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PubMed2026

Immunogenetic diversity of two South Asian cohorts: From Pakistan and India.

Having critical roles in immune defense and reproduction, killer cell immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands are encoded by the most polymorphic regions in the human genome. South Asia comprises over one quarter of the global population and harbors rich genomic diversity. Limiting our understanding of population-specific variation and disease susceptibility, high-resolution immunogenetic studies of South Asian ancestry individuals are lacking. Here, we characterize KIR and HLA class I diversity in two South Asian cohorts: sampling an urban population from Karachi, Pakistan (n = 79), and a Dravidian-speaking Yadav population from southern India (n = 70). Targeted sequencing identified 151 distinct KIR alleles across 13 genes, including 11 previously uncharacterized allotypes. Over 75% of the genotypes were KIR-Bx. We identified 98 HLA class I alleles and extensive haplotypic diversity, with all major KIR binding motifs represented, and a mean of seven potential inhibitory KIR-HLA interactions per individual (6.6 in Karachi, 7.4 in Yadav). Together, these results demonstrate substantial immunogenetic diversity and population-specific KIR and HLA variation within the two studied cohorts. This study expands knowledge of KIR and HLA diversity and offers a framework for further evolutionary and disease-focused in South Asia.

Humans↗

PubMed2025

Allele Level Sequencing of Killer Cell Immunoglobulin-Like Receptor Genes Using Oxford Nanopore Long Read Sequencing.

The human Killer cell Immunoglobulin-like Receptor (KIR) genes, found on chromosome 19, encode for cell surface protein receptors that, through interaction with their ligand, modulate the action of Natural Killer (NK) cells and some subsets of T lymphocytes. KIR genes exhibit extensive variation through variable gene content, copy number, and allele polymorphism. The combination of KIR genes and their ligands is implicated in various clinical settings including haematopoietic stem cell and solid organ transplant, and infectious disease progression. KIR gene content has been used in the selection of optimal stem cell donors with haplotype variations in recipient and donor giving differential clinical outcomes. With the introduction of massively parallel clonal next generation sequencing and single molecule long read third generation sequencing, allele level determination of KIR genotypes has become feasible. We describe a method for amplicon-based long read sequencing on the Oxford Nanopore Technologies platform that provides largely unambiguous allele level typing of KIR genes. The method was validated using DNA extracted from 48 10th International Histocompatibility Workshop (IHWS) cell lines with previously published allele level KIR genotypes and 176 Western Australian samples previously tested for the presence or absence of KIR genes. Our long-read sequencing method was able to accurately determine KIR alleles with an overall concordance of 97%-99% with the published data. Importantly, phasing ambiguity caused by the inability to phase heterozygous base positions over long stretches of gene sequence was resolved in several samples. Thus, our long read PCR sequencing strategy can be used to determine KIR genotypes at allele resolution level.

Humans↗

PubMed2025

Maternal-Foetal HLA-DQB1 Incompatibility Is Associated With Pregnancy-Induced Hypertensive Disorders in a Genetically Isolated Population.

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.

Humans↗