ABSTRACT
Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8.
Subject(s)
Chromosomes, Human, Pair 6 , Diabetes Mellitus, Type 1/genetics , Genetic Linkage , HLA Antigens/genetics , Major Histocompatibility Complex , Adult , Age of Onset , Female , Genetic Predisposition to Disease , Humans , Male , Microsatellite Repeats , Sex CharacteristicsABSTRACT
Loci in the major histocompatibility complex (MHC) on chromosome 6 and the insulin (INS) region on chromosome 11 have been implicated in susceptibility to insulin-dependent diabetes mellitus (IDDM) through candidate gene investigations, but they may account for less than 50% of genetic risk for the disease. Genome-wide linkage studies have led to localization of more than 10 susceptibility loci for insulin-dependent diabetes in the non-obese diabetic (NOD) mouse and the BB rat. Similar studies are now possible in humans through the development of dense genetic maps of highly informative microsatellite loci obtained using polymerase chain reaction analysis. We have applied microsatellite markers from recent Généthon maps, and other highly informative markers, in a genome-wide linkage study in IDDM. Here we report evidence for the localization of a previously undetected susceptibility locus for IDDM in the region of the FGF3 gene on chromosome 11q. Our results shows the potential of genome-wide linkage studies to detect susceptibility loci in IDDM and other multifactorial disorders.
Subject(s)
Chromosomes, Human, Pair 11 , Diabetes Mellitus, Type 1/genetics , Chromosome Mapping , Chromosomes, Human, Pair 8 , Genetic Linkage , Genetic Markers , Genetic Predisposition to Disease , Humans , Major Histocompatibility ComplexABSTRACT
A critical analysis of the evolution during the first 24 hours was undertaken in 41 children and adolescents (age: 10.1 +/- 4.6 years) treated for diabetic ketoacidosis. Three of 4 children presented with ketoacidosis revealing diabetes. One of 4 was less than 6 years of age. Severe ketoacidosis (pH less than 7.15) concerned one third of children and were more frequent in the group of adolescents with already known diabetes. In these patients, ketoacidotic decompensation was attributed to psychosocial factors in most cases. Evolution was favorable in all cases, without complication. Blood glucose levels decreased from 28.7 mmol/l on arrival to 16.2 mmol/l after 2 hours of treatment and became stable at 10 mmol/l from the 12th to the 24th hours. The corrected blood sodium levels were stable, showing the adequacy of infusion solute osmolarities. Blood potassium was maintained at a normal level owing to early potassium supplementation. Ketoacidosis was corrected after about 12 hours, without bicarbonate administration when pH was greater than 7.15. Average perfused volumes were 3 l/m2/24 hours. Insulin doses were 2 UI/kg/24 hours and were inversely correlated with the admission pH (r = -0.6; p = 0.0001). This study shows the efficacy of a treatment taking into account the pathophysiology of diabetic ketoacidosis and the knowledge of the complication risk factors, by foreseeing the adjustments to be done with respect to individual and/or at risk situations. These precise descriptive data, collected on a large group of patients, establish a reference basis to follow evolution in the course of the treatment of diabetic ketoacidosis in children.
