Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure.

OBJECTIVE: The possible molecular mimicry of the Epstein-Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B'/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3-1,025, P < 10(-11)). These results were confirmed at the level of EBV DNA (OR > 10, 95% CI 2.53-infinity, P < 0.002). Much smaller seroconversion rate differences were found against 4 other herpes viruses. Herein, we extend these studies to adults and test the hypothesis that EBV infection is associated with adult SLE. METHODS: We selected 196 antinuclear antibody-positive adult SLE patients (age > or =20 years) and 2 age-, race-, and sex-matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), or varicella-zoster virus (VZV) by standardized enzyme-linked immunosorbent assays. RESULTS: Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV-2, or VZV. CONCLUSION: These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.

Single nucleotide polymorphism in prohibitin 3' untranslated region and breast-cancer susceptibility.

The RNA encoded by the 3' untranslated region of the prohibitin gene arrests cell proliferation by blocking the transition between the G1 and S phases of the cell cycle. The product of a variant allele (T allele) is inactive. We did a case-control study of prohibitin genotype in 205 women with breast cancer and 1046 healthy controls. The results showed an association between the T allele and breast cancer in women who reported a first-degree relative with the disease (odds ratio 2.5, p=0.005). An even stronger association was found in a subset of women diagnosed at or before age 50 years (4.8, p=0.003). These data suggest that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least one first-degree relative with the disease.

The relation between newborn hemoglobin F fractions and risk factors for sudden infant death syndrome.

OBJECTIVES: The aims of this study were to determine and compare fetal hemoglobin (HbF) fractions at birth in newborns exposed and not exposed to selected factors that have been reported to increase the risk of sudden infant death syndrome (SIDS). Previous studies have implicated HbF in the etiology of SIDS by finding higher fractions in infants dying from SIDS compared to age-matched control infants. DESIGN: We performed a cross-sectional study using high-performance liquid chromatography to measure HbF fractions in newborn cord blood samples. Exposure to selected risk factors for SIDS was assessed through review of medical records. PARTICIPANTS: Six hundred thirty-three infants born at Via Christi Regional Medical Center-St Francis Campus, Wichita, Kan, from February 28 through August 5, 1997. MAIN OUTCOME MEASURE: Hemoglobin F fractions at birth were compared in newborns exposed and not exposed to selected risk factors associated with increased incidence of SIDS. RESULTS: Mean HbF fractions were significantly higher in preterm newborns of mothers who smoked and in term newborns with intrauterine growth restriction, pregnancy weight gain less than or equal to 9 kg, and pregnancy complications associated with reduced placental blood flow. An elevated newborn HbF fraction, defined as 77% or greater, was significantly associated with maternal smoking, maternal anemia, intrauterine growth restriction, and pregnancy complications associated with reduced placental blood flow. CONCLUSION: This study suggests a possible mechanism (HbF) by which previously identified factors may increase the risk of SIDS.

Autoantibodies to the 20-kDa ribosomal proteins: identification, characterization, and new aspects on prevalence in systemic Lupus erythematosus.

Autoantibodies to the 20-kDa ribosomal proteins (L12/S10) are not well studied, especially in juveniles with systemic lupus erythematosus (SLE). Randomly selected sera from American juveniles and adults with SLE were screened for antibodies to either 20-kDa protein and P proteins and then assayed for anti-L12 and anti-S10 by immunoblot assays. In a pilot study of patients with anti-P (Cohort 1), IgG antibodies to either 20-kDa protein and, specifically, to L12 were observed in 72 and 42% of juveniles and adults, respectively. IgG antibodies to S10 were detected less frequently. In Cohort 2 patients who were chosen irrespective of autoantibody status, twice as many juveniles as adults had IgG antibodies to either 20-kDa protein. Prevalences of IgG anti-L12 and IgG anti-S10 antibodies in the juveniles were 28 and 16% and in the adults were 13 and 12%, respectively. Anti-L12 were strongly but not invariably associated with anti-P, and usually arose temporally to these antibodies. Anti-S10 activity was due to anti-Sm antibodies. We conclude that IgG anti-L12 are more prevalent in SLE than previously reported, and are responsible for the majority of activity toward the 20-kDa ribosomal proteins, especially in juveniles.

The health agency training program: continuing education courses in biostatistics and epidemiology.

The authors describe the development and evaluation of a continuing education program in biostatistics and epidemiology. Short courses were presented to public health and mental health professionals using teaching strategies that included lecture, discussion, practice-oriented examples, and interactive problem-solving. A total of 1723 health professionals attended one or more of the 120 courses presented from 1992 to 1996 in seven US states. Most course participants were female: the highest education level for 40% was a bachelor's degree, while 42% had advanced degrees. Approximately 66% of participants signed up for continuing education credits. The program represents a successful partnership between an academic institution and health agencies in a seven-state region.

Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving at least hormonal, environmental, and genetic factors. Familial aggregation, a 2%-3% sibling recurrence rate, monozygotic twin concordance >20%, association with several candidate genes, as well as the results of five genome scans support a genetic component. We present here the results of a genome scan of 126 pedigrees multiplex for SLE, including 469 sibling pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sibling pairs and a conditional logistic regression technique for affected relative pairs, we identify a novel linkage to chromosome 4p16-15.2 (P=.0003 and LOD=3.84) and present evidence of an epistatic interaction between chromosome 4p16-15.2 and chromosome 5p15 in our European American families. We confirm the evidence of linkage to chromosome 4p16-15.2 in European American families using data from an independent pedigree collection. In addition, our data support the published results of three independent studies for nine purportedly linked regions and agree with the previously published results from a subset of these data for three regions. In summary, results from two new analytical techniques establish and confirm linkage with SLE at 4p16-15.2, indicate epistasis between 4p16-15.2 and 5p15, and confirm other linkage effects with SLE that have been reported elsewhere.

Secular trends in the prevalence of HIV infection among a population of males with hemophilia, 1988-1997: the Oklahoma Hemophilia Surveillance System.

Tracking the natural history of HIV/AIDS in the hemophilia community is useful for planning future health care needs and for adjusting estimates of the prevalence of hemophilia as the impact of HIV/AIDS wanes over time. The present study was designed to determine the annual prevalence of HIV infection from 1988 through 1997 in a population of males with hemophilia A or B. Data were obtained from the Oklahoma Hemophilia Surveillance System and were limited to individuals who were seen at the Oklahoma Hemophilia Treatment Center. In 1988, the prevalence rate of HIV infection was 34 percent. Rates have declined in each subsequent year through 1997. The highest rates of HIV infection were observed in persons with severe hemophilia and hemophilia A. The overall prevalence rates of HIV infection in this treatment center population are lower than those reported in other populations. No new cases of HIV infection were observed in persons with hemophilia born after 1985.

Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41.

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs. METHODS: Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests. RESULTS: A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229. CONCLUSION: Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.

Practice differences between male and female oral and maxillofacial surgeons: survey results and analysis.

PURPOSE: This study describes the personal and practice characteristics of oral and maxillofacial surgeons, with an emphasis on gender differences. Potential explanations for differences found are offered. MATERIALS AND METHODS: A 39-item questionnaire was designed to address areas of suspected differences between male and female oral and maxillofacial surgeons. It included items regarding training, certification, practice type and location, time spent working, practice composition, and personal characteristics. Identical questionnaires were sent to all of the 130 female oral and maxillofacial surgeons (OMSs) registered with AAOMS, as well as to 264 randomly sampled male OMSs. RESULTS: Of the 192 responses received, 109 were from male surgeons, and 83 were from females, 56.8% versus 43.2% of the total. For men, the response rate was 41.3%, whereas the rate was 68.3% for the women; overall, 48.7% of the 394 oral surgeons responded. Profiles of the "average" male and female OMS showed similarities with regard to race, training, and reasons for choosing an OMS career. Age, marital status, number of children, physical characteristics, and use of time outside of work indicated some significant personal differences, as did practice characteristics, including income, number of years in practice, hours spent working, and number of patients seen. Clear gender-based trends were found regarding opinions of physical and mechanical disadvantages, with women more strongly denying such problems. A variety of both positive and negative viewpoints were elicited by the free comment section. CONCLUSIONS: Although male and female OMSs are similar with regard to most variables investigated, some significant differences do exist.

Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree.

OBJECTIVE: To evaluate an unusual pedigree with 8 members diagnosed with systemic lupus erythematosus (SLE) METHODS: Pedigree members were evaluated through questionnaires, interviews, and medical records. Sixty members contributed serum samples for autoantibody analysis. RESULTS: The 8 affected females shared several disease features, including arthritis (8/8), antinuclear antibodies (ANA) (8/8), pleuritis (6/8), malar rash (6/8), photosensitivity (5/8), and nephritis (4/8). A total of 15 of 51 (29%) blood relatives had autoantibodies; 9 had autoimmune disease, including 7 with SLE, one with psoriasis, and one with Sjögren's syndrome. Five of 11 (45%) nonconsanguineous spouses also had autoantibodies; one spouse had SLE, and 2 others had thyroid disease. Among 68 spouses of patients with SLE in other pedigrees, only 9 (13%) had autoantibodies, and none were symptomatic (p = 0.02). CONCLUSION: The high rate of autoimmunity among both blood relatives and nonconsanguineous mates in this unusual pedigree suggests a complex interaction of genetic and environmental factors contributing to disease.

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Prenatal survival of mouse embryos irradiated in utero with fission neutrons or 250 kV X-rays during the two-cell stage of development.

PURPOSE: To investigate the relationship between radiation dose at the two-cell stage and prenatal survival. MATERIALS AND METHODS: Pregnant mice were irradiated with fast neutrons (0.53-1.94 Gy) or X-rays (1.50-5.00 Gy), or sham irradiated. At selected times up to gestation day 16, the mice were killed and the uterine contents examined. RESULTS: At doses up to 0.82 Gy of neutrons and 2.50 Gy of X-rays, all or virtually all the radiation-induced deaths occurred during the period from the time of implantation to gestation day 10. At higher doses an appreciable proportion of the deaths occurred after day 10. Many neutron-induced deaths in the period from implantation to day 10 occurred before day 7. A mathematical model was developed for estimating survival to gestation day 16 as a function of neutron dose. CONCLUSIONS: The mortality pattern, in which low radiation doses led to early deaths and high doses to both late and early deaths, suggests the existence of two lethal processes. The relationship between neutron dose and survival to gestation day 7 has been interpreted as indicating that the early deaths involved predominantly a two-event inactivation mechanism. An individual cell of a two-cell embryo was found to be less sensitive to lethal radiation injury than a pronuclear zygote.

The presence of masked antiribosomal P autoantibodies in healthy children.

OBJECTIVE: To determine if antiribosomal P (anti-P) autoantibodies are present in healthy children. METHODS: Sera from healthy children were screened for anti-P by conventional enzyme-linked immunosorbent assay and immunoblot techniques. Sera were also treated with immobilized ribosomal P antigens on nitrocellulose strips; affinity-purified fractions were tested for anti-P by high-sensitivity immunoblot. The relative binding affinities were compared for affinity-purified anti-P antibodies from healthy children and adults, and patients with systemic lupus erythematosus. IgG fractions of anti-P-depleted sera from healthy children were assessed for inhibition of autologous anti-P activity. RESULTS: Conventional serologic screening showed no IgG nor IgM anti-P in 88 untreated sera. IgG anti-P were unmasked in all 79 sera treated by the membrane batch affinity technique. IgM anti-P were identified in 27 of the treated sera; the percentage of positive sera decreased with increasing age (chi(2) for linear trend P = 0.00081). Affinity-purified anti-P from children had relative binding affinities similar to those of anti-P from other groups. Sera from healthy children contained inhibitory IgG antibodies to anti-P. CONCLUSION: These results show that anti-P autoantibodies are present in all healthy children. The majority of these autoantibodies are masked by IgG antibodies, suggesting concordant development of a regulatory network.

Anti-ribosomal and 'P-peptide'-specific autoantibodies bind to T lymphocytes.

Patients with systemic lupus erythematosus (SLE) frequently have anti-lymphocyte autoantibodies, some of which also bind to surfaces of neurons. Since anti-ribosomal P protein autoantibodies (anti-P) from SLE patients also bind to surfaces of neurons, we hypothesized that anti-P are anti-lymphocyte antibodies. A panel of human T lymphocytes was evaluated for anti-P binding by indirect immunofluorescence. Affinity-purified anti-ribosomal antibodies were used as a source of anti-P. These autoantibodies bound to the surfaces of all transformed T cell lines tested. This binding was not mediated by Fc receptors. It was inhibitable by ribosomes. Anti-P bound to circulating T lymphocytes from healthy adults and children. They also bound to thymocytes and cord blood T cells from normal neonates. Circulating T cells from SLE patients with anti-P bound less anti-P than cells from healthy controls. Two patients were studied on multiple occasions. The capacity of their T cells to bind anti-P correlated inversely with titres of anti-ribosomal antibodies. Anti-ribosomal antibodies, other than anti-P, also appear to bind to T cells. The surface of T cells contains a protein with the size and antigenicity of the ribosomal P protein, P0. We conclude that anti-ribosomal antibodies are a subset of anti-lymphocyte autoantibodies. Their possible role in the pathogenesis of lymphopenia or lymphocyte dysfunction in SLE has to be defined in further studies.

Logistic transmission modeling for the simulated data of GAW10 problem 2.

A recently developed nonparametric method is a generalization of the transmission disequilibrium test across all alleles of a locus. This approach has been applied to Problem 2 of GAW10 and has been extended to explore the combined contribution of neighboring loci for chromosomes 1, 5, and 8. When applied to the chromosome 5 data of the first replicate of the nuclear pedigrees from Problem 2 of GAW10, the data show that four of the 25 loci obtain a probability less than 0.05. However, when combined models composed of each potentially significant marker (p < 0.05) and its nearest neighbors are considered, the combined contributions of G14 and G15 are the most significant (p = 0.007). Consequently, the region near G14 and G15 is identified as the best candidate region in chromosome 5 for linkage to the common disease.

Immunogenetics of epitopes of the carboxyl terminus of the human 60-kD Ro autoantigen.

Systemic lupus erythematosus is associated with the presence of autoantibodies which bind several ribonucleoproteins, including Ro (or SS-A). We have explored the relationship of the HLA-DQ and T cell receptor alleles in patients producing autoantibodies binding the 13-kD carboxyl terminus fragment of the 60-kD Ro and with autoantibodies binding a peptide epitope within this fragment (amino acid residues 480-494). Antibodies binding the 13-kD fragment are more likely to be found in the sera of patients with particular DQA1 and DQB1 alleles, while antibodies binding the epitope at 480-494 are found almost exclusively in the sera of patients with a Bg/II 9.8-kb polymorphism of the T cell receptor beta gene. Meanwhile, in these same patient sera the level of autoantibodies binding the complete 60-kD Ro particle is associated with a distinct pattern of alleles at these same immunoregulatory loci. These data demonstrate that component parts of autoantibody responses may be under genetic control which can be distinguished from the HLA associations characteristic of the response to the intact, complete autoantigen.

Logistic transmission modeling of simulated data.

A nonparametric method for linkage analysis has been developed and applied to the Problem 1 data set of the Genetic Analysis Workshop 9. Basically, the univariate matched pair strategy of the transmission disequilibrium test has been adapted to multivariate modeling using the conditional logistic function. After setting the critical value for significance at p < or = 0.0001, models at only D5G23 and D1G31 appear to be significant (p < 10(-7)). Logistic transmission modeling is a powerful method for establishing linkage by disequilibrium.

Cooperative association of T cell beta receptor and HLA-DQ alleles in the production of anti-Ro in systemic lupus erythematosus.

The immunogenetics of the autoantibody response to Ro (or SS-A) have been explored in patients with systemic lupus erythematous. Data show that alleles of the T cell beta receptor and HLA-DQ loci are cooperatively associated with the presence of anti-Ro autoantibodies in systemic lupus erythematosus. Identification of HLA-DQ by oligonucleotide probe binding to polymerase chain reaction products demonstrates that the combination of DQB1*0201 and one of DQA1*0101, DQA1*0102, or DQA1*0103 is associated with anti-Ro. Patients possessing a particular pair of T cell receptor beta restriction enzyme polymorphisms along with these specific HLA-DQ alleles produce quantitatively more anti-Ro as measured by a sensitive solid-phase immunoassay than patients without these T cell receptor and DQ alleles. Other work has shown that the autoimmune response is directed against the human Ro antigen. These results are consistent with a central role in the disregulation of autoimmunity involving a trimolecular complex composed of the autoantigen bound by a HLA-DQ molecule which, together, are bound in turn by T cells which express a particular subset of T cell receptors.