Mutation of the glucagon receptor gene and diabetes mellitus in the UK: association or founder effect?

Abstract

Recent evidence suggests that a mutation of the glucagon receptor (GCG-R) gene is involved in the development of type 2 diabetes in French patients. We have examined patients from three geographically distinct regions in the UK and found the GGT40 (Gly) to AGT40 (Ser) mutation to be present in 15/691 (2.2%) of patients with type 2 (non-insulin dependent) diabetes and 1/425 (0.2%) of geographically matched controls and have therefore replicated association of the GCG-R mutation with classical type 2 diabetes (Fisher's exact test p = 0.008). An increased frequency of the mutation of the GCG-R gene was also found in probands of type 1 (insulin dependent) diabetic multiplex (affected sib pair) families, (10/404, 2.5%). However, a lack of preferential transmission from parents heterozygous for the mutation, to affected type 1 diabetic sibs may suggest population stratification. This in turn cannot be excluded as an alternative explanation for the difference in frequency of the GCG-R gene mutation between subjects with type 2 diabetes and normal controls.

Analysis of Gly40Ser polymorphism of the glucagon receptor (GCGR) gene in different ethnic groups

“…These figures are compatible with those reported in other studies on white populations in Europe [5][6][7][8]10,12,13 and elsewhere. 14 Conversely, our study reveals that the Gly40Ser variant of the GCGR was absent in a sample of adult men and women of black African origin and very rare in a comparable sample of South Asian men and women.…”

“…10 This polymorphism is also associated with central adiposity independent from total body mass in white men, 11 suggesting that it might play a role in the metabolic syndrome in white populations. The frequency of this variant ranges from 2 to 8% in French, 7 British, 6 Italian 8 and Australian 9 white populations, whereas it was very rare in studies in Finnish, 12 German 13 and Brazilian 14 and absent in German, 15 Japanese 16,17 and Chinese 18 populations. Given that hypertension, diabetes and the metabolic syndrome are more prevalent in South Asians and in people of black African origin, it is of interest to establish the frequency of this polymorphism in such populations and to assess its potential role.…”

“…A polymorphic variant of the glucagon-receptor (GCGR) gene has been associated with Type 2 diabetes in various white European populations 5,6 and with hypertension in both European whites 7,8 and Australians. 9 The Gly40Ser variant results in a missense mutation at codon 40 in exon 2 of the GCGR gene leading to the substitution of a serine for a glycine amino-acid residue in the encoded protein.…”

The different approaches to the genetic analysis of autoimmune thyroid disease

“…Moreover, it is almost impossible to obtain perfectly matched diseased and normal control populations. False positives arising from population stratification (Gough et al 1995) are also more likely to occur in small data sets. As we shall see later in this review, the major problem of population stratification can be overcome by using family-based association studies.…”

“…Finally, the populationbased case-control study is more sensitive than some of the family-based studies and is more likely to detect genes of modest effect. However, the problem of population stratification can be significant (Gough et al 1995) and it is difficult to ascertain if association is due to linkage disequilibrium or the result of population stratification. The trend, therefore, in the genetic analysis of autoimmune thyroid disease, is towards the use of family-based data sets.…”