Summary
Mutations of the glucokinase gene have been implicated in the development of glucose intolerance in pedigrees with maturity-onset diabetes of the young. However, the contribution of the glucokinase gene to the aetiology of common Type 2 (non-insulin-dependent) diabetes mellitus is uncertain. We have studied the role of the glucokinase gene in the pathogenesis of Type 2 diabetes in South Indians, using both population-association and linkage methodology. A pair of CA-repeat sequences (GCK(3′) and GCK(5′)) straddling the glucokinase gene were employed as markers, each subject being typed using the polymerase chain reaction and polyacrylamide gel electrophoresis. Comparisons of allele frequencies at these markers were made between 168 Type 2 diabetic subjects and 70 racially-matched control subjects. No differences in allele frequencies were apparent at the GCK(5′) marker; however, there were significant differences in allele frequencies at the GCK(3′) marker between the Type 2 diabetic subjects and control subjects (χ 2=11.6, df=3, p=0.009) with an increase of the z allele (78.0% vs 66.4%) and a decrease of the z+2 allele (13.7% vs 25.0%) amongst the diabetic subjects. Linkage between glucose intolerance and the glucokinase gene was studied in 53 nuclear pedigrees under a variety of genetic models. Linkage was excluded (lod score <−2) at a recombination fraction of zero under five of the ten models used and highly unlikely (−2 < lod score <−1) under the others. The combination of positive association and negative linkage suggests that glucokinase acts as a minor gene influencing the development of Type 2 diabetes within this population.
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Hitman GA, McCarthy MI (1991) Genetics of non-insulin dependent diabetes mellitus. Bailliere Clin Endocrinol Metab 5: 455–476
Serjeantson SW, Zimmet P (1991) Genetics of non-insulin dependent diabetes mellitus in 1990. Bailliere Clin Endocrinol Metab 5: 477–493
Elston RC, Namboodiri KK, Nino HV, Pollitzer WS (1974) Studies on blood and urine glucose in Seminole Indians: indications for segregation of a major gene. Am J Hum Genet 26: 13–34
Zimmet P, Whitehouse S (1978) Bimodality of fasting and two-hour glucose tolerance distributions in a Micronesian population. Diabetes 27: 793–800
Raper LR, Taylor R, Zimmet P, Milne B, Balkau B (1984) Bimodality in glucose tolerance distributions in the urban Polynesian population of Western Samoa. Diabetes Res 1: 19–26
Rushforth NB, Bennett PH, Steinberg AG, Burch TA, Miller M (1971) Diabetes in the Pima Indians. Evidence of bimodality in glucose tolerance distributions. Diabetes 20: 756–765
Turner R, O'Rahilly S, Levy J, Rudenski A, Clark A (1989) Does type II diabetes arise from a major gene defect producing insulin resistance or β-cell dysfunction? In: Nerup J, Mandrup-Poulsen T, Hökfelt B (eds) Genes and gene products in the development of diabetes mellitus. Elsevier, Amsterdam, pp 171–183
Magnuson MA (1990) Glucokinase gene structure: functional implications of molecular genetic studies. Diabetes 39: 523–527
Matschinsky FM (1990) Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes 39: 647–652
Froguel Ph, Vaxillaire M, Sun F et al. (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356: 162–165
Hattersley AT, Turner RC, Permutt MA et al. (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339: 1307–1310
Vionnet M, Stoffel M, Takeda J et al. (1992) Nonsense mutation in the glucokinase gene causes early-onset non insulin-dependent diabetes mellitus. Nature 356: 721–723
Stoffel M, Patel P, Lo YMD et al. (1992) Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nature Genetics 2: 153–156
Vionnet N, Stoffel M, Takeda J et al. (1992) Mutations in glucokinase gene cause early onset type 2 diabetes. Diabetologia 35 [Suppl 1]: A62 (Abstract)
Permutt MA, Chiu KC, Tanizawa Y (1992) Glucokinase and NIDDM: a candidate gene that paid off. Diabetes 41: 1367–1372
Froguel Ph, Vionnet N, Stoffel M et al. (1992) Different pheno-typic expression by three mutant alleles of glucokinase gene in MODY. Diabetologia 35 [Suppl 1]: A63 (Abstract)
Velho G, Froguel Ph, Clement K et al. (1992) Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 340: 444–448
Page RCL, Hattersley A, Turner R (1992) Beta-cell secretory defect caused by mutations in the glucokinase gene. Lancet 340: 1162 (Letter)
Page RCL, Hattersley AT, Barrow B et al. (1992) Clinical characteristics of type 2 diabetes linked to the glucokinase gene. Diabetologia 35 [Suppl 1]: A62 (Abstract)
Chiu KC, Province MA, Dowse GK et al. (1992) A genetic marker at the glucokinase gene locus for Type 2 (non-insulin-dependent) diabetes mellitus in Mauritian Creoles. Diabetologia 35: 632–638
Chiu KC, Province MA, Permutt MA (1992) Glucokinase gene is genetic marker for NIDDM in American Blacks. Diabetes 41: 843–849
Saker PJ, Hattersley AT, Patel P et al. (1992) The contribution of glucokinase to type 2 (non-insulin-dependent) diabetes — a population association study. Diabetologia 35 [Suppl 1]: A139 (Abstract)
Cook JTE, Hattersley AT, Christopher P et al. (1992) Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees. Diabetes 41: 1496–1500
Ramachandran A, Jali MV, Mohan V, Snehalatha C, Viswanathan M (1988) High prevalence of diabetes in an urban population in south India. BMJ 297: 587–589
Ramachandran A, Snehalatha C, Dharmaraj D, Viswanathan M (1992) Prevalence of glucose intolerance in Asian Indians — urban-rural difference and significance of upper body adiposity. Diabetes Care 15: 1348–1355
Viswanathan M, Mohan V, Snehalatha C, Ramachandran A (1985) High prevalence of Type 2 (non-insulin-dependent) diabetes among the offspring of conjugal type 2 diabetic parents in India. Diabetologia 28: 907–910
Snehalatha C, Mohan V, Ramachandran A, Jayashree R, Viswanathan M (1984) Pancreatic beta cell function in offspring of conjugal diabetic parents. Assessment by IRI and C-peptide ratio. Horm Metab Res 16 [Suppl]: 142–144
Hitman GA, Karir PK, Sachs JA et al. (1988) HLA-D region RFLPs indicate that susceptibility to insulin-dependent diabetes mellitus in south India is located in the HLA-DQ region. Diabetic Med 5: 57–60
World Health Organisation Study Group (1985) Diabetes Mellitus. WHO Tech Rep Ser, no 727, Geneva
Balnaves ME, Nasioulas S, Dahl HHM, Forrest S (1991) Direct PCR from CVS and blood lysates for detection of cystic fibrosis and Duchenne muscular dystrophy deletions. Nucleic Acids Res 19: 1155
Matsutani A, Janssen R, Donis-Keller H, Permutt MA (1992) A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p. Genomics 12: 319–325
Nishi S, Stoffel M, Xiang K, Shows TB, Bell GI, Takeda J (1992) Human pancreatic beta-cell glucokinase: cDNA sequence and localization of the polymorphic gene to chromosome 7, band p 13. Diabetologia 35: 743–747
Tanizawa Y, Matsutani A, Chiu KC, Permutt MA (1992) Human glucokinase gene: isolation, structural characterization, and identification of a microsatellite repeat polymorphism. Mol Endocrinol 6: 1070–1081
Norusis MJ (1990) SPSS/PC + advanced statistics 4.0. SPSS Inc. USA, pp B137–B158
Lathrop GM, Lalouel JM (1984) Easy calculation of lod score and genetic risk on small computers. Am J Hum Genet 36: 460–465
Morton NE, Shields DC, Collins A (1991) Genetic epidemiology of complex phenotypes. Ann Hum Genet 55: 301–314
Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31: 312–321
Ott J (1991) Analysis of human genetic linkage (revised edition). Johns Hopkins University Press, Baltimore
Martinez MM, Goldin LR (1989) The detection of linkage and heterogeneity in nuclear families for complex disorders: one versus two marker loci. Am J Hum Genet 44: 552–559
Ploughman LM, Boehnke M (1989) Estimating the power of a proposed linkage study for a complex genetic trait. Am J Hum Genet 44: 543–551
Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain A (1988) Reconstruction of human evolution: bringing together genetic, archeological and linguistic data. Proc Natl Acad Sci USA 85: 6002–6006
Dowse GK, Gareeboo H, Zimmet PZ et al. (1990) High prevalence of NIDDM and impaired glucose tolerance in Indian, Creole and Chinese Mauritians. Diabetes 39: 390–396
Cox NJ, Bell GI (1989) Disease associations: chance, artifact or susceptibility genes? Diabetes 38: 947–950
Lathrop GM (1989) The power of linkage studies of Mendelian and multifactorial genetic disease in man. In: Nerup J, Mandrup-Poulsen T, Hökfelt B (eds) Genes and gene products in the development of diabetes mellitus. Elsevier, Amsterdam pp 373–379
Gershon ES, Martinez M, Goldin LR, Gejman PV (1990) Genetic mapping of common diseases: the challenges of manicdepressive illness and schizophrenia. Trends Genet 6: 282–287
Greenberg DA (1993) Linkage analysis of “necessary” disease loci versus “susceptibility” loci. Am J Hum Genet 52: 135–143
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879
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McCarthy, M.I., Hitchins, M., Hitman, G.A. et al. Positive association in the absence of linkage suggests a minor role for the glucokinase gene in the pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus amongst South Indians. Diabetologia 36, 633–641 (1993). https://doi.org/10.1007/BF00404073
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DOI: https://doi.org/10.1007/BF00404073