Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population.

Alzheimer's disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.

HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls.

C282Y/C282Y genotype is the prevalent genotype in Hereditary Haemochromatosis (HH), however, other genotypes have been associated with the disease. The objective of our study was to analyse the frequency of the three main mutations of HFE gene in HH patients and controls from the Basque population with differential genetic characteristics. Thirty five HH patients and 116 controls were screened for C282Y, H63D and S65C mutations using a PCR-RFLP technique. The association of HLA-A and-B alleles and HFE mutations was also studied in Basque controls. The frequency of C282Y homozygotes in the group of patients was only 57%. The rest of the patients presented heterogeneous genotypes, including compound heterozygotes: 11% of them were C282Y/H63D; and 2.85% were H63D/S65C. H63D or S65C heterozygotes had a frequency of 11% and 2.85 respectively and 5.71% patients lacked any mutation The high frequency of H63D in the healthy Basque population is confirmed in this study. A considerable incidence of S65C is observed either in controls and in HH (3%) or in iron overloaded patients. The peculiar genetic characteristics of Basques could explain the heterogeneity of genotypes in HH patients of this group. Further studies should be carried out to confirm these findings although the implication of other genetic or external factors in the development of HH is suggested.

The contribution of the HLA-A, -B, -C and -DR, -DQ DNA typing to the study of the origins of Spaniards and Basques.

The high polymorphism of the HLA system has been used as a powerful genetic tool to single out individuals and populations. By studying characteristic allele frequencies and extended HLA haplotypes in different populations, it is possible to identify ethnic groups and establish the genetic relationships among them. In the present study, HLA-A, -B, -C, -DR and -DQ typing at the serological/antigenic and the DNA level has been used for the first time to assign specific HLA frequencies and haplotypes to Spaniards and Basques and compare them with frequencies in other populations, particularly with North Africans. Allelic frequencies do not significantly differ between Spaniards and Basques. HLA genetic distances and their respective dendrogram together with the results on complete HLA haplotypes place Basques and Spaniards closer to paleo-North African populations than to other Europeans. This goes in favour of the Basques being a relative genetic isolate coming from the primitive Iberian/paleo-North African people. In addition, a tentative assignment of the most common Spanish HLA haplotypes to the different people who populated Iberia according to historical records has been done.

HLA class I, class II, and class III antigen sharing is not found in couples with unexplained infertility.

OBJECTIVE: To find the degree of HLA antigen sharing in couples with infertility of unknown etiology and compare it with that in couples with infertility of known etiology as well as couples with normal fertility. SUBJECTS: Eleven couples with infertility of unknown etiology, 26 with infertility of known etiology, and 31 fertile couples were tested for HLA class I (A, B, C), class II (DR, MLC), and class III (Bf) antigens and GLO alleles. HLA lymphocytotoxic antibodies and anti-sperm antibodies in both partners were also searched. RESULTS: Gene frequencies and the number of HLA antigens shared between the two members of the couple were similar in all groups. When "intra-couple" MLC reactivity was measured, no quantitative differences were found in the infertile group with unknown etiology, as compared to the group of known etiology: spouses in couples of either group usually reacted in both ways as expected for unrelated individuals" lymphocytes. Lymphocytotoxic antibody frequency did not differ between the nonfertile groups, and anti-sperm antibodies, found in ten patients in the group of known etiology, were not associated with any HLA antigen. In spite of that, GLO and all the HLA antigen classes described (I, II and III) were analyzed. CONCLUSIONS: Although the results are negative, these and others' (negative) results concerning couples with infertility of unknown etiology do not disprove that HLA has a role in fertilization, because HLA-related factors still unknown may exist. Exhaustive HLA available marker typing in international cooperative efforts may be needed to reach a significant number of carefully selected couples fully HLA typed to elucidate this problem.

Differential contribution of C4 and HLA-DQ genes to systemic lupus erythematosus susceptibility.

The particular histocompatability antigen (HLA) gene(s) that may confer systemic lupus erythematosus (SLE) susceptibility remains unknown. In the present study, 58 unrelated patients and 69 controls have been analyzed for their class I and class II serologic antigens, class II (DR and DQ) DNA restriction fragment length polymorphism, their deduced DQA1 and B1 exon 2 nucleotide sequences and their corresponding amino acid residues. By using the etiologic fraction (delta) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative SLE susceptibility locus, it has been found that the strength of association of the HLA marker may be quantified as follows: DQA1*0501 (associated to DR3) or DQB1*0201 (associated to DR3) > non Asp 57 beta DQ/Arg 52 alpha DQ > DR3 > non Asp 57 beta DQ. Thus, molecular HLA DQ markers tend to be more accurate as susceptibility markers than the classical serologic markers (DR3). However, dominant or recessive non Asp 57 beta DQ susceptibility theories, as previously postulated for insulin-dependent diabetes mellitus, do not hold in our SLE nephritic population; indeed, three patients bear neither Arg 52 alpha DQ nor Asp 57 beta DQ suscepibility factors. On the other hand, nonsusceptibility factors are included in our population in the A30B18CF130-DR3DQ2(Dw25) haplotype and not in A1B8CS01-DR3DQ2(Dw24); this distinctive association has also been recorded in type I diabetes mellitus and may reflect the existence of common pathogenic HLA-linked factors for both diseases only in the A30B18CF10DR3DQ2(Dw25) haplotype. Finally, the observed increase of deleted C4 genes (and not 'null' C4 proteins) in nephritic patients shows that C4 genes are disease markers, but probably without a pathogenic role.

Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as type 1 (insulin-dependent) diabetes mellitus predictive risk markers in the Spanish population.

The question of HLA susceptibility to Type 1 (insulin-dependent) diabetes mellitus remains unresolved. In the present study, 127 diabetic patients and 177 unrelated control subjects have been analysed for their class I and class II serological antigens, class II (DR, DQ) DNA restriction fragment length polymorphisms and DQA1 and B1 exon-2 nucleotide sequences and their corresponding amino acid residues. By using the aetiologic fraction (delta) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative Type 1 diabetes susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DR4 less than DR3 less than DR3 or DR4 less than non-Aspartate 57 beta DQ and Arginine 52 alpha DQ less than Arginine 52 alpha DQ. Thus, molecular HLA-DQ markers appear to be more accurate as susceptibility markers than the classic serologically defined ones (DR3 and DR4); however, any effect of DQ markers disappears when non-DR3/DR4 individuals are considered, suggesting that DR factors (or others in between DQ and DR) are also important. In addition, a dominant non-Aspartate 57 beta DQ susceptibility theory does not hold (but a recessive one does) in our diabetic population (probably due to the high frequency of the protective DR7-non-Aspartate 57 beta DQ haplotypes); Arginine 52 alpha DQ is the best single HLA marker found in our population, both as a recessive or as a dominant one. Also there are 13 patients in our sample who bear neither Arginine 52 alpha DQ nor non-Aspartate 57 beta DQ susceptibility factors.(ABSTRACT TRUNCATED AT 250 WORDS)

T-lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies.

Gut epithelial cell autoantibodies have been considered a hallmark of autoimmune enteropathy, a disorder occurring in children with protracted diarrhea of unknown etiology. Four patients (two male and two female) with such autoantibodies were studied. Immunofluorescence analysis showed two different disjunctive staining patterns: complement-fixing apical (three of four) and cytoplasmic (the remaining fourth one), which are shown to be directed against different structures. All three patients positive for complement-fixing apical gut epithelial cell autoantibodies had abnormal T-cell responses in vitro, one of them with an immunoglobulin G2 immunoglobulin deficiency and another with an immunoglobulin A deficiency. An immunoglobulin A deficiency without T-cell alterations was also diagnosed in the cytoplasmic gut epithelial cell autoantibody-positive patient. These findings suggest that different immunologic alterations (either a T-cell abnormality or immunoglobulin deficiency) may favor the appearance of gut epithelial cell autoantibodies (complement-fixing apical or cytoplasmic, respectively). Furthermore, these autoantibodies should not be considered a specific marker of autoimmune enteropathy, because they may not always be associated with such a disease: two patients with apical gut epithelial cell autoantibodies showed no signs of intestinal lesion or diarrhea.