diabetes Core Update
    • ADA's DiabetesPro
    • ADA Member Directory
    • Diabetes.org

    © 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.