HLA antigens in patients with and without a family history of schizophrenia

Frequencies of HLA antigens (A, B, C and DR) were studied in patients with (n = 49) and without (n = 67) a family history of schizophrenia and in controls. Among the patients with a family history of schizophrenia significant increases were found in the A3 and B5 antigens while significant decreases were observed for the A1, A11 and B8 antigens. In a material of schizophrenic siblings the sharing of HLA haplotypes was consistent with normal segregation.     

Role of HLA antigens in Rh (D) alloimmunized pregnant women from Mumbai, Maharashtra, India

Immunogenetic studies in various diseases provide potential genetic markers. We have studied the incidence of HLA A, B, C, DR and DQ loci antigen in Rh (D) antigen isoimmunized mothers compared to those nonimmunized isoimmunized Rh negative mothers. Seventy six mothers who were immunized to Rh (D) antigen due to pregnancy (responders) and fifty four mothers who did not develop Rh (D) isoimmunization despite positive pregnancies (nonresponders) were selected for the study. Standard methods of serological HLA typing, ABO and Rh (D) groups, and screening for Rh D antibodies were used. 392 unrelated individuals from the population were compared as controls. In addition 45 unrelated individuals from the same population were typed for HLA DRB and DQB gene using PCR-SSP kits. The genotype frequencies of HLA A2, A3, A28, B13, B17, B35, B52, B60, Cw2, Cw6, DR4, and DQ3 were significantly increased, while the frequencies of the HLA A11, A29, A31, B7, B37, B51, Cw1 and DR9 were decreased in the responder women when compared to the non-responder women. HLA A30 (19) split antigen was not identified in immunized women while HLA A23 (9) split antigen was not identified in non immunized women. HLA A3, B17, Cw2 and DR4 showed a significant relative risk among the immunized responder women. When compared with Rh immunized women (responders) reported from USA, England and Hungary the phenotype frequencies of HLA A11, A24, A28, B5, B17, B40, DR2 and DR5 were increased while HLA A23, B8, B18, and DR6 were decreased in the Indian Rh immunized women. Two locus haplotype frequency analysis observed among the responders women revealed that among the significant haplotypes expressed A2–B5, B7–Cw1, DR2–DQ1 were highly significant haplotypes in positive linkage, while A1–B5, and A1–B7 were in significant negative linkage disequilibrium. The haplotype frequencies were ≤one when these common hapoltypes were compared with control population. Thus in the present study it is evident that the inheritance of HLA A3, B17, Cw2 and DR4 increases the relative risk factor by 2.6 times among Indian Rh isoimmunized women. Further, it is evident that there are significant differences in the observed HLA antigen frequencies and two locus haplotypes in Rh isoimmunized women when compared to women from USA, UK and Hungary due to extreme HLA polymorphism in different populations of the world     

HLA genotypes and HLA-linked genetic markers in Italian patients with classical 21-hydroxylase deficiency

Summary HLA genotype and HLA-linked marker data for 40 unrelated patients from central Italy and 2 unrelated patients from Sardinia with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH-def) were analyzed. The results confirm that the HLA-linked 21-OH-def gene is associated with several different HLA determinants and complete HLA haplotypes, although the only determinant with significantly increased frequency was the complement C2 allele C2B. The HLA antigens B8 and DR3 were found in significantly decreased frequencies. The haplotype A3, Cw6, Bw47, BfF, DR7, which is exceptionally rare in the general population but which has been found in many other 21-OH-def patients from diverse geographical origins, was also found in one of the Italian patients. This and other HLA haplotype associations found among the Italian patients may represent mutations that have occurred on HLA haplotypes with genetic linkage disequilibrium or, alternatively, may represent mutations that have not yet had time to become randomly associated with different HLA complex determinants. The marked negative associations with B8 and DR3 could, however, result from an interaction between the gene products of the HLA complex and the 21-OH-def phenotype.     

Association between HLA class II antigens and hepatitis C virus infection

The aim was to confirm the influence of HLA Class II antigens on the progression of HCV infection and to assess the relationship between these antigens and histological damage, HCV viral load and HCV genotype. 143 patients were enrolled and divided into three groups. Group A included 34 anti-HCV positive, HCV-RNA negative patients with ALT persistently normal; group B included 39 patients with HCV-RNA positive and abnormal ALT level; group C included 70 normal subjects. Serological HCL typing was performed with lymphocytotoxicity test by Terasaky and McClelland, using lymphobeads HLC class II. The frequency of HLA DR11 (5) was significantly higher in the control group (52.9%) and in group A (64.7%), than in group B (28.2%). Allele HLA DR6 was demonstrated in a similar proportion (26%) among control group and group B, while HLA DR14 (6) was less frequent among controls (18% vs 1.4%). In group A the frequency of HLA DR14 (6) was 3% compared to group B, HLA DR17 (3) was prevalent (15.4%) in group B. Liver damage was associated with the detection of HLA DR14 (6) and HLD DR17 (3) antigens. Significantly lower levels of HCV-RNA were measured in subjects with HLA DR11 (5) than in these with either DR6 or DR17 (3). HLA class II antigens appear crucial for resolution or progression of HCV hepatitis. The punctual identification of these genetic factors may, therefore, prove to be useful in predicting disease evolution, in guiding the appropriate therapy for patients with poor prognosis, and in encouraging the development of now therapeutic strategies.     

Superiority of B locus matching over other HLA matching in renal graft survival.

Graft survival after 348 consecutive first cadaver-donor renal transplants was significantly improved by HLA matching when recipients who had received pretransplant blood transfusions were matched with their kidney donor for two HLA-B locus antigens. No other type of HLA matching significantly improved graft survival in transfused recipients nor did any type of HLA matching in non-transfused recipients. Matching for one HLA-DR antigen had no benefit in transfused recipients. Only two patients received kidneys matched for both DR antigens and only two of those in whom DR matching had been performed had not been transfused. These results indicate that pretransplant blood transfusion and selection of graft recipients predominantly on the basis of HLA-B matching has significantly reduced the renal graft rejection rate in Newcastle upon Tyne over two years. Thus, HLA-B antigen matching should be adopted as the main criterion for kidney sharing between transplant centres.     

Some essential elements in maternal and cord blood in relation to birth weight and gestational age of the baby

Maternal and cord blood were collected from 54 Indian women at parturition and analyzed for Zn, Cu, and Fe by flame atomic absorption spectrophotometry to determine the relationship between levels of these elements in mother’s and infant’s blood and maternal age, birth weight, and gestational age of the baby. The blood Zn level of mothers in the age group 24–28 yr was significantly higher than those of mothers in the age group of 18–23 yr (p<0.05). Similarly, mothers in the 24 to 28-yr group also had higher blood Fe level than mothers in the group 29–38 yr (p<0.05). The levels of Zn, Cu, and Fe were higher in the maternal blood and lower, but not significantly, in the cord blood of low-birth-weight babies than in those of normal-birth-weight babies. However, differences in the levels of Zn, Cu, and Fe between maternal and cord blood of the two birth-weight groups was statistically significant. There were no significant differences in the levels of the three elements in maternal or cord blood by the gestational age of the baby. A weak but significant correlation was found between the birth weight of the baby and the Fe level in the cord blood (r=0.26; p<0.05). Also, weak significant correlations were observed between gestational age of the baby and Fe (r=0.23; p<0.05) and Cu (r=0.31; p<0.05) levels in the cord blood. Although, there are many confounders of low birth weight and preterm deliveries, a diminished placental transfer of these essential elements could be one of the several etiological factors for low birth weight of newborns.     

Development of Overweight in Children in Relation to Parental Weight and Socioeconomic Status

The purpose of the study was to test the hypothesis that socioeconomic status (SES) moderates the association between parental weight and changes in BMI from childhood to early adolescence. Participants included 428 twin children from 100 families with obese parents (“obese families”) and 114 sociodemographically matched families with normal‐weight parents (“lean families”) who were assessed in their homes (age = 4.4). Follow‐up study was conducted 7 years later (age = 11.2) on 346 children (81%). Complete data were available for 333 children. Family SES was indexed with maternal education. Children's weights and heights were measured to calculate BMI s.d. scores based on 1990 British norms. Overweight was defined as >91st BMI centile. In children with obese parents, BMI s.d. scores increased from 0.51 at age 4 to 1.06 at age 11. In children with lean parents, BMI s.d. scores decreased from 0.11 to 0.05. Prevalence of overweight remained stable from age 4 to 11 in children with lean parents (8% to 9%), but it more than doubled in children with obese parents (17% to 45%). There was a significant interaction between parental weight and family SES (P < 0.01), so that in children with lean parents there was no SES difference in the BMI status from age 4 to 11; however, in children with obese parents, the increase in adiposity was significantly greater in lower SES families. These results suggest that parental leanness confers significant protection against development of overweight in children regardless of family SES, while parental obesity is an adverse prognostic sign, especially in lower SES families.     

Distribution of HLA Antigens in the Armenian Population of Nagornyi Karabakh

Characteristics of the distribution of 31 HLA antigens of classes I (A, B, and Cw) and II (DR) in Nagornyi Karabakh Armenians are reported for the first time. It has been found that the antigens most common in this population are A2, A3, A9, B5, B7, B12, Cw4, DR4, DR2, and DR3; the least common antigens are B15, B16, and B40. The results are compared with the data for Armenians living in Armenia and those for major ethnic groups. The frequencies of HLA antigens in Nagornyi Karabakh Armenians match those in Armenians living in Armenia. In the HLA-antigen distribution, Armenians are generally close to Caucasoids.     

Distribution of HLA antigens in the armenian population of Nagornyi Karabakh

Characteristics of the distribution of 31 HLA antigens of classes I (A, B, and Cw) and II (DR) in Nagornyi Karabakh Armenians are reported for the first time. It has been found that the antigens most common in this population are A2, A3, A9, B5, B7, B12, Cw4, DR4, DR2, and DR3; the least common antigens are B15, B16, and B40. The results are compared with the data for Armenians living in Armenia and those for major ethnic groups. The frequencies of HLA antigens in Nagornyi Karabakh Armenians match those in Armenians living in Armenia. In the HLA-antigen distribution, Armenians are generally close to Caucasoids.     

Decreased HLA heterogeneity in parents of children with Down syndrome.

HLA-A and B antigens were determined in a study of 37 couples and their children with trisomy 21 Down syndrome (DS), using a standard microlymphocytotoxicity test. The comparison groups included 76 couples and their healthy children. All individuals were Caucasians from the same geographical area, and there was no history of consanguinity. The parents of children with DS did not show an association with a specific HLA antigen or haplotype. Sixteen of the 37 couples (43.24%) having children with DS share two or more antigens at the A and/or B locus. This was significantly higher than the proportion in the control group (6/76, or 7.88%). Of the 16 couples having children with DS and sharing two or more antigens, eight had a haplotype in common, in contrast with only two couples in the control group. The data suggest that sharing of parental HLA-A and B antigens may be related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.     

Low birth weight, maternal birth-spacing decisions, and future reproduction

The aim of this study is an analysis of the possible adaptive consequences of delivery of low birth weight infants. We attempt to reveal the cost and benefit components of bearing small children, estimate the chance of the infants’ survival, and calculate the mothers’ reproductive success. According to life-history theory, under certain circumstances mothers can enhance their lifetime fitness by lowering the rate of investment in an infant and/or enhancing the rate of subsequent births. We assume that living in a risky environment and giving birth to a small infant may involve a shift from qualitative to quantitative production of offspring. Given high infant mortality rates, parents will have a reproductive interest in producing a relatively large number of children with a smaller amount of prenatal investment. This hypothesis was tested among 650 Gypsy and 717 non-Gypsy Hungarian mothers. Our study has revealed that 23.8% of the Gypsy mothers had low birth weight (<2,500 g) children, whose mortality rate is very high. These mothers also had more spontaneous abortions and stillbirths than those with normal weight children. As a possible response to these reproductive failures, they shortened birth spacing, gaining 2–4 years across their reproductive lifespan for having additional children. Because of the relatively short interbirth intervals, by the end of their fertility period, Gypsy mothers with one or two low birth weight infants have significantly more children than their ethnic Hungarian counterparts. They appear to compensate for handicaps associated with low birth weights by having a larger number of closely spaced children following the birth of one or more infants with a reduced probability of survival. The possible alternative explanations are discussed, and the long-term reproductive benefits are estimated for both ethnic groups.     

Association of HLA DR1 with high D-penicillamine binding to monocytes in females

Binding of D-Penicillamine (D-Pen) to human monocytes was examined by flow cytometry with fluorescent D-Pen conjugate. Cells from HLA DR1-positive healthy females bound significantly more D-Pen than cells from DR1-negative healthy females (P = 0.015), and DR1 was associated with the highest binding among HLA DR antigens. In contrast, DR4 was associated with the lowest binding in healthy females. A difference in D-Pen binding between healthy females who were DR1-positive, DR4-negative and those who were DR1-negative, DR4-positive was statistically significant (P = 0.026). Neither healthy females nor healthy males showed significant associations of D-Pen binding with HLA A, B, or C antigens, nor did healthy males show an association between strength of D-Pen binding and any DR antigens.     

Susceptibility of major groups of Tamil Nadu to diseases: 1. Psoriasis vulgaris

Eighty-three patients with psoriasis vulgaris, living in Madurai, Tamil Nadu, India, were studied for HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ antigen frequencies and compared with seventy-seven controls studied using the same batch of reagents. A highly significant increase of frequency of HLA-Bw57, a split of HLA-B 17, was found in the patients; Bw58, another split of B17, was absent. Relative risk was high for A1, B17, Bw57 and DR7 individuals; it was highest for Bw57. Frequencies of the haplotypesAl-Bw57 andDR7-DQw3 were also significantly higher in patients. Analysis of the HLA data based on ethnic differences identified as major groups revealed high relative risk for B17, Bw57 and DR7 only in major group III, a Western brachycephal Armenoid group, but not in major group II, a Mediterranean one thought to be an earlier settler of this region. Analysis of the data based on age and sex subgroups yielded interesting information. The age at onset of the disease in the total patient sample showed a bimodal distribution. The two sexes differed in their age-at-onset distributions: females showed a preponderance of early onset of the disease (< 30 years of age, 68%), while the majority of males had late onset (>30 years of age, 71%). HLA data for the early-onset patients indicate very high relative risk for B17, Bw57 and DR7. This suggests that psoriasis may be influenced by sex, and that the early-onset and late-onset forms of the disease may be of different aetiopathogenesis. These observations stress the importance of considering the ethnic origin or composition of samples, and age, sex and other parameters in HLA and disease association studies.     

HLA-A2 Antigen status predicts metastasis and response to immunotherapy in gastric cancer

 Our previous studies have shown that HLA-DR4 and -B52 antigens are associated with an increased risk of lymph node metastasis in patients with gastric cancer. We hypothesized that a putative HLA antigen, correlated with a low risk of lymph node metastasis, may also be correlated with the response to anticancer therapy. The microcytotoxicity assay was used to examine 49 HLA antigens of the A, B, C, DR, and DQ loci, and the association between HLA class I and II antigen status and lymph node metastasis in 847 patients with gastric cancer as well as the response to the therapy in 739 patients were analyzed. HLA-A2 antigen was significantly associated with a low risk of lymph node metastasis in patients with T2-T4 advanced cancer [58.8% compared to 37.0% in patients with lymph node metastasis; corrected P, P _c (98), =0.011], especially in those with moderately differentiated adenocarcinoma [71.0% compared to 26.4% in patients with lymph node metastasis, P _c (294)=0.00294] and with a better response to postoperative immunotherapy using protein-bound polysaccharide K (PSK), a nonspecific immunomodulator, than to chemotherapy. HLA alleles may be associated with resistance or susceptibility to lymph node metastasis and HLA-A2 antigen may be a useful predictor of the response to PSK. The data suggest that the predictive power of this HLA antigen may prove useful in the selection of anticancer therapy. Received: 29 May 1997 / Accepted: 15 July 1997     

Genetic determination of rheumatoid arthritis. Distribution of certain Mendelian markers in the light of correspondence of the disease heritability to the model of single autosomal two-allele locus with incomplete penetrance

The study on the nature of distribution of certain mendelian markers aimed at specifying their role in determination of rheumatoid arthritis disease was carried out, based on the material from the Family Data Bank of the Department of Epidemiology and Genetics of the rheumatic diseases in this institute comprising data on 200 families of patients with definite rheumatoid arthritis (RA). Antigens of HLA-system (the loci A, B, DR), ABO blood groups, Rh, MN and P, phenotypes of acid erythrocyte phosphatase and the types of haptoglobin were studied. Based on the data from this and the previous studies, it is established that the steadiest deviations of the RA patients groups from the general population concerned the frequency of HLA A11, B12, B27 and DR4, blood group P and phenotypes of the acid erythrocyte phosphatase. When using additional controls--a group of healthy mothers of women-probands from the families with the type of marriage "healthy x healthy", and analysing some pair combinations of the HLA system antigens, it was demonstrated that the most clearly their role in formation of the disease display the antigens DR4, and in their absence--DR3, and B12, whereas accumulation of A11 and B27 depended on the presence of other antigens of HLA loci--A and B. Taken together, these data may imply that genetic markers under study serve, when in certain combinations, as "modifiers" of the major gene, or, in a general case, of major genes of multifactorial disease affecting its appearance and clinical manifestations.     

Gastroschisis, low maternal age, and fetal morbidity outcomes

OBJECTIVE: To determine if the risk for fetal growth inhibition among gastroschisis-afflicted fetuses is heightened among younger gravidas (teen mothers). METHOD: This was a retrospective cohort study on live-born infants with isolated gastroschisis delivered in New York State from 1983 through 1999. We compared infants of mature (>20 years) mothers with those of younger (<20 years) mothers with respect to the following indices of fetal morbidity outcomes: low birth weight and very low birth weight, preterm and very pre-term, and small for gestational age. We used adjusted odds ratios to approximate relative risks. RESULTS: A total of 368 infants with isolated gastroschisis were analyzed. The two groups differed in terms of mean gestational age at delivery [Mean + standard deviation(SD) for infants with gastroschisis born to mature mothers = 37.2 weeks +/- 2.8 versus 36.3 weeks + 3.6 for those of teenage mothers(p = 0.01)], as well as mean birth weight [mean birth weight +/- SD for infants with gastroschisis born to mature mothers = 2562.4 grams +548.8 versus 2367.9 grams +/- 645.2 for those of younger mothers (p = 0.004)]. Infants of teen mothers were about twice as likely to be of low birth weight (OR = 1.70; 95% CI = 1.05-2.77) and about three times as likely to be born very preterm when compared to those of mature mothers (OR = 2.80; 95% Cl = 1.02-8.00). No significant differences were observed with respect to very low birth weight, pre-term and small for gestational age. CONCLUSION: Low maternal age appears to be a risk factor for low birth weight and very preterm birth among gastroschisis-affected fetuses. This information is potentially useful for planning by care providers and in counseling affected parents.     

Frequency of HLA antigens in patients with psoriasis or psoriatic arthritis.

A study of 138 patients with psoriasis--74 with psoriasis alone and 64 with psoriatic arthritis--revealed a significantly increased frequency of the HLA antigens A1, A28, B13, DR7 and MT3 in those with psoriasis alone and of Bw39 in those with psoriatic arthritis. The frequency of B17 was higher in both patient groups than in a control group of healthy individuals. The frequency of DRw6 was slightly higher in the patients with psoriasis alone (17.8%) than in the controls (4.7%), and that of DR7 was higher in the patients with psoriatic arthritis (52.9%) than in the controls (32.6%). Elevated levels of serum IgG and IgA along with positive results of tests for antinuclear antibody or rheumatoid factor or both were present in less than a tenth of the patients with psoriatic rash alone and in up to a third of those with psoriatic arthritis. Psoriatic arthritis was found to be less likely to develop in patients with purely guttate psoriasis than in those with other types of psoriasis. Clinical subtypes of psoriatic rash or psoriatic arthritis were not associated with the presence of particular HLA antigens.     

Human cytotoxic T cell clones directed against herpes simplex virus-infected cells. I. Lysis restricted by HLA class II MB and DR antigens

In contrast to general findings that mouse and human cytotoxic T lymphocytes (CTL) are restricted in cytotoxic activity by major histocompatibility complex (MHC) class I antigens, we previously found that some herpes simplex virus (HSV) type I-infected cells that shared no HLA class I antigens with the HSV-1-stimulated lymphocytes were lysed. In this study, we addressed the question of the role of HLA antigens in human T cell-mediated lysis of HSV-1-infected cells by generating clones of HSV-1-directed CTL from two HSV-1-seropositive individuals. CTL clones that lysed autologous HSV-1-infected lymphoblastoid cell lines (LCL), but not natural killer-sensitive K562 cells or uninfected or influenza virus-infected LCL, were tested for cytotoxicity against a panel of allogeneic HSV-1-infected LCL. Clone KL-35 from individual KL lysed only HSV-1-infected LCL sharing the HLA class II MB1 antigen with KL. With all four CTL clones isolated from individual PM, only HSV-1-infected LCL sharing DR1 with PM were lysed. Monoclonal antibody s3/4 (directed against MB1 ), but not TS1/16 or B33 .1 (directed against a DR framework determinant), blocked lysis of autologous HSV-1-infected cells by KL-35. In contrast, B33 .1, but not s3/4, blocked lysis of autologous HSV-1-infected cells by the PM CTL clones but not by KL-35. Together, these results indicate that our five human CTL clones which are directed against HSV-1-infected cells, and which are all OKT3+, OKT4+, OKT8-, are restricted in lytic activity by HLA class II MB and DR antigens. These results suggest that the HLA D region-encoded class II antigens may be important in the recognition and destruction of virus-infected cells by human CTL.     

HLA antigens and acetylcholine receptor antibodies in penicillamine induced myasthenia gravis.

Antibodies to the acetylcholine receptor and HLA antigens have been studied in patients with myasthenia gravis occurring in association with penicillamine treatment. The properties of the antiacetylcholine receptor in these patients differed from those in patients with idiopathic myasthenia gravis in terms of specificity and affinity. These patients had an increased prevalence of HLA Bw35 and DR1 compared to controls and a decreased frequency of B8 and DR3 compared to patients with idiopathic myasthenia gravis. Likewise, they had a decreased frequency of DR4 compared to patients with rheumatoid arthritis. These data provide supportive evidence for a role for penicillamine in the induction of myasthenia gravis in genetically predisposed individuals.     

Rethinking Stress in Parents of Preterm Infants: A Meta-Analysis

Background

With improved medical outcome in preterm infants, the psychosocial situation of their families is receiving increasing attention. For parents, the birth of a preterm infant is generally regarded as a stressful experience, and therefore many interventions are based on reducing parental stress. Nevertheless, it remains unclear whether parents of children born preterm experience more stress than parents of term-born children, which would justify these interventions. This meta-analysis provides a comprehensive account of parental stress in parents of preterm infants, from birth of the infant through to their adolescence. Mean levels of stress in specific domains of family functioning were investigated, and stress levels in parents of preterm and term infants, and fathers and mothers of preterm infants, were compared. Furthermore, we investigated moderators of parental stress.

Methods and Findings

A random-effects meta-analysis was conducted including 38 studies describing 3025 parents of preterm (<37 wk) and low birth weight (<2500 g) infants. Parental stress was measured with two parent-reported questionnaires, the Parenting Stress Index and the Parental Stressor Scale: Neonatal Intensive Care Unit. The results indicate that parents of preterm-born children experience only slightly more stress than parents of term-born children, with small effect sizes. Furthermore, mothers have slightly more stress than fathers, but these effect sizes are also small. Parents report more stress for infants with lower gestational ages and lower birth weights. There is a strong effect for infant birth year, with decreasing parental stress from the 1980s onward, probably due to increased quality of care for preterm infants.

Conclusions

Based on our findings we argue that prematurity can best be regarded as one of the possible complications of birth, and not as a source of stress in itself.