TY - JOUR
T1 - Maternal-Foetal HLA-DQB1 Incompatibility Is Associated With Pregnancy-Induced Hypertensive Disorders in a Genetically Isolated Population
AU - Hof, Liseanne J Van't
AU - van der Hoorn, Marie-Louise P
AU - Migdis, Selena
AU - Haasnoot, Geert W
AU - Peereboom, Emma T M
AU - Spierings, Eric
AU - van der Linden, Pieter J E
AU - Anholts, Jacqueline D H
AU - de Vreede, Heleen
AU - Ottenhof, Winnie
AU - Roelen, Dave L
AU - Eikmans, Michael
AU - Mathijssen, Inge B
AU - Lashley, Lisa E E L O
N1 - Publisher Copyright:
© 2025 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.
PY - 2025/8
Y1 - 2025/8
N2 - In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disorders. Nonetheless, maternal-foetal HLA-DQB1 mismatch seems to play a role in the aetiology of hypertensive complications during pregnancy in this population.
AB - In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disorders. Nonetheless, maternal-foetal HLA-DQB1 mismatch seems to play a role in the aetiology of hypertensive complications during pregnancy in this population.
KW - Adult
KW - Alleles
KW - Case-Control Studies
KW - Female
KW - Genotype
KW - HLA-DQ beta-Chains/genetics
KW - Histocompatibility Testing
KW - Histocompatibility, Maternal-Fetal/genetics
KW - Humans
KW - Hypertension, Pregnancy-Induced/genetics
KW - Pre-Eclampsia/genetics
KW - Pregnancy
KW - Receptors, KIR/genetics
U2 - 10.1111/tan.70374
DO - 10.1111/tan.70374
M3 - Article
C2 - 40842414
SN - 2059-2302
VL - 106
JO - HLA
JF - HLA
IS - 2
M1 - e70374
ER -