Linkage Analysis of Glucokinase Gene With NIDDM in Caucasian Pedigrees

Cook, J. T. E.; Hattersley, Andrew T.; Christopher, P.; Bown, E.; Barrow, B A; Patel, P.; Shaw, J. A. G.; Cookson, W. O. C. M.; Permutt, M. A.; Turner, R. Elaine

doi:10.2337/diab.41.11.1496

Cited by 32 publications

(14 citation statements)

References 20 publications

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“…Because of uncertainty as to the mode of inheritance, we have tested for linkage with type II diabetes in nuclear families under different model assumptions with the use of moderately low penetrance parameters (19). Pedigrees in which a negative LOD score is found, usually because of obligate recombinants, can be excluded from additional study.…”

Section: Discussionmentioning

confidence: 99%

Availability of Type II Diabetic Families for Detection of Diabetes Susceptibility Genes

Cook

Page²,

O'Rahilly³

et al. 1993

Diabetes

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Type II diabetes is a familial disorder, as evidenced by the increased prevalence in monozygotic cotwins and first-degree relatives of affected subjects; however, its genetic etiology is largely unknown. Well-characterized pedigrees are an essential resource for the study of susceptibility genes for type II diabetes. This study describes a 5-yr search for type II diabetic families in Oxfordshire, U.K. We interviewed 950 type II diabetic subjects concerning the availability of first-degree relatives; 127 Caucasian families ascertained through a proband with type II diabetes were studied, and 589 first-degree relatives were characterized. Three large pedigrees with maturity-onset diabetes of the young, and 8 multiplex multigenerational type II diabetic pedigrees were identified. We identified 12 sib-pairs in which both siblings had type II diabetes; however, only 7 sib-pairs had both parents alive, and 2 of these had both parents affected. If one also considers one sib having diabetes and one sib having glucose intolerance as being an affected sib-pair, we identified 30 sib-pairs of which 7 had both parents affected and probably had bilineal inheritance. We identified 76 complete nuclear families with both parents and offspring available for study, but only 6 were of optimal structure for linkage analysis. In conclusion, multiplex pedigrees and type II diabetic sib-pairs with living parents are uncommon, and their ascertainment requires a substantial investment of resources. Large-scale collaborative multicenter initiatives would be needed to collect a large resource of family material for the study of susceptibility genes for type II diabetes.

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Section: Discussionmentioning

confidence: 99%

Availability of Type II Diabetic Families for Detection of Diabetes Susceptibility Genes

Cook

Page²,

O'Rahilly³

et al. 1993

Diabetes

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“…The present study indicates that a dominant model is most applicable, but the possibility of a polygenic component implies that linkage analysis could model more than one locus; when a single locus model is used, lower penetrance parameters should be included [45,46]. The best fit model with COMDS gave a susceptibility gene frequency 7.4 % and the penetrance factors derived in this study may be applied to future linkage analysis.…”

Section: Discussionmentioning

confidence: 99%

“…In any case, the premature disease mortality and late-onset of this disease means that suitable pedigrees with one affected and one unaffected parent are unusual [47]. Thus, linkage analysis is most appropriate in pedigrees with specific monogenic disorders such as MODY [48,49] although it can be useful in excluding a major dominant gene effects in a series of NIDDM nuclear families [46]. If sufficient numbers of pedigrees are being studied, the two-locus model could be applied, although combined segregation and linkage analysis of plasma glucose levels and diabetes with candidate genes in a given data set is an alternative approach [38].…”

Section: Discussionmentioning

confidence: 99%

Segregation analysis of NIDDM in Caucasian families

et al. 1994

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Summary Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypotheses, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4 %. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity. [Diabetologia (1994[Diabetologia ( ) 37: 1231[Diabetologia ( -1240 Key words Non-insulin-dependent diabetes mellitus, genetic epidemiology, genetic linkage.Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder with considerable morbidity and mortality. Despite evidence for a substantial genetic component, the mode of inheritance and the molecular basis of this inheritance remain un-

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“…Froguel et al (45) found no evidence of linkage or evidence for mutations in 21 French NIDDM families. Both Cook et al (47) and our laboratory (48) failed to find linkage in Northern European families, and Janssen et al (42) reported no linkage in Pima Indians. Although Chiu et al suggested that glucokinase mutations were important in American blacks based on an association study (49), screening of this population did not identify important mutations (50).…”

Section: Glucokinase (Mody-2)mentioning

confidence: 92%