Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.

Abstract

The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.

Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin

“…European parent-offspring trios (n = 150) were ascertained through probands with a clinical diagnosis of Type II diabetes and two living parents [35]. The principal ascertainment criteria were: Age at diagnosis is given as medians (range), BMI as geometric means (SD range), and WHR as means (SD).…”

“…The principal ascertainment criteria were: Age at diagnosis is given as medians (range), BMI as geometric means (SD range), and WHR as means (SD). a in the urban survey, this refers to the age at study (1) probands with a diagnosis of Type II diabetes after age 25; (2) four grandparents of European origin; (3) exclusion of Type I (insulin-dependent) diabetes, maturity-onset diabetes of the young (MODY) and mitochondrial diabetes by personal and family history, GAD-antibody measurements and genetic screens for MODY and the mt3243 mutation [35]. Clinical details on probands are given in Table 1 .…”

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

“…In the first case-control analysis, we compared unrelated type 2 diabetes probands (n=565) from the Diabetes UK Warren 2 sibpair repository (Warren 2 probands; W2P) [16] with 347 random UK population control samples from the European Collection of Cell Cultures (ECACC; Salisbury, UK). For the second comparison, the case sample combines two sets of young-onset type 2 diabetes subjects (YT2D, n=293) with almost identical clinical characteristics: (1) offspring from parent-offspring trios (n=157) ascertained for type 2 diabetes [17]; and (2) young onset Continuous data are means (SD) a Age information was available for only 34% of subjects in this group b BMI in females was measured during pregnancy: meaningful measures of WHR not available (<45 years) type 2 diabetes subjects (n=136) [18]. These cases were compared with 910 unrelated parents from a consecutive birth cohort (the Exeter Family Study; EFS), 825 of whom were normoglycaemic [18].…”

“…All case samples are, therefore, strongly selected for inherited type 2 diabetes on the basis of early disease onset and/or positive family history. Other types of diabetes were excluded using a combination of clinical, immunological and genetic criteria, as previously described [16,17]. Given the position of TNF within the MHC (and the potential for linkage disequilibrium [LD] with HLA alleles implicated in islet autoimmunity), it is important to note that we excluded autoimmune diabetes in all cases through standard clinical criteria (including an age of disease onset above 25, insulin independence following diagnosis, no ketoacidosis, no close family history of type 1 diabetes) combined with GAD antibody typing [16,17].…”

Human calcium/calmodulin-dependent protein kinase II gamma gene (CAMK2G): cloning, genomic structure and detection of variants in subjects with Type II diabetes

“…These SNPs are not likely to be pathogenic and can only be used to assess other pathogenic non-coding variants that are in linkage disequilibrium. Both variants have allele frequencies greater than 10 % which makes them suitable for large scale family±based association studies to determine the role of CAMK2G in the susceptibility to Type II diabetes [11].…”