Impact of transplantation on neutrophil extracellular trap formation in patients with end-stage renal disease: A single-center, prospective cohort study.

ABSTRACT: Increased neutrophil extracellular trap (NET) formation associates with high cardiovascular risk and mortality in patients with end-stage renal disease (ESRD). However, the effect of transplantation on NETs and its associated markers remains unclear. This study aimed to characterize circulating citrullinated Histone H3 (H3cit) and Peptidyl Arginase Deiminase 4 (PAD4) in ESRD patients undergoing transplantation and evaluate the ability of their neutrophils to release NETs.This prospective cohort study included 80 healthy donors and 105 ESRD patients, out of which 95 received a transplant. H3cit and PAD4 circulating concentration was determined by enzyme-linked immunosorbent assay in healthy donors and ESRD patients at the time of enrollment. An additional measurement was carried out within the first 6 months after transplant surgery. In vitro NET formation assays were performed in neutrophils isolated from healthy donors, ESRD patients, and transplant recipients.H3cit and PAD4 levels were significantly higher in ESRD patients (H3cit, 14.38 ng/mL [5.78-27.13]; PAD4, 3.22 ng/mL [1.21-6.82]) than healthy donors (H3cit, 6.45 ng/mL [3.30-11.65], P < .0001; PAD4, 2.0 ng/mL [0.90-3.18], P = .0076). H3cit, but not PAD4, increased after transplantation, with 44.2% of post-transplant patients exhibiting high levels (≥ 27.1 ng/mL). In contrast, NET release triggered by phorbol 12-myristate 13-acetate was higher in neutrophils from ESRD patients (70.0% [52.7-94.6]) than healthy donors (32.2% [24.9-54.9], P < .001) and transplant recipients (19.5% [3.5-65.7], P < .05).The restoration of renal function due to transplantation could not reduce circulating levels of H3cit and PAD4 in ESRD patients. Furthermore, circulating H3cit levels were significantly increased after transplantation. Neutrophils from transplant recipients exhibit a reduced ability to form NETs.

The immunogenetic diversity of the HLA system in Mexico correlates with underlying population genetic structure.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) allele groups and alleles by PCR-SSP based typing in a total of 15,318 mixed ancestry Mexicans from all the states of the country divided into 78 sample sets, providing information regarding allelic and haplotypic frequencies and their linkage disequilibrium, as well as admixture estimates and genetic substructure. We identified the presence of 4268 unique HLA extended haplotypes across Mexico and find that the ten most frequent (HF > 1%) HLA haplotypes with significant linkage disequilibrium (Δ'≥0.1) in Mexico (accounting for 20% of the haplotypic diversity of the country) are of primarily Native American ancestry (A*02~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*08~DQB1*04, A*68~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*14~DQB1*03:01, A*24~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*04~DQB1*03:02, A*02~B*40:02~DRB1*04~DQB1*03:02, A*68~B*35~DRB1*04~DQB1*03:02, A*02~B*15:01~DRB1*04~DQB1*03:02). Admixture estimates obtained by a maximum likelihood method using HLA-A/-B/-DRB1 as genetic estimators revealed that the main genetic components in Mexico as a whole are Native American (ranging from 37.8% in the northern part of the country to 81.5% in the southeastern region) and European (ranging from 11.5% in the southeast to 62.6% in northern Mexico). African admixture ranged from 0.0 to 12.7% not following any specific pattern. We were able to detect three major immunogenetic clusters correlating with genetic diversity and differential admixture within Mexico: North, Central and Southeast, which is in accordance with previous reports using genome-wide data. Our findings provide insights into the population immunogenetic substructure of the whole country and add to the knowledge of mixed ancestry Latin American population genetics, important for disease association studies, detection of demographic signatures on population variation and improved allocation of public health resources.

Genetic diversity of HLA system in two populations from Nayarit, Mexico: Tepic and rural Nayarit.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 161 Mexicans from the state of Nayarit living in Tepic (N = 97) and rural communities (N = 64), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes found in the state of Nayarit include eight Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in the state of Nayarit are Native American (50.79 ±â€¯5.03% by ML; 42.24% of Native American haplotypes) and European (37.04 ±â€¯6.21% by ML; 35.72% of European haplotypes), while African genetic component is less apparent but relatively high (12.17 ±â€¯2.50% by ML; 13.36% of African haplotypes).

Genetic diversity of HLA system in four populations from Baja California, Mexico: Mexicali, La Paz, Tijuana and rural Baja California.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 250 Mexicans from the states of Baja California Norte and Baja California Sur living in Mexicali (N = 100), La Paz (N = 75), Tijuana (N = 25) and rural communities (N = 50) to obtain information regarding allelic and haplotypic frequencies. The most frequent haplotypes for the Baja California region include nine Native American and five European haplotypes. Admixture estimates revealed that the main genetic components are European (50.45 ±â€¯1.84% by ML; 42.03% of European haplotypes) and Native American (43.72 ±â€¯2.36% by ML; 40.24% of Native American haplotypes), while the African genetic component was less apparent (5.83 ±â€¯0.98% by ML; 9.36% of African haplotypes).

Genetic diversity of HLA system in two populations from Sinaloa, Mexico: Culiacán and rural Sinaloa.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 286 Mexicans from the state of Sinaloa living in Culiacán (N = 103) and rural communities (N = 183) to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes for the state of Sinaloa include ten Native American most probable ancestry and five European most probable ancestry haplotypes. The admixture estimates revealed that the main genetic components in the state of Sinaloa are European (62.39 ±â€¯3.47%) and Native American (37.61 ±â€¯2.85%), while the African genetic component was estimated as virtually absent (0.00 ±â€¯1.86%).

Genetic diversity of HLA system in three populations from Guanajuato, Mexico: Guanajuato City, León and rural Guanajuato.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 262 Mexicans from the state of Guanajuato living in the cities of Guanajuato (N = 78), León (N = 22) and rural communities (N = 162), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes found in the state of Guanajuato include 12 Native American and three European haplotypes. Admixture estimates revealed that the main genetic components in the state of Guanajuato are Native American (50.64 ±â€¯2.11% by ML, 43.35% of Native American haplotypes) and European (44.14 ±â€¯1.14% by ML; 39.35% of European haplotypes), while African genetic component is less apparent (5.22 ±â€¯2.08% by ML; 8.36% of African haplotypes).

Genetic diversity of HLA system in a population sample from Aguascalientes, Mexico.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 95 Mexicans from the state of Aguascalientes to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We find that the most frequent haplotypes in the state of Aguascalientes include four Native American, three European and one Asian haplotypes. Admixture estimates revealed that the main genetic components in the state of Aguascalientes are Native American (54.53 ±â€¯3.22% by ML; 44.21% of Native American haplotypes) and European (44.34 ±â€¯0.45% by ML; 40.53% of European haplotypes), and a relatively low African genetic component (1.13 ±â€¯2.33% by ML; 5.26% of African haplotypes).

Genetic diversity of HLA system in two populations from Michoacán, Mexico: Morelia and rural Michoacán.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 498 Mexicans from the state of Michoacán living in the city of Morelia (N = 150) and rural communities (N = 348), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes found in the state of Michoacán include 12 Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in the state of Michoacán are Native American (48.79 ±â€¯1.44%) and European (43.10 ±â€¯0.86%), while African genetic component is less apparent (8.11 ±â€¯0.85%). Our findings add to the growing knowledge on the population genetics of Western Mexico and provide new HLA data on populations from Michoacán.

Genetic diversity of HLA system in six populations from Jalisco, Mexico: Guadalajara city, Tlajomulco, Tlaquepaque, Tonalá, Zapopan and rural Jalisco.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2046 Mexicans from the state of Jalisco living in the city of Guadalajara (N = 1189), Tlajomulco (N = 30), Tlaquepaque (N = 39), Tonalá (N = 35), Zapopan (N = 168) and rural communities (N = 585), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes found in the state of Jalisco include nine Native American most probable ancestry and three European haplotypes. Admixture estimates revealed that the main genetic components in the state of Jalisco are European (48.45 ±â€¯1.18% by ML; 41.66% of European haplotypes) and Native American (44.02 ±â€¯1.24% by ML; 39.86% of Native American haplotypes), while African genetic component is less apparent (7.53 ±â€¯0.30% by ML; 9.62% of African haplotypes).

Genetic diversity of HLA system in two populations from Colima, Mexico: Colima city and rural Colima.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 104 Mexicans from the state of Colima living in the city of Colima (N = 61) and rural communities (N = 43), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Colima include eight Native American, two European and one African haplotype. Admixture estimates revealed that the main genetic components in the state are Native American (52.74 ±â€¯3.88% by ML; 48.10% of Native American haplotypes) and European (37.52 ±â€¯8.94% by ML; 26.66% of European haplotypes), and a relatively high African genetic component (9.74 ±â€¯8.40% by ML; 11.91% of African haplotypes).