Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia.

A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis ("HH") and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.

Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia / Human leucocyte antigen gene (HLA-A, HLA-B, HLA-DRB1) frequencies in deceased organ donors

Introducción. La caracterización genética del sistema HLA es de gran utilidad en estudios antropogenéticos, en la comprensión de mecanismos asociados a susceptibilidad o resistencia a diversas enfermedades, en los fenómenos inmunológicos durante el embarazo y en la selección de donantes/receptores en trasplantes de órganos. Objetivo. Determinar las frecuencias alélicas, genotípicas y haplotípicas HLA-A, -B, -DRB1 en donantes fallecidos en Medellín. Materiales y métodos. Se incluyeron 926 donantes entre febrero de 1989 y septiembre de 2006, a los cuales se les realizó la tipificación HLA-A, -B, -DRB1 por PCR-SSP (single specific primer-polymerase chain reaction) de mediana resolución. Las frecuencias alélicas, genotípicas y haplotípicas fueron estimadas mediante el algoritmo de máxima verosimilitud. Se evaluó el ajuste al equilibrio de Hardy-Weimberg por una prueba exacta análoga a la de Fisher usando la cadena de Markov, así como el desequilibrio de ligamiento entre pares de loci. Resultados. Se identificaron 22, 43 y 14 alelos para los loci HLA-A, -B, -DRB, respectivamente, de los cuales los más frecuentes fueron: A*02, A*24, B*35 y DRB1*04. En los loci HLA-A y -B se observó deficiencia en la frecuencia de heterocigóticos esperada (p<0,01 y p<0,00001, respectivamente). Los haplotipos más frecuentes fueron HLA-A*24, B*35 (7,7 por ciento), HLA-B*35 DRB1*04 (6,4 por ciento) y HLA-A*24, DRB1*04 (8,9 por ciento) para HLA-A, -DRB1, y para 3 loci fueron HLA-A*24, B*35, DRB1*04 (4,6 por ciento) y HLA-A*24, B*61, DRB1*04 (2,0 por ciento). Conclusiones. Estos resultados corroboran la composición triétnica de nuestra población, en la cual predomina el grado de mezcla caucásica, a diferencia de otras latinoamericanas, y podrán ser usados como referencia para otros estudios y aplicaciones en esta población.

Introduction. Genetic characterization of the human leucocyte antigen (HLA) system has provided insights into mechanisms of susceptibility to diverse diseases and immunological phenomena during pregnancy, as well as providing evidence for compatibility in the selection of organ transplant donors and recipients. Objective. The HLA-A,-B,-DRB1 allele, genotype and haplotype frequencies were determined in deceased organ donors in Medellín, Colombia. Materials and methods. The genotypes of 926 deceased donors were evaluated over a 17-year period (1989- 2006). HLA-A, HLA-B and HLA-DRB1 typing was performed by sequence specific primer-polymerase chain reaction (SSP-PCR). Maximum likelihood frequencies were estimated by the zipper version of expectation maximation algorithm. Hardy-Weinberg equilibrium were determined by an exact test analogous to Fisher’s test by using Markov’s chain, and linkage disequilibrium between pairs of loci. Results. Twenty-two, 43 and 14 alleles were identified for HLA-A, -B and -DRB loci, respectively. The most frequent were A*02, A*24, B*35, and DRB1*04. A deficiency in the proportion of heterozygotes in HLA-A and B loci (p<0.01 and p<0.00001, respectively). The most frequent haplotypes were as follows: HLA-A*24, B*35 (7.7%) for HLA-A,-B; HLA-B*35, DRB1*04 (6.4%) for HLA-B,-DRB1 and HLA-A*24, DRB1*04 (8.9%) for HLA-A,-DRB1. For the 3 loci HLA-A,-B,-DRB1, the most frequent haplotypes were A*24, B*35, DRB1*04 (4.6%) and A*24, B*61,DRB1*04 (2.0%). Conclusions. These results confirm the three-ethnic ancestry of the Medellin population. The predominance of Caucasian admixture differs from many other Latin-American populations and can serve as a reference for comparative studies of these populations as well as applications within the Medellin population.

[Human leucocyte antigen gene (HLA-A, HLA-B, HLA-DRB1) frequencies in deceased organ donors]. / Frecuencias alélicas, genotípicas y haplotípicas HLA-A, HLA-B, HLA-DRB1 en donantes fallecidos, Medellín, Colombia.

INTRODUCTION: Genetic characterization of the human leucocyte antigen (HLA) system has provided insights into mechanisms of susceptibility to diverse diseases and immunological phenomena during pregnancy, as well as providing evidence for compatibility in the selection of organ transplant donors and recipients. OBJECTIVE: The HLA-A,-B,-DRB1 allele, genotype and haplotype frequencies were determined in deceased organ donors in Medellín, Colombia. MATERIALS AND METHODS: The genotypes of 926 deceased donors were evaluated over a 17-year period (1989- 2006). HLA-A, HLA-B and HLA-DRB1 typing was performed by sequence specific primer-polymerase chain reaction (SSP-PCR). Maximum likelihood frequencies were estimated by the zipper version of expectation maximation algorithm. Hardy-Weinberg equilibrium were determined by an exact test analogous to Fishers test by using Markovs chain, and linkage disequilibrium between pairs of loci. RESULTS: Twenty-two, 43 and 14 alleles were identified for HLA-A, -B and -DRB loci, respectively. The most frequent were A*02, A*24, B*35, and DRB1*04. A deficiency in the proportion of heterozygotes in HLA-A and B loci (p<0.01 and p<0.00001, respectively). The most frequent haplotypes were as follows: HLA-A*24, B*35 (7.7%) for HLA-A,-B; HLA-B*35, DRB1*04 (6.4%) for HLA-B,-DRB1 and HLA-A*24, DRB1*04 (8.9%) for HLA-A,-DRB1. For the 3 loci HLA-A,-B,-DRB1, the most frequent haplotypes were A*24, B*35, DRB1*04 (4.6%) and A*24, B*61, DRB1*04 (2.0%). CONCLUSIONS: These results confirm the three-ethnic ancestry of the Medellin population. The predominance of Caucasian admixture differs from many other Latin-American populations and can serve as a reference for comparative studies of these populations as well as applications within the Medellin population.

Evaluation of T-cell receptor repertoires in patients with long-term renal allograft survival.

The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (> or = 9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vss usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR V beta families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.