Analysis of HLA-G long-read genomic sequences in mother–offspring pairs with preeclampsia

Abstract

Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal–fetal morbidity and mortality. HLA-G is thought to play important roles in maternal–fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother–offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.

Cellular immune responses in the pathophysiology of preeclampsia

“…In line with these findings, the expression of the immune tolerance‐promoting HLA‐G 127,128 and its receptors, such as LILRB1, 182 was decreased in placentas from women with preeclampsia 183 . A link between fetal HLA genotype and maternal preeclampsia risk was further supported by the reported association between a poly‐T stretch within the downstream region of the HLA‐G*01:01:01:01 allele and the occurrence of preeclampsia 184 . Based on these observations, the determination of local NK‐cell status in early pregnancy (e.g.…”

“…183 A link between fetal HLA genotype and maternal preeclampsia risk was further supported by the reported association between a poly-T stretch within the downstream region of the HLA-G*01:01:01:01 allele and the occurrence of preeclampsia. 184 Based on these observations, the determination of local NK-cell status in early pregnancy (e.g. the evaluation of maternal KIRs and paternal/fetal HLA genotype) could potentially have predictive value for preeclampsia.…”