Summary
Though a genetic basis for non-insulin-dependent diabetes mellitus (NIDDM) is clear, the likely mode of inheritance is not known. The segregation of NIDDM was studied in 64 nuclear South Indian pedigrees (449 individuals) ascertained through an affected proband having both parents and more than 1 sibling alive and available for oral glucose tolerance testing. A high proportion of parents were found to be of abnormal glucose tolerance [89 of 128 (70%) diabetic and 11 of 128 (9%) impaired]. Complex segregation analysis was performed using (1) POINTER which implements the mixed model and distinguishes major gene, multifactorial and nontransmitted environmental contributions to affection and (2) COMDS which implements an oligogenic model with major gene, modifier gene and environmental contributions to a) affection and b) diathesis (an ordered polychotomy amongst non-affected family members, based on 2-h plasma glucose level). Using POINTER, there was no formal support for a major gene and the most parsimonious solutions were achieved with multifactorial models. Using COMDS, we found i) significant improvements in models when information on glucose levels in non-diabetic family members (diathesis) was included, ii) support for segregation of a diallelic gene as well as background familial resemblance, and iii) under the best-supported model, this diallelic locus featured incomplete dominance (d=0.8) and a disease-predisposing allele frequency of 14%. In South Indians, segregation of NIDDM is inadequately described by simple major gene models: more complex models provide more satisfactory descriptions. This finding, if applicable in other populations, has important implications for the search for diabetes-susceptibility genes.
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Abbreviations
- MODY:
-
maturity onset diabetes of the young
- DRC-MVH:
-
Diabetes Research Centre-MV Hospital for Diabetes
- OGTT:
-
oral glucose tolerance test
- AIC:
-
Akaike Information Content
- IGT:
-
impaired glucose tolerance
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- IDDM:
-
insulin-dependent diabetes mellitus
References
McCarthy MI, Hitman GA (1993) The genetic aspects of non-insulin-dependent diabetes mellitus. In: Leslie RDG (ed) The causes of diabetes. Wiley, London, pp157–183
Raper LR, Taylor R, Zimmet P, Milne B, Baikau B (1984) Bimodality in glucose tolerance distributions in the urban Polynesian population of Western Samoa. Diabetes Research 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
Zimmet, P, Whitehouse S (1978) Bimodality of fasting and two-hour glucose tolerance distributions in a Micronesian population. Diabetes 27:793–800
Fajans S (1990) Scope and heterogeneous nature of MODY. Diabetes Care 13:49–64
Bell GI, Xiang K-S, Newman MV et al. (1991) Gene for non-insulin-dependent diabetes mellitus (maturity onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20 q. Proc Natl Acad Sci USA 88:1484–1488
Hattersley AT, Turner RC, Permutt MA et al. (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339:1307–1310
Froguel Ph, Vaxillaire M, Sun F et al. (1992) Close linkage of glucokinase locus on chromosome 7 p to early-onset non-insulin-dependent diabetes mellitus. Nature 356:162–165
Simpson NE (1964) Multifactorial inheritance. A possible hypothesis for diabetes. Diabetes 13:462–471
Cooke AM, Fitzgerald MG, Malins JM, Pyke DA (1966) Diabetes in children of diabetic couples. BMJ 2:674–676
Kahn CB, Soeldner JS, Gleason RE, Rojas L, Camerini-Davalos RA, Marble A (1969) Clinical and chemical diabetes in offspring of diabetic couples. New Engl J Med 281:343–347
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
Tattersall RB, Fajans SS (1975) Prevalence of diabetes and glucose intolerance in 199 offspring of thirty-seven conjugal diabetic parents. Diabetes 24:452–462
Rich SS (1990) Mapping genes in diabetes: genetic epidemiological perspective. Diabetes 39:1315–1319
O'Rahilly S, Turner R (1988) Early onset type 2 diabetes vs maturity onset diabetes of youth: evidence for the existence of two distinct diabetic syndromes. Diabet Med 5:224–229
Thompson GS (1965) Genetic factors in diabetes mellitus studied by the oral glucose tolerance test. J Med Genet 2:221–226
Cook JTE, Hattersley AT, Levy JC et al. (1993) Distribution of type II diabetes in nuclear families. Diabetes 42:106–113
Clerget-Darpoux F, BonaÏti-Pellié C (1992) Strategies based on marker information for the study of human diseases. Ann Hum Genet 56:145–153
Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31:312–321
Morton NE, Rao DC, Lalouel J-M (1983) Methods in genetic epidemiology. Karger, Basel
Morton NE, MacLean CJ (1974) Analysis of family resemblance III. Complex segregation of quantitative traits. Am J Hum Genet 26:489–503
Lalouel JM, Rao DC, Morton NE, Elston RC (1983) A unified model for complex segregation analysis. Am J Hum Genet 35:816–826
MacLean CJ, Morton NE, Yee S (1984) Combined analysis of genetic segregation and linkage under an oligogenic model. Comput Biomed Res 17:471–480
Morton NE, Shields DC, Collins A (1991) Genetic epidemiology of complex phenotypes. Ann Hum Genet 55: 301–314
Mohan V, Ramachandran A, Viswanathan M (1988) Diabetes in the tropics. In: Alberti KGMM, Krall LP (eds) Diabetes annual 4. Elsevier Science Publishers, Amsterdam pp 46–55
Kambo P, Hitman G, Mohan V et al. (1989) The genetic predisposition to fibrocalculous pancreatic diabetes. Diabetologia 32:45–51
World Health Organisation Study Group (1985) Diabetes mellitus. WHO Tech Rep Ser, no 727
Polymeropoulos MH, Xiao H, Rath DS, Merril CR (1991) Tetranucleotide repeat polymorphism at the human tyrosine hydroxylase gene (TH). Nucleic Acids Res 19: 3753
Matsutani A, Janssen R, Donis-Keller H, Permutt MA (1992) A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7 p. 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
Akaike H (1987) Factor analysis and AIC. Psychometrika 52:317–332
Morton NE, Chung CS (1959) Formal genetics of muscular dystrophy. Am J Hum Genet 11:360–379
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
Morton NE (1982) Outline of genetic epidemiology. Karger, Basel
Ramachandran A, Mohan V, Snehalatha C, Viswanathan M (1988) Prevalence of non-insulin-dependent diabetes mellitus in Asian Indian families with a single diabetic parent. Diabetes Res Clin Pract 4:241–245
Vieland VJ, Hodge SE, Greenberg DA (1992) Adequacy of single-locus approximations for linkage analyses of oligogenic traits. Genet Epidemiol 9:45–59
Ott J (1990) Cutting a Gordian knot in the linkage analysis of complex human traits. Am J Hum Genet 46:219–221
O'Rahilly S, Wainscoat JS, Turner RC (1988) Type 2 (non-insulin-dependent) diabetes mellitus: new genetics for old nightmares. Diabetologia 31:407–414
Devi AR, Rao NA, Bittles AH (1988) Consanguinity, fecundity and post-natal mortality in Karnataka, South India. Ann Hum Biol 8:469–472
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
Köbberling J, Tillil H (1982) Empirical risk figures for first degree relatives of non-insulin-dependent diabetics. In: Köbberling J, Tattersall R (eds) The genetics of diabetes mellitus. Academic Press London, pp 201–209
Steinberg AG, Rushforth NB, Bennett PH, Burch TA, Miller M (1970) On the genetics of diabetes. Nobel Symposium 13:237–264
Omar MAK, Seedat MA, Dyer RB, Motala AA, Knight LT, Becker PJ (1994) South African Indians show a high prevalence of NIDDM and bimodality in plasms glucose distribution pattern. Diabetes Care 17:70–73
Yamashita T, Mackay W, Rushforth N, Bennett P, Houser H (1984) Pedigree analyses of non-insulin dependent diabetes mellitus (NIDDM) in the Pima Indians suggest dominant mode of inheritance. Am J Hum Genet 36 [Suppl]:183S (Abstract)
Serjeantson SW, Zimmet P (1991) Genetics of non-insulin dependent diabetes mellitus in 1990. Baillieres Clin Endocrinol Metabol 5:477–493
Mimura G, Oshiro S, Koganemaru K, Haraguchi T, Hashihuchi J (1964) Studies on the heredity of diabetes mellitus in Japan II. Inheritance of the fasting blood sugar value and the blood sugar value two hours after meal in Uto and Tomiai inhabitants. Kumamoto Med J 17:50–57
Williams WR, Morton NE, Rao DC, Gulbrandsen CL, Rhoads GG, Kagan G (1983) Family resemblance for fasting blood glucose in a population of Japanese Americans. Clinical Genetics 23:287–293
Rice T, Laskarzewski PM, Rao DC (1992) Commingling and complex segregation analysis of fasting plasma glucose in the Lipid Research Clinics Family Study. Am J Med Genet 44:399–404
Laskarzewski PM, Rao DC, Glueck CJ (1984) The Cincinnati Lipid Research Clinic Family Study: analysis of commingling and family resemblance for fasting blood glucose. Genet Epidemiol 1:341–355
Boehnke M, Moll PP, Kottke BA, Weidman WH (1987) Partitioning the variance of fasting plasma glucose levels in pedigrees. Am J Epidemiol 125:679–689
Friedlander Y, Kark JD, Bar-On H (1987) Family resemblance for fasting blood glucose: the Jerusalem Lipid Research Clinic. Clinical Genetics 32:222–234
King H, Rao DC, Bhatia K, Koki G, Collins A, Zimmet P (1989) Family resemblance for glucose tolerance in a Melanesian population, the Tolai. Hum Hered 39:212–217
Stunkard AJ, Harris JR, Pedersen NL, McClearn GE (1990) The body-mass index of twins who have been reared apart. New Engl J Med 322:1483–1487
Cahill GF (1988) Beta-cell deficiency, insulin resistance or both? New Engl J Med 318:1268–1270
Schumacher MC, Hasstedt SJ, Hunt SC, Williams RR, Elbein SC (1992) Major gene effect for insulin levels in familial NIDDM pedigrees. Diabetes 41:416–423
Lillioja S, Mott D, Zawadzki JK et al. (1987) In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes 36:1329–1335
Rossetti L, Giaccori A, De Fronzo RA (1990) Glucose toxicity. Diabetes Care 13:610–630
Ott J (1991) Analysis of human genetic linkage. Revised edn. Johns Hopkins University Press, Baltimore
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
Clerget-Darpoux F, BonaÏti-Pellié C (1993) An exclusion map covering the whole genome: a new challenge for genetic epidemiologists? Am J Hum Genet 52:442–443 (Letter)
Greenberg DA (1993) Linkage analysis of “necessary” disease loci versus “susceptibility” loci. Am J Hum Genet 52:135–143
Weeks DE, Lange K (1988) The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42:315–326
Risch N (1984) Segregation analysis incorporating linkage markers. I. single-locus models with an application to type 1 diabetes. Am J Hum Genet 36:363–386
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McCarthy, M.I., Hitman, G.A., Shields, D.C. et al. Family studies of non-insulin-dependent diabetes mellitus in South Indians. Diabetologia 37, 1221–1230 (1994). https://doi.org/10.1007/BF00399796
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DOI: https://doi.org/10.1007/BF00399796