Biomedical subjects

Paul J Norman

Publications and source records attributed to Paul J Norman.

11 recordsLinked to original sources

PubMed2026

Recovering the precolonial population structure of Khoe-San descendant populations.

San populations from Botswana and Namibia retain exceptional linguistic, cultural, and genetic diversity, but few Khoisan-speaking groups remain south of the Kalahari Desert. However, historically, far southern Africa was home to many San and Khoekhoe groups. Popular opinion often implies that such populations do not contribute to the ancestry of contemporary South Africans. Here, we characterize the genetic ancestry of self-identified South African Coloured groups and reconstruct precolonial and colonial population structures from 620 newly sampled individuals. These groups retain the majority of Khoe-San genetic ancestry (>48%), suggesting the persistence of Khoe-San ancestry to the present day. By isolating the Khoe-San ancestry component, we show that it is intermediate between the ≠Khomani San and Nama and distinct from Kalahari Khoe-San populations. We also find that signatures of the Indian Ocean slave trade can be traced to Indonesian islands such as Sulawesi, Java, and Flores, while the South Asian ancestry is regionally nonspecific.

Humans↗

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↗

PubMed2006

Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration.

BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation. OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles. METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed. RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls. CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.

Age Factors↗

PubMed2006

High KIR diversity in Amerindians is maintained using few gene-content haplotypes.

Interaction between killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands influences the innate and adaptive immune response to infection. The KIR family varies in gene content and allelic polymorphism, thereby, distinguishing individuals and populations. KIR gene content was determined for 230 individuals from three Amerindian tribes from Venezuela: the Yucpa, Bari and Warao. Gene-content haplotypes could be assigned to 212 individuals (92%) because only five different haplotypes were present-group A and four group B. Six different haplotype combinations accounted for >80% of individuals. Each tribe has distinctive genotype frequencies. Despite few haplotypes, all 14 KIR genes are at high frequency in the three tribes, with the exception of 2DS3. Each population has an even frequency of group A and B haplotypes. Allele-level analysis of 3DL1/S1 distinguished five group A haplotypes and six group B haplotypes. The high frequency and divergence of the KIR haplotypes in the Amerindian tribes provide greater KIR diversity than is present in many larger populations. An extreme case being the Yucpa, for whom two gene-content haplotypes account for >90% of the population. These comprise the group A haplotype and a group B haplotype containing all the KIR genes, except 2DS3, that typify the group B haplotypes. Here is clear evidence for balancing selection on the KIR system and the biological importance of both A and B haplotypes for the survival of human populations.

Gene Frequency↗

PubMed2005

Isolation, purification and flow cytometric analysis of human intrahepatic lymphocytes using an improved technique.

Intrahepatic lymphocytes (IHL) with their diverse and distinctive subsets emphasise the importance of the liver as a site of immunological activity, but special care is required for their isolation and characterisation. Protocols for IHL isolation, purification and FACS analysis were devised and compared with published extraction protocols. We have reduced the time that IHL are exposed to potentially damaging enzymes during extraction and purified specific subsets using monoclonal antibody (mAb)-coated magnetic microbeads. This has yielded IHL populations with higher viability than previously described protocols (92-95%, compared with 39-86%). Flow cytometric characterisation of IHL subset immunophenotypes was optimised by combining CD45 staining (fluorescence gating) with traditional light scatter properties. Using a panel of mAb and liver biopsies obtained from 23 cadaveric liver transplant donors, we show that the normal liver contains a heterogeneous IHL population with distinctive phenotypes. CD8+ IHL was the predominant population with a mean CD4/CD8 ratio of 1:1.7. Up to 40% of IHL expressed gammadeltaTCR and a third expressed CD56 NK marker; indicating a site of intense immunological activity. The techniques described will allow these cell types to be isolated, fully characterised and their physiological functions to be determined. The histologically normal liver contains heterogeneous and diverse IHL with large numbers of CD8+, NK, NKT and gammadelta+ cells.

Adolescent↗

PubMed2005

Complex interactions: the immunogenetics of human leukocyte antigen and killer cell immunoglobulin-like receptors.

The killer cell immunoglobulin-like receptors (KIR) for human leukocyte antigen (HLA) modulate innate and adaptive immunity by controlling effector cells. HLA and KIR are encoded in genomic regions that have complex organization and exhibit exceptional diversity within and among human population groups. This diversity is likely to have arisen to combat a constantly evolving pathogen challenge. Numerous variations influence the expression level or function of KIR molecules and can affect their interaction with HLA, with important implications for the immune response. The functional variety of natural immune responses that are controlled by HLA and KIR interactions is genetically determined and maintained by natural selection.

Animals↗

PubMed2004

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex.

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

Chromosomes, Human, Pair 19↗

PubMed2003

Natural killer-cell activity after human renal transplantation in relation to killer immunoglobulin-like receptors and human leukocyte antigen mismatch.

BACKGROUND: Natural killer (NK) cells use killer immunoglobulin-like receptors (KIR) that bind to self-class I major histocompatibility complex (MHC) molecules to prevent killing of autologous cells. Mismatched allografts, which do not express recipient MHC class I molecules, can therefore be potential targets for NK-cell killing. In our living related-unrelated renal transplantation program, donor-recipient pairs vary in the amount of both HLA and KIR genes they share. This provides us with a unique opportunity to dissect the influence of KIR on NK-cell function after transplantation. METHODS: Recipient NK cells were used in a cytotoxicity assay against donor peripheral blood mononuclear cells 2 days before, on the day of, and 3 days after transplantation. Results were correlated to HLA-KIR compatibility between donor and recipient. RESULTS: NK killing, in a direct ex vivo setting, was demonstrated to be HLA mismatch dependent. Recipient NK antidonor cytotoxicity was unaltered despite having received 2 days' treatment with cyclosporine A before transplantation. However, cytotoxicity increased 3 days after transplantation in 71% of recipients. Recipients exhibiting increased NK cytotoxicity against their donors after transplantation were found to possess more activating KIR genes specific for donor class I MHC molecules than those in whom killing activity did not increase (P<0.04). CONCLUSIONS: NK cells are activated after transplantation despite quadruple immunosuppression, suggesting that recipient NK-cell cytotoxicity against the donor may be a previously unrecognized area of the rejection process, especially in poorly matched donor-recipient pairs where the recipient may not express the correct repertoire of inhibitory receptors to prevent killing of donor cells.

Adult↗

PubMed2003

DNA sequence variation and molecular genotyping of natural killer leukocyte immunoglobulin-like receptor, LILRA3.

Leukocyte immunoglobulin-like receptors (LILRs) resemble killer cell immunoglobulin-like receptors (KIR) in structure and function and the KIR and LILR gene families form the major part of the leukocyte receptor cluster (LRC) of human chromosome 19q13.4. Unlike KIR, the LILR gene clusters do not vary in gene number. However, some individuals lack expression of LILRA3. This null allele has a 6.7-kb deletion, which encompasses the first six translated exons. This haplotype enabled unambiguous direct sequencing of LILRA3 alleles using genomic DNA from individuals heterozygous for the deletion. We have performed nucleotide sequencing of a 2.5-kb region within LILRA3 and identified eight bi-allelic substitutions, four of which were non-synonymous. Two from four previously identified LILRA3 cDNA sequences were confirmed and a further six alleles characterised, of which four will encode unique peptides. At least one of the polymorphic positions identified (encoding residue 84 of the first Ig domain) is likely to directly influence ligand binding. A PCR-SSP molecular genotyping system was developed and used to describe a panel of 172 Caucasoid individuals from South-East England. Six alleles were present in this group but they were unevenly distributed, as three alleles accounted for 88% of the studied chromosomes.

Antigens, CD↗

PubMed2003

A multi-laboratory characterization of the KIR genotypes of 10th International Histocompatibility Workshop cell lines.

Killer immunoglobulinlike receptors (KIRs) are expressed on natural killer and T cells. Both inhibitory and noninhibitory forms have been described, leading to inhibition or continuation of cellular killing activity. The natural ligands identified so far of KIRs are class I human leukocyte antigens (HLA). In particular, the interaction of some KIRs with HLA-Cw has been well characterized. Recent work has implicated KIRs in affecting the outcome of hematopoietic stem-cell transplant (HSCT). This may well lead to a requirement for prospective KIR typing of donor and recipient. We have utilized different typing systems (two using polymerase chain reaction-sequence-specific primers, and one using polymerase chain reaction-sequence-specific oligonucleotide probes) in three separate laboratories to characterize the KIR gene complement of 25 cell lines from the 10th International Histocompatibility Workshop. There were consistent results in 22, and minor differences in 3. When compared with previous results for some of these cell lines, no further differences were found. The differences are due to typing of KIRs KIR2DL1 and KIR2DS5, and may be explained by technical differences or the inability to type new variants. Further improvements in typing may be required if population and clinical studies are to produce accurate results.

Cell Line↗

PubMed2002

A comparison of HLA-DR and -DQ allele and haplotype frequencies in Trinidadian populations of African, South Asian, and mixed ancestry.

Using polymerase chain reaction-sequence-specific primer (PCR-SSP) typing, this study determined the frequency of human leukocyte antigen (HLA) DR- and -DQ alleles and haplotypes in individuals of African (n = 75), South Asian (n = 98), and mixed (n = 102) ancestry from the Caribbean island of Trinidad. We detected 19 different haplotypes containing DRB3, 8 containing DRB4, 6 containing DRB5, and 6 different haplotypes without DRB3/4/5 genes. Twenty-nine haplotypes were identified in Africans, 24 in the South Asians, and 32 in the mixed group. We detected significant differences between the populations, principally at the DQA1 and DQB1 loci, although the allele frequency for DRB1*0901 was highest in the Africans (p(c) < 0.05). Trinidad African and mixed groups were generally more diverse than the South Asians and displayed a wider range of DRB1-DQB1 associations; DQB1*02 and DQB1*0301 each associated with five to six different DRB1 alleles in the Africans and mixed group but only two in South Asians. In the Africans and the mixed group, DQB1*04 was found with DRB1*0302 and DRB1*04, but only with DRB1*08 in the South Asians. Trinidad Africans revealed consistencies with populations in Western, Central, and Northern Africa, but differed considerably from individual populations on the African continent. Trinidad South Asians displayed similar allele frequencies and associations to other populations from Northern India.

Alleles↗