Etiological heterogeneity in Hodgkin's disease: HLA linked and unlinked determinants of susceptibility independent of histological concordance

Forty-one multiplex families, from published sources and new data from the National Cancer Institute, segregating for Hodgkin's disease and HLA, have been studied. A reanalysis of these data strongly suggests a recessive mode of inheritance for susceptibility to Hodgkin's disease. The HLA haplotype sharing data between affected relatives demonstrate that approximately 60% of cases in multiplex families are due to an HLA-linked susceptibility gene, the remaining 40% being due to other familial factors. The data clearly support the hypothesis of etiological heterogeneity for Hodgkin's disease, with both HLA-linked and HLA-unlinked factors being responsible. Finally, there is an increased concordance of histological types between affected relatives, but this concordance seems independent of HLA sharing.     

Extended HLA profile of an inbred isolate: The Schmiedeleut Hutterites of South Dakota

HLA-A, -B, -C, -DR, and -DQ typings of the Schmiedeleut Hutterites of South Dakota were collected as part of an ongoing genetic-epidemiologic study of HLA and fertility. A total of 1,082 individuals, including 852 married adults representative of the reproductive population of this isolate, were characterized for five-locus HLA haplotypes. HLA-A1, A2, A3, and A24 accounted for 75% of observed HLA-A alleles and HLA-B27, B35, B51, and B62 accounted for 55% of observed HLA-B alleles. S-leut Hutterites are derived from 68 or fewer ancestors. However, only 48 ancestral HLA haplotypes were observed and nine of these accounted for over 52% of the observed haplotypes. Measures of two-locus linkage disequilibrium derived from these haplotypes indicated that one-third to half of the observed HLA-A/B, B/DR, and A/DR allele combinations exhibited highly statistically significant linkage disequilibrium. Allele and haplotype frequencies did not differ between males and females. Recombination rates of 0.004% and 0.005% between HLA-A and -C and between HLA-B and -DR, respectively, were observed. This HLA profile points out a paucity of HLA alleles and haplotypes in this population and marked linkage disequilibrium among the HLA alleles that are present. © Wiley-Liss, Inc.     

Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred.

We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA-linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA-DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P less than 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well-established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib-pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA-DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P less than 0.001). The same results were obtained by an independent method which considered HLA-DR transmission from affected parents to their affected children. The affected sib-pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA-linked locus on familiarity accounted for only a 1.61-fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non-HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.     

HLA-A and -B antigens in chronic bronchitis

The A- and B- types of Human Leucocyte Antigens (HLA) were examined in a group of Greek patients with a diagnosis of chronic bronchitis. The results were compared to those of 400 healthy unrelated controls (smokers and non-smokers) from the same population. A statistically significant increase of HLA-A1 and HLA-B17 was noted; a similar increase was also noted when only healthy smokers were utilized as a control group. These results support the hypothesis that genetic factors are also involved in the pathogenesis of this common disease.     

HLA and Down syndrome (DS): parents at the origin of the nondisjunction share no more HLA-A and -B antigens with their DS child than controls

Fifty couples and their children with Down syndrome (D.S.) were typed for HLA-A and HLA-B antigens and compared to 50 control families and 464 blood donors. The parental origin of the extra chromosome 21 was determined by cytogenetic methods. All individuals were caucasians and there was no history of consanguinity. No excessive HLA sharing was present in D.S. parents. The mothers of D.S. shared no more HLA antigens with their D.S. children than the control mothers with their normal children (14% vs. 18%). Thirteen of the fifty pairs (26%) (parent in whom the nondisjunction occurred and D.S. child) shared three HLA antigens at the A and/or B locus. This was not significantly higher than the proportion in the control group (12/50 or 24%). These data suggest that it is not the sharing of HLA-A and HLA-B antigens between the parents or between the parent who was the origin of the nondisjunction and the D.S. child that is related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.     

Correlation of HLA antigens and idiopathic hemochromatosis in Hungary

The aim of our present work was to collect data on HLA distribution in patients with idiopathic haemochromatosis in Hungary. Ten unrelated patients with idiopathic haemochromatosis (6 men, 4 women) were studied. Idiopathic haemochromatosis was diagnosed on clinical, biochemical and histological grounds. HLA typing was performed in 10 probands and in all of their first degree relatives available (24) through 7 pedigree studies. HLA A3 was present in 6 of 10 probands [6/10 vs. 18.8% in the group of healthy blood donors (No 53) and 22.4% in Hungarian population (No 1910]. HLA B7 was present in 4 of 10 probands (40% vs. 11.3% and 14.6%). A3B7 antigen association has been found in 4 of 10 patients. A3B7 and A2B38 haplotypes were present twice in 4 of 7 genotyped probands. Pedigree studies revealed one nonaffected homozygote, 17 heterozygotes and 6 non carriers. Extended family and population studies are necessary to establish the gene frequency in Hungary and the probability of the involved haplotypes other than A3B7.     

Affective disorder not linked to HLA

These analyses focused on the relationship of affective disorders to HLA. The sample of 86 previously unpublished families from Ontario and 10 unpublished pedigrees from Newfoundland, as well as the original Weitkamp et al. [1981] sample of 20 families, the samples provided by NIMH [Goldin et al., 1982] (18 families), and Egeland et al. [1987] (2 large pedigrees), were examined using sib pair methods as well as standard linkage analysis of the full pedigrees. A variety of genetic models were examined. There was no evidence for linkage from any of the samples based on either analytic approach or for any genetic model. Groups of sibling pairs concordant for affective illness, concordant for being well, or discordant for affective illness did not differ in the proportion of genes identical by descent. No group differed significantly from 50%. From the analysis of full pedigrees, linkage to HLA could be excluded to a distance of approximately 20 to 25 centimorgans. There was no evidence for linkage heterogeneity. These results argue against linkage of affective disorder to HLA.     

Modeling of HLA class II susceptibility to Type I diabetes reveals an effect associated with DPB1.

In this report, we present evidence that the HLA class II DPB1 locus (or a locus with alleles in linkage disequilibrium with DPB1) contributes to Type I diabetes (IDDM) susceptibility in addition to the contribution of the HLA DR and DQ loci. The marker association segregation chi-square (MASC) method, which fits both genotype frequency and affected sib-pair identity-by-descent (IBD) distributions, was applied to 257 sib pairs affected with IDDM. Fitting DR-DQ as the sole HLA susceptibility loci was strongly rejected. Next, we considered the DPB1 contribution to disease susceptibility. Published reports indicate a predisposing role for alleles DPB1*0301 and DPB1*0202, including our previous stratification analyses of association data on this sample. IDDM probands were stratified into those not carrying the alleles DPB1*0301 and DPB1*0202 (group DPB1-A), and those carrying at least one copy of either allele (group DPB1-B). Both groups of probands have almost identical frequencies of DR and DQ haplotypes but significantly different IBD distributions in the subset of families with probands who do not carry the highly predisposing DR3/DR4 genotype. In these data, DPB1 (or a locus in linkage disequilibrium), in addition to DR-DQ, is involved in IDDM susceptibility and affects IBD in the HLA region. Addition of DPB1 in a genetic model of IDDM gives a better fit to the data than consideration of DR-DQ alone. Our results are consistent with previous reports implicating DPB1 in IDDM susceptibility.     

HLA DQ beta 3.2 identifies subtypes of DR4+ haplotypes permissive for IDDM

The HLA class II-related susceptibility to type I insulin-dependent diabetes mellitus (IDDM) is examined in 94 multiplex families sorted by the presence or absence of a DR4+ haplotype in at least one diabetic family member. The families with DR4+ haplotypes are then sorted by the presence or absence of a DR4-linked DQ beta 3.2 allele. Further analysis assumes each multiplex family to represent a single diabetic genetic event and identifies the HLA class II haplotype(s) present in all affected members. The DQ beta 3.2 allele is present in over 95% of the multiplex families where DR4+ haplotypes segregate with IDDM, implying a major permissive role in determining susceptibility to IDDM.     

乙型肝炎疫苗免疫不应答与HLA基因单体型的相关性研究

目的 分析接种乙型肝炎疫苗的人群中,不能产生良好的免疫应答反应的群体主要组织相容性复合性（HLA）基因单体型,为乙型肝炎疫苗免疫不应答遗传机制的破译提供有意义的结果。方法 以来自广西自治区的样本107例为研究对象,通过PCR扩增和电泳对样本个体进行HLA－DR、DQ区域的DNA分型,并对不应答家系的个体进行初步HLA－DR、DQ单体型别的确定。通过相对危险性估计、关联分析、连锁不平衡检测等统计学分析模式对不／弱应答群体与强应答群体HLA分型结果进行统计分析。结果 中国人中与乙型肝炎疫苗免疫接种不应答密切相关的HLA单体型为：HLA－DRB1＊0401－22,1122－DRB4＊01011010102／3－DQB1＊04,即HLA－DR4,1122－DQOB4。结论 乙型肝炎疫苗免疫不应答与特异的HLA等位基因单体型密切相关。     

HLA antigen frequencies in flax byssinosis patients.

Not all workers exposed to flax dust contract byssinosis. It is not known what determines susceptibility or insusceptibility. This study is an attempt to establish whether the incidence of histocompatibility antigens is involved in susceptibility to the disease. Forty patients suffering from flax byssinosis were tissue-typed for HLA-A and -B antigens. HLA-B27 was significantly more common in the patients (22.5%) than in the controls (5.5%); P = 0.029 after correction for the number of antigens compared. HLA-A11 was present in twelve patients (30%) compared with 14% in the controls; after correction for the number of comparisons, this is not a statistically significant increase. Because HLA-B27, though significantly more common in flax byssinosis, is not necessary for its occurrence (77.5% of our patients did not have it), it is possible that the increase in the frequency of HLA-B27 is attributable to an association with other genes, perhaps those regulating the immune response or coding for antigens at other HLA loci.     

HLA antigen frequencies in flax byssinosis patients.

Not all workers exposed to flax dust contract byssinosis. It is not known what determines susceptibility or insusceptibility. This study is an attempt to establish whether the incidence of histocompatibility antigens is involved in susceptibility to the disease. Forty patients suffering from flax byssinosis were tissue-typed for HLA-A and -B antigens. HLA-B27 was significantly more common in the patients (22.5%) than in the controls (5.5%); P = 0.029 after correction for the number of antigens compared. HLA-A11 was present in twelve patients (30%) compared with 14% in the controls; after correction for the number of comparisons, this is not a statistically significant increase. Because HLA-B27, though significantly more common in flax byssinosis, is not necessary for its occurrence (77.5% of our patients did not have it), it is possible that the increase in the frequency of HLA-B27 is attributable to an association with other genes, perhaps those regulating the immune response or coding for antigens at other HLA loci.     

Linkage analysis and genetic models for IDDM

The multiplex insulin-dependent diabetes mellitus (IDDM) families have been examined for linkage with the human leukocyte antigen (HLA), Gm, Km, and insulin loci. For the last three, no evidence of linkage (as measured by haplotype sharing in affected siblings) was found. For HLA, strong evidence of linkage was demonstrated, as expected from previous studies of both haplotype sharing and HLA association. The haplotype sharing in affected siblings from this and previous studies would explain a relative risk of about 3.7 in the sibling of an affected individual (95% confidence limits 2.8 to 5.4), considerably less than the values of 10-15 given by epidemiological studies. This discrepancy may be explained by other predisposing genes unlinked to HLA, or be due to common environmental factors. Analysis conditional on the affection status of all individuals, and on the parental HLA haplotypes clearly rejects both a dominant and recessive mode of inheritance in favor of a two-allele model with a reduced risk for heterozygotes, and provides some support for a three-allele model. Some evidence of age effects was found; in particular there was some suggestion of greater haplotype sharing in siblings both affected at a young age, and there was some suggestion that individuals with the predisposing HLA-DR3/DR4, DR3/DRx, and DR4/DRx genotypes were affected at a younger age. These results may be diagnostic artifacts, however, and need investigation in future studies.     

Insulin dependent diabetes mellitus epidemiology: HLA genotype study in 12 north eastern Italian families with two siblings affected by type I diabetes

The purpose of our study was to evaluate the relationship between the histocompatibility antigens and type 1 diabetes mellitus in families living in the north-eastern part of Italy. In each family two siblings were affected by diabetes.HLA-antigens were determined with the lymphocytotoxicity test, utilizing antisera of the series A-B-C-DR.The phenotypic frequencies were compared with those observed in controls.We showed that diabetes has a strong association with HLA DR 3 and/or DR 4 antigens.In particular we registered high frequency of compound heterozygous DR 3 — DR 4 subjects, and this fact supports the hypothesis of the existence of two different genes for diabetes associated with these HLA antigens.Moreover we observed a particular haplotype segregation with a very high percentage of HLA identity between patients belonging to the same family, confirming the association between HLA and genetic susceptibility to insulin dependent diabetes. These results confirm data in the literature and, completed by other data from other patients' families living in our area, will be useful in providing reliable genetic counselling.     

HLA and disease

Association of HLA and diseases is well known. Several population studies are available suggesting evidence of association of HLAs in more than 40 diseases. HLA found across various populations vary widely. Some of the reasons attributed for such variation are occurrence of social stratification based on geography, language and religion, consequences of founder effect, racial admixture or selection pressure due to environmental factors. Hence certain HLA alleles that are predominantly associated with disease susceptibility or resistance in one population may or may not show any association in other populations for the same disease. Despite of these limitations, HLA associations are widely studied across the populations worldwide and are found to be important in prediction of disease susceptibility, resistance and of evolutionary maintenance of genetic diversity. This review consolidates the HLA data on some prominent autoimmune and infectious diseases among various ethnic groups and attempts to pinpoint differences in Indian and other population.     

Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.     

湖北汉族人群HLA-A、B、DRB1基因多态性研究

目的了解湖北汉族人群HLA—A、B、DRB1基因分布特征。方法采用聚合酶链反应．序列特异性引物（PCR-SSP）和聚合酶链反应-序列特异性寡核苛酸探针（PCR-SSOP）流式细胞技术检测4026份湖北汉族骨髓捐献志愿者HLA—A、B、DRB1等位基因（中低分辨），分析等位基因频率，并与南北汉族人群进行比较。结果共检出A位点等位基因17种，B位点等位基因32种，特异性42种，DRBI位点等位基因13种。其中，A位点以A^＊02、A^＊11、A^＊24、A^＊33最常见．B位点以B^＊46、B^＊40（60）、B^＊13、B^＊15（62）、B^＊58、B^＊51最常见，DRBI位点以DRB1^＊09、DRB1^＊04、DRB1^＊15、DRB1^＊12、DRB1＊08、DRB1^＊07、DRB1^＊14、DRB1^＊ 11、DRB1^＊13最常见，未检出A^＊25、A^＊36、A^＊43、A^＊80、B^＊42、B^＊78。结论湖北汉族人群HLA—A、B、DRB1等位基因分布接近南方汉族人群之间，并有其自身特点。     

A test of nonrandom segregation

Within a family, associations between a disease and a marker locus are often inferred when affected offspring share marker alleles more often than is expected by chance. Generally, this is due to nonrandom parental transmission of marker alleles and specifically could be due to linkage, epistatic gene action, or segregation distortion at the marker locus. In this paper, we discuss the statistical properties of a general test of nonrandom segregation of a marker gene. The exact probability distribution of the test under the null hypothesis of random segregation is derived, as is the distribution under the alternative hypothesis of genetic linkage. We compute the mean and variance of these distributions as a means of judging the adequacy of random segregation to explain disease-marker data but also provide a method for computing the exact significance value under the null hypothesis. These methods have been utilized for studying HLA segregation in families with tuberculoid leprosy. On the assumption that this type of leprosy is autosomal recessive, we find evidence that a gene controlling susceptibility to infection by Mycobacterium leprae resides on human chromosome 6, approximately 13 map units away from the HLA locus in males.     

The association between HLA antigens and the presence of certain diseases

The association between the presence or absence of two HLA antigens and coeliac disease, thyrotoxicosis and ankylosing spondylitis has been studied in patients and controls. The simple empirical logistic model and a refinement due to Dyke and Patterson have been used to examine which conditional associations are important.     

No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer disease

Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3′ to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at α = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (SimIBD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported. Genet. Epidemiol. 14:307–315,1997. © 1997 Wiley-Liss, Inc.