Search

SUMMARYPica is a condition associated with a number of physical and mental health diagnoses. The potentially fatal consequences of pica and the links with significant physical health problems are not always recognised. Pica is like other forms of behaviour that can challenge: clinicians must seek the underlying cause and treat this first, before primarily pursuing a behavioural form of treatment. In this article, we discuss the associations, consequences, assessment and management options available for pica to guide professionals. Pica often presents in a way individual to the particular patient, so tailoring of assessment and treatment is important.

Purpose This paper aims to investigate the use of Part VI of the Criminal Procedure (Scotland) Act 1995 (CPSA) for people with Learning Disability (LD) and/or Autism. This is in the context of a recent review commissioned by the Scottish Government into whether the provisions in the Mental Health (Care and Treatment) (Scotland) Act 2003 (MHA) meet the needs of these groups which would also affect associated legislation such as CPSA. Design/methodology/approach All CPSA orders active on the 3 January 2018 were identified and analysed for a number of variables including diagnoses, detention length, level of hospital security and medication use. Findings Of the 580 people on CPSA orders, 69 (11.9%) had LD and 27 (4.7%) had possible/definite Autism. Most people with LD (56.5%) did not have a mental illness or personality disorder. Most (81.2%) had mild LD. There were two patients whose only diagnosis was Autism. Mean duration of detention was longer for those with LD than for those without. Most patients with LD alone were prescribed medication (61.5%) and, if in hospital, were managed in low secure units (59%). Originality/value The results indicate that people with LD or Autism are differently affected by the application of the CPSA from other people with mental disorders, and that this is potentially discriminatory, if it is not objectively justified . It supports the stance from the recent review that to reduce the potential for discrimination, substantial changes to MHA and CPSA should be considered in the wider review of the MHA in Scotland.

Aims and MethodTwelve intellectual disability psychiatry trainee representatives and 13 training programme directors were surveyed to assess the current state of training, to establish what motivated specialty trainees to choose intellectual disability psychiatry, and to explore issues that might affect retention.ResultsThe combined survey response rate was 83%. All trainees had chosen intellectual disability psychiatry after experience in either their personal or working life. Overall, specialty trainees were satisfied with their training; the majority felt supported to meet training requirements. Trainee isolation was the main concern for current trainees.Clinical implicationsRecruitment for specialty training in intellectual disability psychiatry is acknowledged to be a concern for workforce planning and could affect access to and quality of psychiatric care for people with intellectual disability. The results of this survey could be used as a guide to improve efforts to attract trainees. Acknowledging and reducing trainee isolation could improve trainee morale.

SUMMARYThis article initially highlights that although the prevalence of alcohol use disorders in people with intellectual disability (PWID) appears to be low, it is a significant issue. This group can be more vulnerable to the adverse effects of alcohol and it is likely that many PWID who have alcohol use disorders are not being identified. We go on to review the limited existing literature on treatment for PWID who have alcohol use disorders and the challenges in meeting the needs of this patient group. We explore how assessment and treatment of alcohol use disorders in this population can be and needs to be tailored to the needs of PWID on an individual basis. There is also discussion about the use of incapacity legislation to treat this group.LEARNING OBJECTIVES•Be aware that alcohol use disorders can be especially problematic for PWID, that such disorders can often go undetected and that adapted screening techniques may be needed to identify such problems•Understand the difficulties that this population has in accessing addiction services and that successful management of PWID who misuse alcohol is usually dependent on appropriate joint working between intellectual disability and addiction services•Be aware that PWID are not a homogeneous group, rather they vary widely in their abilities, necessitating interventions tailored to the individual, and that the use of compulsory measures to manage PWID who lack capacity regarding to their alcohol use should be done with cautionDECLARATION OF INTERESTNone.

Background The sexual health needs of younger adults with intellectual disability (ID) are not currently being met by mainstream sexual health services. Little research has been conducted into improving these services’ accessibility.Method Thirty-four people with ID aged 16–35, who attended ID services in Lothian, Scotland, completed a questionnaire at a face-to-face interview about whom they could go to for advice and information about sex and relationships, which information sources they used, their experiences of sexual health services, and their preferences regarding these services.Results Most participants wanted to attend mainstream services and felt staff from these services should be able to meet their special needs. Preferences on services varied between individuals.Conclusions It is important that there continues to be a variety of sexual health services available and that staff are appropriately trained in working with people with ID. Further research is needed to identify and resolve u...

Killer cell immunoglobulin-like receptor genotyping was performed on a cohort of American Caucasian patients with psoriasis to investigate any possible relationship between these chromosome 19 genes and autoimmune-linked disease. This patient cohort also contained a subgroup of patients who had been additionally diagnosed as positive for psoriatic arthritis (PsA). Because of the known association of human leucocyte antigen (HLA)-Cw*06 with psoriasis, the study concentrated on the five KIR genes that have HLA-C as their recognized ligand (i.e., KIR2DL1, -2DL2, -2DL3, -2DS1, and -2DS2). An increase in the frequency of the activating KIR2DS1 gene was detected in the PsA patients, compared with psoriasis patients negative for PsA and an unaffected American Caucasian control group.

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that ∼4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1–5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane. See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425743

Allelic definition within the killer cell immunoglobulin-like receptor gene, KIR3DL2, has been achieved through a sequence-specific oligonucleotide probe methodology, designed around the specific amplification of the D0 and D1 domains and a section of the cytoplasmic tail of this gene. The system has been applied to a healthy Northern Irish control group, establishing frequencies for this Caucasian population. Additionally, the KIR3DL2 allele status of cell line DNA and Centre d'Etude du Polymorphisme Humain (CEPH) families, both from the 13th International Histocompatibility Workshop, has been established. A high level of KIR3DL2 allelic polymorphism has been identified.

The allelic variation of one of the chromosome 19 KIR genes, KIR2DL3, has been investigated using a polymerase chain reaction sequence-specific oligonucleotide probe-based methodology. The procedure has been applied to a healthy Northern Irish control group in order to establish phenotype and genotype frequencies in this Caucasian population. In addition, cell line DNA and Centre d'Etude du Humaine (CEPH) families, both from the 13th International Histocompatibility Workshop have been investigated, establishing control data for this gene.

A stem cell registry population from Hong Kong, of Chinese ethnicity, was examined for HLA-A and HLA-B alleles using a two-stage sequence-specific oligonucleotide probe system. Comparison of the HLA-A and HLA-B frequencies with different populations showed a close relationship with a Chinese population from Singapore, although there were several differences in the presence/absence of alleles at the HLA-B locus. Having the data available on these registry donors will influence the search strategy and the ongoing compilation of new donors to the registry. In addition, knowing which alleles do/do not occur in this population will aid in the distinction of ambiguities which result from the use of many of the typing kits available.

Polymerase chain reaction-sequence-specific oligonucleotide probes typing methods have been applied to 1000 individuals from the Northern Ireland population to give human leukocyte antigen DRB1 (HLA-DRB1) allele assignment. HLA-DRB1 allele frequencies and four-locus haplotypes (A/B/C/DR) for this Caucasian population, based on HLA class I and class II allele assignment, are now presented. No significant deviations from Hardy-Weinberg proportions were observed. The HLA-C locus exhibited marginal evidence of selection (p0.03, uncorrected one-sided test) in the direction of balancing selection; the HLA-A, -B, and -DRB1 allele frequency distributions were compatible with expectations under a neutral model (which does not mean that selection is not operating). Evidence for selection was seen on haplotypes HLA-A*010101-B*0801-DRB1*030101 and HLA-A*290201-B*440301-DRB1*070101 based on their patterns of linkage disequilibrium.

Multiple copies of the killer immunoglobulin-like receptor gene, 3DL/S1, have been identified in certain individuals. Additionally, allele determination of the killer immunoglobulin-like receptor gene (KIR), 2DL4, has identified three alleles of this gene present in these same individuals. This event has been confirmed by isolating three distinct KIR2DL4 allele clones in each individual, which sequenced as the alleles identified by the allele identification technique. It is our assumption that an unequal crossover event has occurred between differing KIR haplotypes resulting in the duplication of the 2DL4, 3DS1/3DL1 genes on the newly formed haplotype(s).

The extreme polymorphism found at some loci of the HLA system has made it an invaluable tool for population genetic analyses. In this study eight diverse ethnic groups from Pakistan were analyzed at the HLA-A locus using sequence specific primers for polymerase chain reaction (PCR-SSP) and then further typed to the allele level using a two-stage sequence specific oligonucleotide probe (SSOP) strategy. Four of these ethnic groups (Burusho, Hazara, Kalash, Pathan) were from the north and four (Baloch, Brahui, Sindhi and Parsi) were from the south of Pakistan. Nine alleles were identified as unique to a particular ethnic group within Pakistan. Maximum variation was seen in the HLA-A*02 allele family for which 11 alleles were detected in the eight Pakistani ethnic groups. The alleles that showed significant variation between the Pakistani ethnic groups include A*0101, A*0206, A*0209, A*0207, A*0217, A*1101, A*2402/09 N/11 N, A*2902, A*3301 and A*3001. A phylogenetic tree based on DA distances for HLA-A allele frequencies separated the Pakistani populations from other world populations and also separated the only Dravidian speaking population of Pakistan, the Brahui, from the remaining Indo-European speaking ethnic groups of Pakistan.

We describe a variant HLA-B*39 allele present in two individuals from Oman, which has been officially named HLA-B*3921. In addition we confirm the existence of HLA-B*4415, an allele closely related to HLA-B*4501 differing only at the Bw4/Bw6 epitope ( Note).

During the development of an HLA-A polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) method for the identification of HLA-A*24 and -A*30 alleles, group amplification resulted in the formation of an unusual PCR product in certain individuals. This fragment was approximately 900 bp smaller than the expected product and was also detected in some non-HLA-A*24- and -A*30-positive individuals acting as negative controls for the group specific amplification. Nucleotide sequence analysis of this product identified it as a unique class I gene sequence displaying homology to both primate and human class I A-locus genes. The entire gene was amplified using PCR and the complete DNA sequence information from exon 1 to exon 8, including introns, was determined. A recombination event was identified which results in the fusion of intron 2 with intron 3, causing a deletion of the intervening exon 3 sequence. In addition, there are two cytosine insertions in the poly-cytosine stretch at the start of exon 4 which cause a frameshift and premature termination. The exon 1 and 2 sequences most closely align with the gorilla allele A*0501, displaying only five mismatches. PCR analysis has established that the gene is associated with the following HLA-A types: HLA-A*3001, -A*3301, -A*3303, -A*6802, -A*2901, -A*0203, -A*0205 and -A*31012. Reverse transcription (RT)-PCR analysis of individuals containing this gene failed to detect any mRNA transcription, suggesting that this is a previously undescribed non-expressed class I pseudogene which we have provisionally named HLA-BEL. Its unique gene structure gives a possible insight into the evolutionary pathway that created HLA class I genes.

High-resolution polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) typing methods for HLA-A identification have been established. The four systems, which operate independently of each other, are intended for use as secondary typing systems following HLA-A identification with a medium-resolution PCR-SSOP technique. The systems, all using digoxigenin-labelled probes, are based on group specific amplifications for resolution of: i) HLA-A*29 & -A*33; ii) HLA-A*24 & -A*30; and iii) HLA-A*26, -A*25, -A*11, -A*34, -A*66 and -A*68 alleles, respectively. The fourth system, for the detection of HLA-A*02 alleles, is a modification of a previously reported PCR-SSOP subtyping system. The methods have been applied to individuals from the local bone marrow registry and HLA-A allele frequencies for the Northern Ireland population have been established.

The molecular analysis of HLA class I loci has demonstrated that, although, the genetic profile is restricted in Amerindians, several micropolymorphisms may be important in conferring a biological advantage. We analyzed the HLA-A and B genetic profile of Seris, a Mexican Indian tribe living in northwestern Mexico in the state of Sonora. There are presently only 619 individuals. Our study included 100 Seris belonging to nine families. HLA-A and -B loci typing was performed by polymerase chain reaction using an amplification refractory mutation system (PCR-ARMS) on a select group of samples; all of them were typed by polymerase chain reaction using sequence-specific oliogonuoleotide probes (PCR-SSOP) at a low-intermediate resolution level. The correlation between the techniques was 100%. Only five HLA-A alleles and seven HLA-B alleles were found. A*0201, A*68, A*31, A*24, B*3501, B*40, B*51, B*3512 and B*15 were present in over 5% of the individuals. B*27052 was detected in 2%. B27 is absent in any other Mexican Indian groups previously studied. The presence of B27 may be the result of a founder effect due to different waves of southward migrations. The B-locus is more diverse and the prevalent haplotypes were: A*0201-B*3501, A*0201-B*40, A*0201-B*3512, A*31-B*51, A*68-B*3501 and A*68-B*40. This genetic profile is different from the pattern of other Mexicans. The phylogenetic tree suggests that Seris are more closely related to the Warao Indians from Venezuela, who live in a similar ecosystem, and to some groups of Argentina, than they are to the Mexican Lacandones who live in the jungle. These data emphasize the relevance of the interaction between genes and environment.

A comparison of serological and DNA HLA class I typing data identified a serological "blank" HLA-B15 antigen in a volunteer donor on the bone marrow registry. Isoelectric focusing and Western blot analysis of a cell line established from this individual confirmed that the HLA-B15 antigen is not expressed at the cell surface. Nucleotide sequence analysis of the HLA-B*15 null allele revealed a 10-bp deletion near the 3' end of intron 1, when compared to the normal HLA-B*1501 sequence. All of the HLA-B*15 specific cDNA clones examined retained the intron 1 sequence. Reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis demonstrated that the HLA-B*15 mRNA molecule contained the intron 1 sequence, indicating an inability to efficiently splice out intron 1 from the mRNA transcript. The retention of the mutated intron 1 sequence in the mRNA causes a frameshift and premature termination of translation at the start of exon 2, explaining the HLA-B*1501 null phenotype. Our data predicts that the HLA-B*1501 null allele would express a small truncated protein containing the signal sequence fused to an ORF within intron 1 and terminating (out of frame) just within exon 2.

A number of cases have been identified (seven unrelated individuals from the Northern Ireland bone marrow donor registry and two family groups) where an HLA-A*24 allele fails to express the normal HLA-A24 antigen. Family information has revealed common haplotypes with respect to each non-expressed allele indicating that the occurrence of these mutations has been a recent event. Two methods for the clinical typing of these alleles have been evaluated - PCR-SSOP and PCR-SSCP analysis.

HLA has been shown to be associated with many diseases. To find out whether host genetic factors like the HLA are involved in susceptibility to kala-azar (visceral leishmaniasis) in India, we formulated an association study with genetically related controls. All samples were typed by PCR SSOP (sequence specific oligonucleotide probes) for HLA class I (A and B) and class II (DR) antigens. The test of association we used was the transmission disequilibrium test (TDT). No significant evidence for association with any of the three HLA loci was obtained.

In natural killer cells, killer immunoglobulin-like receptors (KIRs) loci code for either inhibitory or activating receptors, and according to the number of genes present in each individual, it is possible to identify a high rate of polymorphism in the populations. We performed KIR typing by polymerase chain reaction– sequence-specific oligonucleotide probing in 402 Argentinean Caucasoid and in two Amerindian populations (101 Wichis and 54 Chiriguanos) from the North of Argentina. KIR2DL4, KIR3DL2, KIR3DL3 and KIR3DP1 were always present, whereas the frequencies of KIR2DL1, KIR2DL3, KIR2DS4, KIR3DL1 and KIR2DP1 ranged between 84% and 96%. The frequencies of KIR2DS2, KIR2DL2, KIR2DL5, KIR2DS5, KIR2DS1 and KIR3DS1 ranged between 41% and 62%. The KIR2DS3 with a frequency of 29% in Argentinean Caucasoid population was present at a very low frequency in Amerindian populations. Haplotype segregation studies performed in 10 Wichi families showed the presence of only three haplotypes: A, B5 and B1. The Amerindian populations showed several similarities to Asian but not to Caucasoid populations with regard to the frequency of KIR2DS3, full-length KIR2DS4 gene and KIR2DL4 alleles. Fil: Flores, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Marcos, Cintia Yanina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Paladino, Natalia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Capucchio, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Theiler, Gerardo Raul. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Arruvito, Maria Lourdes. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pardo, R.. Hospital Rural Nueva Pompeya; Argentina Fil: Habegger, A.. Gobierno de la Provincia de Chaco. Hospital Julio Cecilio Perrando.; Argentina Fil: Williams, F.. Belfast City Hospital; Irlanda Fil: Middleton, D.. Belfast City Hospital; Irlanda Fil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Three cohorts of patients with laryngeal, bladder or colorectal tumours were investigated for frequency of killer immunoglobulin-like receptor (KIR) genes compared with a normal control population. The frequency of KIR3DL1 and KIR2DS4 was significantly increased (but not after correction for number of comparisons made) in patients with bladder tumour compared with controls. No other significant differences were found in gene frequencies or in the frequencies of those KIR genes with and without their human leucocyte antigen (HLA) ligands. Furthermore, no significant differences were found in KIR gene frequencies, taking into consideration the type of loss of HLA expression in the individual tumours. Finally, in the group of colorectal carcinomas, there was an overall significant difference in the frequencies of C group heterozygosity and homozygosity with HLA alterations on the tumour.

The present study demonstrated that patients who have recurrent spontaneous abortions (RSA) presented a decreased number of killer immunoglobulin-like inhibitory receptors (KIR), in particular KIR2DL2. The KIR AA genotype was found increased in comparison with controls. Individuals AA will also be homozygous for 2DL3, which in contrast to 2DL2, show a weaker interaction with C1 ligands and therefore a weaker inhibition. The present study might support that in RSA patients, the balance between inhibitory and activating receptors present in natural killer cells is inclined toward an activating state that may contribute to pregnancy loss. Fil: Flores, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Marcos, C. Y.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Paladino, Natalia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Arruvito, Maria Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Williams, F.. Belfast City Hospital; Irlanda Fil: Middleton, D.. Belfast City Hospital; Irlanda Fil: Fainboim, Leonardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

This study was designed to investigate the role of KIR genes in the outcome of HCV infection. In patients who cleared the virus (HCV RNA-) we found a decrease of 2DL2 (p=0.04), and 2DS2 (p=0.014) accompanied by an increase of 2DS5 (p=0.04). Those RNA+ patients with elevated levels of hepatic transaminases (HCV RNA+ elevatedALT) showed an increased frequency of 2DS3 (p=0.018). Additionally, in cirrhotic patients we found an increased frequency of individuals having two copies of 3DS1 and HLA-Bw4 (p=0.016). We conclude that higher NK cytotoxicity might be associated with a worse progression of the HCV infection. Fil: Paladino, Natalia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Flores, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Marcos, Cintia Yanina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Fainboim, Hugo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Theiler, Gerardo Raul. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Arruvito, Maria Lourdes. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Williams, F.. Belfast City Hospital; Irlanda Fil: Middleton, D.. Belfast City Hospital; Irlanda Fil: Fainboim, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; Argentina

BackgroundEpstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study.MethodologyWe included 90 families with 90 HL index cases (age 16-35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families.Principal findingsFive KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23-0.85] and 0.42[0.21-0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18-71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells.ConclusionsThis work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.

This review updates the on-going investigations into KIR genes and their alleles with the main emphasis on what has taken place in this laboratory over the last 3 years.

Polymerase chain reaction–sequence-specific oligonucleotide probes typing procedures identifying alleles of the killer immunoglobulin–like gene (KIR2DL4) have been established. The methods, designed around the specific amplification of the D0 and D2 domains of this gene, produce discrimination of KIR2DL4 alleles. The methods have been applied to a healthy Northern Irish control group, establishing frequencies for this Caucasian population. Additionally, the KIR2DL4 allele status of cell line DNA and CEPH families, from the 13th International Histocompatibility Workshop and local families, have also been investigated.

The major histocompatibility complex (MHC) is located in the region 9p216pter on the short arm of chromosome 6 and encompasses approx 4000 kilobases of genomic DNA. Contained within this complex are numerous genes with immune-related functions: notably the class I and class II human leukocyte antigens (HLA), tumor necrosis factor A and B, the complement genes, and genes that orchestrate the transport (TAP) and processing (LMP) of antigens for presentation. The HLA class I (HLA-A, HLA-B, HLA-C) and HLA class II (HLA-DR, HLA-DQ, HLA-DP) cell surface glycoproteins present antigenic peptides to CD8(+) and CD4(+) T cells, respectively, and play a central role in mediating the immune response. The HLA class I and class II genes display extreme degrees of polymorphism, making the MHC region the most polymorphic and densely populated area of the human genome. It is now well established that certain HLA specificities are strongly associated with numerous diseases, especially those with an autoimmune dimension, and confer resistance/susceptibility to certain infectious diseases. The possibility that HLA identity may have a genetic role in longevity in humans has long been suspected, spurred on by the importance of the HLA antigens in the immune response and data from studies in mice indicating that genes in the MHC region are associated with a significant effect on life-span. The results to date from these studies are confusing and contradictory, with no consistent association found as yet (1).

The polymorphic nature of the KIR3DL1/S1 gene complex has been investigated through the development of a polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) allele typing system. The KIR3DL1/S1 system was applied to a healthy group of Northern Irish individuals to establish allele frequencies within this Caucasian population. Additionally, cell line DNA and CEPH families, both from the 13th International Histocompatibility Workshop, and local families have been investigated. The generated data emphasize the complexity and highly polymorphic nature of this KIR gene complex; 11 allelic variations were identified, 2 of which are novel to this study. Use of the PCR-SSOP system has confirmed the presence of multiple copies of KIR3DL1/S1 alleles in a number of individuals.

PCR-SSOP identification procedures for IL-2, IL-6, IL-10, TNF-α and TNF-β cytokine polymorphisms have been developed. Application of the procedures to a range of diverse geographically distributed populations has identified ethnic differences within the groups studied. Five populations were investigated, Northern Ireland, South African Zulu, Omani, Singapore Chinese and Mexican Mestizos.

A DNA typing procedure, based on a two stage polymerase chain reaction–sequence-specific oligonucleotide probe (PCR-SSOP) typing strategy, has been developed and applied to DNA from 1000 healthy individuals from the Northern Ireland region. The two-stage procedure involves human leukocyte antigen (HLA-C) identification through the use of a medium resolution PCR-SSOP system, followed by four secondary group specific PCR-SSOP systems, to enable allele resolution. The PCR-SSOP systems were designed for the identification of HLA-Cw alleles with possible discrimination within exons 2 and 3 of the HLA-C gene, i.e. , HLA-Cw*01–Cw*16. PCR-SSP tests were designed for the resolution of HLA-Cw*17 and -Cw*18 alleles. The systems can also be used independently of each other if selective allele resolution is required. HLA-Cw allele frequencies occurring within the Northern Ireland population have been compiled, along with estimations of HLA-B/Cw haplotype frequencies.

High resolution PCR-SSOP typing methods for HLA-B identification have been established and applied to a Northern Ireland population, using large enough numbers to give dependable allele frequencies. The six systems, which operate independently of each other, are intended for use as secondary typing systems following HLA-B identification with a medium resolution PCR-SSOP technique.