Análisis de ligamiento genético de la diabetes mellitus tipo 1, a marcadores de los cromosomas 2 y 11 en familias Antioqueñas

Abstract

DIABETES MELLITUS (DM) comprises e heterogeneous group of hypoglycemic disorders, that are grouped according to their physiopathology and etiology; the most notorious ones are type 1 DM (DM1) and type 2 DM (DM2); DM1 is characterized by early onset and absolute lack of insulin; therefore, patients suffering from it depend on insulin since the beginning of their symptoms; in contrast, DM2 manifests during adult life and not all patients depend on insulin. DM1 is classified as DM1A when it results from an autoimmune response of pancreatic b cells, and DM1B if it is of unknown origin (idiopathic). Studies on the etiology of DM1 have revealed that both types have a strong genetic component but their inheritance pattern is complex since its pathogenesis may result from the interaction with environmental factors of variants in multiple genes. By means of genetic studies on DM1, susceptibility loci known as IDDM have been identified, namely: for DM1A the first locus (IDDM1) was found in the HLA-DR/QD region, located in 6p21, that modulates the effect of other genes involved in the disease; the second one (IDDM2) is located in 11p15, the site of the insulin gene. That means, DM1 exhibits wide genetic heterogeneity so that more than 18 loci involved in susceptibility to this disease have been identified, among them, 3 on chromosome 2 (IDDM 7, 12, and 13), and 1on chromosome 14 (IDDM 11), the latter being associated to DM1B. The aim of this study was the search for loci on chromosomes 2 and 11 involved in the susceptibility to DM, in three families from Antioquia, Colombia; for that purpose, parametric linkage analysis was performed to 23 microsatellite markers on chromosome 2, and to 18 on chromosome 11. In order to determine the power for making linkage analysis, simulation was carried out on the families, coded as DM1 (11 affected members), family 1 (2 affected members), and family 10 (3 affected members); results demonstrated power enough for that purpose since in DM1 the maximum odds ratio (Lod score or Z maximum) was 3.57 without recombination (=0=0), above 3, the accepted value for determining linkage; when the three families were taken together, a maximum Z of 5.76 was obtained. With the linkage analysis for chromosome 11, it was found that only in family 10 there was a positive Z value, 1.18 to marker D11S925 with =0=0, above the simulation value for this family (0.75); as regards chromosome 2, positive Z values were obtained to marker D2S319 in DM1 and family 10: 2.08 and 0.88, respectively, with =0=0. When the three families were taken as a whole and Z values were calculated for markers D11S925 and D2S319, a value of 2.5 was obtained, with =0=0, which confirms that in the analysed families 2 loci are involved, located in the regions of chromosomes 11 and 2 signaled by such markers. If it is taken into account that the D1S925 marker is located in the region 11q23-3, and the D2S319 marker, in the region 2qter, it may be said that in this work two new loci of susceptibility to DM1 have been identified in three families from Antioquia, Colombia, since these regions do not agree with those so far reported; besides, since results were negative in linkage analysis to IDDM1 (data not shown), the studied cases of DM1 could be classified as DM1B.