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Biomedical subjects

E Lawlor

Publications and source records attributed to E Lawlor.

At least 19 recordsLinked to original sources
PubMed2006

Human leucocyte antigen class II polymorphism in Irish patients with multiple sclerosis.

The contribution of human leucocyte antigen (HLA) to the genetic risk for multiple sclerosis (MS) in patients of Northern European Caucasoid ancestry has been known since the 1970s. The northern part of Ireland, including county Donegal, is known to be a high-risk area for the development of MS. Recorded prevalence rates for county Wexford in the south-east Ireland have been markedly lower and suggest the existence of a prevalence gradient within the island. To evaluate the association of HLA-DRB1 and -DQB1 haplotypes with MS in both Wexford and Donegal, we examined a total of 118 patients and 400 regionally matched controls. The aim of this exploratory study was to test the possibility of heterogeneity in HLA class II associations with MS and to identify potential predisposing or protective haplotypes, associated with MS risk in Ireland. We confirmed the association of DRB1*1501-DQB1*0602 haplotype carriage with MS in both Wexford [odds ratio (OR) = 2.95, P= 0.0020, P(cor)= 0.0220] and Donegal (OR = 2.29, P= 0.0030, P(cor)= 0.0420). A higher frequency and a significantly higher homozygosity rate of this haplotype in Donegal are likely contributing factors to the higher prevalence of MS in Donegal compared with Wexford. The distribution of HLA class II alleles among Irish MS patients and controls establishes that there is heterogeneity in HLA class II associations with MS within Ireland.

Adult↗
PubMed2003

Two sets of HLA Class II DRB and DQB1 alleles co-segregate among family members in a single maternal haplotype.

HLA class II typing by sequence specific oligonucleotide probes (SSOP) on the family of a Burkit's Lymphoma patient produced hybridization patterns indicating the presence of two DRB1, and two linked DQB1 genes on the same maternal chromosome. DRB and DQB1 exon 2 amplification products associated with the novel maternal haplotype were identified by DNA typing techniques: These products corresponded to DRB1*0101, DRB1*1501, DRB5*01, DQB1*0501 and DQB1*0602 alleles. These alleles were seen to co-segregate among siblings sharing the same maternal haplotype. The patient, his mother and two of his siblings each appeared to possess elements of three DRB1, DQA1 and DQB1 genes. HLA DNA typing results indicated that a DNA sequence of approximately 100 Kb, spanning the region between, and including, DRB1 and DQB1 genes was inserted into the maternal haplotype. Serological typing on EBV transformed B lymphocytes obtained from the patient's mother showed three expressed DRB1 antigens. Serology on EBV transformed patient's cells also indicated multiple DRB1 antigen expression. The expression of three DRB1 and DQB1 genes on the cells of this patient would make it virtually impossible to obtain a suitably matched unrelated stem cell donor.

Alleles↗
PubMed2002

Identification and nucleotide sequence of a new null allele, HLA B*3540N.

We report the definition of an HLA class I null allele that has been identified within the B35 group by a combination of serological and molecular typing. This allele, which has been named B*3540N, was detected in a French, potential unrelated hematopoietic stem cell donor of unknown ethnic origin, selected as a probable match for an Irish patient. The presence of the null allele was initially determined by the absence of B35 reactivity by serological typing, in contrast to positive reactions by PCR-SSP and PCR-SSO typing. Subsequent sequencing of clones containing the full genomic sequence of the B*35 allele identified a single nucleotide deletion within exon 4 which resulted in the introduction of a stop codon downstream within exon 4.

Alleles↗
PubMed2001

Case report: four donors with granulocyte-specific or HLA class I antibodies implicated in a case of transfusion-related acute lung injury (TRALI).

A 54-year-old female patient with a history of chronic liver disease and portal hypertension was admitted for an elective cholecystectomy. Preoperative evaluation revealed a prolonged prothrombin time of 17.4 seconds (control 12 to 15.5 seconds). Six units of fresh frozen plasma (FFP) were prescribed after failure of correction of the coagulopathy with intravenous vitamin K (10 mgs). During infusion of the fifth unit of FFP, the patient became acutely dyspneic. Arterial blood gas analysis revealed marked hypoxemia (PO(2) 6.58 kPa) and the chest X-ray showed new diffuse bilateral alveolar infiltrates. The patient remained hypoxemic with unstable oxygen saturations over the following 7 days, during which time she required 60 to 100 percent oxygen administered by face mask. Intravenous methylprednisolone (200 mgs) was given for 5 days. Mechanical ventilation was not required. The lung infiltrates gradually cleared over 3 to 4 days and the patient showed clinical improvement after 1 week. Four of the donors of the implicated units of plasma were female and all had a history of pregnancy. Two donors had HLA class I antibodies and two had granulocyte-specific antibodies detectable in their serum. In crossmatch studies, granulocyte-reactive antibodies from two donors bound to granulocytes from the patient, which suggested that these antibodies were clinically relevant. These clinical and serologic findings support a diagnosis of transfusion-related acute lung injury (TRALI).

Journal Article↗
PubMed2000

The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C.

BACKGROUND & AIMS: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype 1b from a single inoculum. METHODS: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects. RESULTS: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs. 8.8% and 14.2%, respectively; P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively; P = 0.001). Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy. CONCLUSIONS: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection.

Adult↗
PubMed1999

A likelihood-based method of identifying contaminated lots of blood product.

BACKGROUND: In 1994 a small cluster of hepatitis-C cases in Rhesus-negative women in Ireland prompted a nationwide screening programme for hepatitis-C antibodies in all anti-D recipients. A total of 55 386 women presented for screening and a history of exposure to anti-D was sought from all those testing positive and a sample of those testing negative. The resulting data comprised 620 antibody-positive and 1708 antibody-negative women with known exposure history, and interest was focused on using these data to estimate the infectivity of anti-D in the period 1970-1993. METHODS: Any exposure to anti-D provides an opportunity for infection, but the infection status at each exposure time is not observed. Instead, the available data from antibody testing only indicate whether at least one of the exposures resulted in infection. Using a simple Bernoulli model to describe the risk of infection in each year, the absence of information regarding which exposure(s) led to infection fits neatly into the framework of 'incomplete data'. Hence the expectation-maximization (EM) algorithm provides estimates of the infectiousness of anti-D in each of the 24 years studied. RESULTS: The analysis highlighted the 1977 anti-D as a source of infection, a fact which was confirmed by laboratory investigation. Other suspect batches were also identified, helping to direct the efforts of laboratory investigators. CONCLUSIONS: We have presented a method to estimate the risk of infection at each exposure time from multiple exposure data. The method can also be used to estimate transmission rates and the risk associated with different sources of infection in a range of infectious disease applications.

Algorithms↗
PubMed1999

Variation of hepatitis C virus following serial transmission: multiple mechanisms of diversification of the hypervariable region and evidence for convergent genome evolution.

We have studied the evolution of hepatitis C virus (HCV) from a common source following serial transmission from contaminated batches of anti-D immunoglobulin. Six secondary recipients were each infected with virus from identifiable primary recipients of HCV-contaminated anti-D immunoglobulin. Phylogenetic analysis of virus E1/E2 gene sequences [including the hypervariable region (HVR)] and part of NS5B confirmed their common origin, but failed to reproduce the known epidemiological relationships between pairs of viruses, probably because of the frequent occurrence of convergent substitutions at both synonymous and nonsynonymous sites. There was no evidence that the rate at which the HCV genome evolves is affected by transmission events. Three different mechanisms appear to have been involved in generating variation of the hypervariable region; nucleotide substitution, insertion/deletion of nucleotide triplets at the E1/E2 boundary and insertion of a duplicated segment replacing almost the entire HVR. These observations have important implications for the phylogenetic analysis of HCV sequences from epidemiologically linked isolates.

Adolescent↗
PubMed1999

Transmission rates of hepatitis C virus by different batches of a contaminated anti-D immunoglobulin preparation.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the hepatitis C virus (HCV) infection rate of recipients of different batches of anti-D immunoglobulin associated with an outbreak of HCV infection which occurred in 1977 and its relationship to the polymerase chain reaction (PCR) status of the implicated batches. This study was undertaken to determine the predictive value of HCV genome detection and quantification for subsequent infection in recipients of an HCV-contaminated anti-D immunoglobulin product for intravenous use. MATERIALS AND METHODS: Sera from recipients of anti-D were tested by HCV enzyme immunoassay and if found positive were subsequently tested by recombinant immunoblot assay and HCV PCR in a national HCV anti-D screening programme set up in 1994. The HCV status of 1,342 known recipients of infectious or potentially infectious batches has been compared to the amount of HCV RNA in the anti-D batch they received so as to determine the value of PCR in the prediction of infectivity in immunoglobulin preparations. RESULTS: It has been demonstrated that HCV-infected plasma derived from batches of anti-D showing levels of viral genome in excess of 10(4) genomes per millilitre led to infection of up to 60% of recipients. In contrast, batches with undetectable levels of HCV genome very rarely transmitted infection. CONCLUSIONS: The presence of HCV RNA in intravenous immunoglobulin preparations which have not undergone a specific viral inactivation step is a predictor of HCV infection in recipients.

Disease Outbreaks↗
PubMed1999

A second outbreak of hepatitis C virus infection from anti-D immunoglobulin in Ireland.

OBJECTIVE: To investigate the infectivity for hepatitis C virus (HCV) of intravenous anti-D immunoglobulin batches manufactured in Ireland between 1991 and 1994. METHODS: Women who had received anti-D manufactured between 1991 and 1994 were screened for serological markers of HCV infection and for the presence of HCV RNA by RT-PCR amplification and virus genotyping. RESULTS: 44 women exposed to anti-D manufactured between 1991 and 1994 were polymerase chain reaction positive for HCV RNA, 19 of whom were infected with genotype 3a virus shown by phylogenetic analysis of the NS5B gene to be closely related to that from the single implicated donor. CONCLUSIONS: Anti-D manufactured in 1991-1994 transmitted infection of HCV genotype 3a. The prevalence of HCV-specific antibody in anti-D recipients was relatively low (0.59%), consistent with the low level of virus RNA in these anti-D batches.

Disease Outbreaks↗
PubMed1998

Risk of hepatitis C infection in neonates transfused with blood from donors infected with hepatitis C.

This look-back study was undertaken to identify newborn infants who had been infected with the hepatitis C virus (HCV) as a result of transfusions received before the introduction of routine screening in 1991 and to determine the transmission rates and persistence of transfusion-transmitted HCV infection acquired in the neonatal period. A total of 24 infants, transfused between 1980 and 1991, were identified as having received potentially infected blood from 11 blood donors. Ten of the donors had been administered batches of anti-D in 1977 known to have transmitted HCV genotype 1b infection. HCV RNA was detected in five of these donors when tested in 1994-95; the past donations of five of the donors, who had received anti-D immunoglobulin and had serological evidence of previous HCV infection but who were PCR negative when tested in 1994-95, were considered of lower risk. The source and time of acquisition of HCV infection for the one remaining donor in the study was not determined. Twenty-one (88%) of the 24 children were living at time of lookback. The median age at transfusion was 12 days. The median age at time of testing was 6.3 years. One child, who tested negative, was excluded from further analysis of HCV transmission, due to incomplete transfusion records. Overall, 12 of 20 (60%) children tested were positive for anti-HCV and seven (35%) were HCV RNA positive. Twelve (71%) of the 17 recipients of viraemic blood were ELISA positive and seven (41%) were PCR positive. Resolved HCV infection, as determined by ELISA pos, RIBA pos or indeterminate and PCR negativity, occurred in five of 12 (42%). In many instances there was more than one recipient per HCV infected donation. All of the reported children are clinically asymptomatic. However, the duration of HCV infection is relatively short and there is evidence of a degree of hepatitis in five of the seven children who are HCV RNA positive as judged by mildly elevated transaminase levels. The three who have undergone liver biopsy show mild hepatitis. The lower rates of persistence of HCV infection in this study may be due to the young age at exposure or to the source of infection which for all but one of the children was linked to one HCV genotype from female donors. Sharing of units of blood among multiple infants should be discouraged.

Adolescent↗
PubMed1998

Long-term evolution of the hypervariable region of hepatitis C virus in a common-source-infected cohort.

The long-term evolution of the hepatitis C virus hypervariable region (HVR) and flanking regions of the E1 and E2 envelope proteins have been studied in a cohort of women infected from a common source of anti-D immunoglobulin. Whereas virus sequences in the infectious source were relatively homogeneous, distinct HVR variants were observed in each anti-D recipient, indicating that this region can evolve in multiple directions from the same point. Where HVR variants with dissimilar sequences were present in a single individual, the frequency of synonymous substitution in the flanking regions suggested that the lineages diverged more than a decade previously. Even where a single major HVR variant was present in an infected individual, this lineage was usually several years old. Multiple lineages can therefore coexist during long periods of chronic infection without replacement. The characteristics of amino acid substitution in the HVR were not consistent with the random accumulation of mutations and imply that amino acid replacement in the HVR was strongly constrained. Another variable region of E2 centered on codon 60 shows similar constraints, while HVR2 was relatively unconstrained. Several of these features are difficult to explain if a neutralizing immune response against the HVR is the only selective force operating on E2. The impact of PCR artifacts such as nucleotide misincorporation and the shuffling of dissimilar templates is discussed.

Amino Acid Sequence↗
PubMed1997

The origin of hepatitis C virus genotypes.

For many RNA viruses, relatively recent times of origin of extant viruses are implied by the high rate of substitution observed in longitudinal studies. However, extrapolation of short-term rates of substitution can give misleading estimates of times of divergence. We show here that the common ancestor of different types of hepatitis C virus (HCV) is older than previously thought. The rate of HCV sequence change was measured amongst a cohort of individuals infected following administration of anti-D immunoglobulin. Virus sequences were obtained in the E1 and NS5B genes and compared with each other and with sequences from an infective batch. Taking account of the bias towards synonymous transition substitutions, the time of divergence of variants of subtype 1b is estimated to have occurred 70-80 years ago. The numerous subtypes of HCV are proposed to derive from more than 300 years of endemic infection in certain geographical regions, with recent spread of some subtypes to other parts of the world. Estimation of the time of origin of the major HCV genotypes (types 1-6) is problematic, but our data and analogy with other viruses suggest that divergence occurred at least 500-2000 years ago.

Antibodies, Anti-Idiotypic↗
PubMed1997

Distribution of HLA-A, B and DR genes and haplotypes in the Irish population.

The distribution of HLA phenotypes, genes and haplotypes in the normal population is of considerable importance in, for example, disease susceptibility studies, platelet transfusion support and transplantation. HLA population genetics studies have been carried out on numerous population samples, however, no major studies have been performed on Irish Caucasoids. We have analysed the HLA-A, B and DR phenotypes of 1,910 healthy unrelated Irish blood donors recruited onto the Irish Bone Marrow Donor Panel. HLA typing was performed by a combination of serology, the polymerase chain reaction with sequence-specific primers and reverse hybridisation. We calculated Hardy-Weinberg fit, phenotype and gene frequencies and two- and three-locus haplotype frequencies, linkage disequilibrium (LD) values and their significance levels and relative LD values. Compared to many other European populations, the Irish show a high frequency of HLA-A1, B7, B8 and DR2 and a reduced frequency of HLA-A9, A30, B15 and DR4. Two- and three-locus haplotypes and the combinations of alleles in positive LD were all typical of northern European populations. However, the Irish have especially high frequencies of the common HLA-A1/B8, A2/B44, A3/B7, HLA-B8/DR3, B7/DR2, B44/DR4 and B44/DR7 haplotypes, while the frequency of other relatively common haplotypes, e.g. HLA-A2/B15, is reduced. These frequencies are of particular value for estimating the likelihood of finding bone marrow donors in patients' extended families and unrelated donor panels.

Adolescent↗
PubMed1996

Association of celiac disease with microsatellite polymorphisms close to the tumor necrosis factor genes.

Celiac disease is tightly linked to the MHC class II region on chromosome 6. We have studied two highly polymorphic microsatellite loci, TNFa and b, near the TNF genes in the class III region of the MHC, for evidence of their association to CD, as compared to a control population. Our findings show that the microsatellite allele most significantly associated with the disease is TNFb3, which is found in 86.3% of CD patients versus 24.5% of controls, with allele frequencies of 0.5392 and 0.1290, respectively (p < 0.001). The TNFa2 allele had a frequency of 0.6122 in CD patients and 0.2627 in controls (p < 0.001), with phenotype frequencies of 87.8% and 50.0%, respectively. TNFa6 and -a11 and TNFb5 have significantly reduced frequencies in CD patients. TNFb3 shows a maximal level of linkage disequilibrium with HLA-DQB1*0201 in celiac patients. However, while the DQB1*0201/TNFa2 haplotype was strongly associated with CD, DQB1*0201 was not significantly in linkage disequilibrium with TNFa2, suggesting that TNFa2 is independently associated with CD. This association could have functional significance as TNFa2 has been correlated with high TNF production.

Celiac Disease↗
PubMed1996

Hepatitis A transmission by factor IX concentrates.

Factor IX concentrates unlike factor VIII concentrates have not to date been associated with the transmission of hepatitis A virus (HAV). A retrospective study by reverse transcriptase polymerase chain reaction on a batch of factor IX concentrate used to treat two haemophilia B patients who developed jaundice and IgM anti-HAV antibodies within 50 days of factor IX administration in 1985 revealed the presence of HAV RNA. These findings indicate that factor IX concentrates can transmit HAV and that appropriate viral inactivation steps to inactivate nonenveloped viruses as well as enveloped viruses are necessary to ensure the safety of factor IX concentrates.

Adult↗