Use of HLA marker associations and HLA haplotype linkage to estimate disease risks in families with gluten-sensitive enteropathy

Based on a two-locus, double recessive model, we derive formulas for the risks that relatives of individuals with gluten-sensitive enteropathy (GSE) will also develop the disease. The calculations take advantage of: the linkage between the HLA locus and one of the two proposed GSE loci, and the preferential association of the HLA-DR3 and DR7 alleles with the GSE disease allele that occupies the HLA-linked locus. We use Bayes' rule to quantitate the strength of the association between the GSE disease allele and the HLA marker allele. This method predicts that siblings of the proband have an overall 10% risk for GSE, which is consistent with observed family data. This predicted risk rises to 30% when siblings are HLA-identical to the proband (also consistent with observed data) or when the sibling has the DR3 allele in the HLA haplotypes not shared with the proband. In those populations where DR7 also is associated with GSE, siblings of probands have a 10% predicted risk for GSE when only one HLA haplotype is shared with the proband and DR7 is included in the unshared haplotype. Other DR alleles are associated with much lower disease risks. By separating individuals into high and low risk groups, HLA typing identifies those individuals who would benefit from further diagnostic procedures. This general strategy should be applicable to other multilocus, marker-associated diseases.     

Familial steatocystoma multiplex: HLA, Gm, Km genotyping and chromosomal analysis in two unrelated families

Steatocystoma Multiplex (S.M.) is an inherited condition characterized by the appearance of cysts during the first or second decade of life. Familial cases have occasionally been reported. We studied 13 patients affected by S.M. from two unrelated families, focusing our attention on HLA, Gm and Km genotypes and on chromosomal analyses. Although we failed to correlate the syndrome with a particular HLA, Gm or Km haplotype, we report some peculiarities and differences between these two families and the healthy Italian population.     

Irish study of high-density schizophrenia families: Field methods and power to detect linkage

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorders. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia. © 1996 Wiley-Liss, Inc.     

African-American HLA class II allele and haplotype diversity

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB1*1501) and some haplotypes of DRB1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.     

Excess of HLA parental sharing in families with Turner patients

In utero selection processes are probably related to mother-father compatibility as has been reported in abortion-prone couples and in Down syndrome studies. In order to analyse this phenomenon, we investigated families with chromosomal imbalance (Turner syndrome). We chose this model because previous data indicated a high frequency of HLA-A31 and B38 in Turner patients and in their mothers. We report high HLA antigen sharing in Turner families and great histocompatibility between mother and affected daughter, not related to abortion histories. The proportion of HLA-A homozygous cases among Turner children was higher than expected. The level of lymphocytotoxic antibodies against fetus in mothers of Turner patients was comparable to that of mothers of families with normal fertility and probably favoured these pregnancies.     

African-American HLA class II allele and haplotype diversity

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB 1*1501) and some haplotypes of DRB 1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.     

HLA structure of the Sardinian population: A haplotype study of 551 families

A study on the HLA structure of the Sardinian population was carried out on 551 healthy unrelated families representing all of the island districts. Altogether 2202 HLA-A, B, Cw, DR individual haplotypes and 853 different haplotypes were determined. Cavalli-Sforza and Edwards' genetic distance index for the total of 62 tested alleles showed a modest heterogeneity between one district and another (0.09-0.16). The genetic distance between Sardinians and the rest of the Italian population was 0.23 (0.22-0.26) and progressively increased in comparisons with caucasoids (0.26), negroids (0.34) and mongoloids (0.41). Sixty-three two-locus haplotypes with a high positive linkage disequilibrium were observed in our family sample. The percentages of two-locus haplotypes in LD shared with other populations turned out to be 45% with caucasoids, 20% with negroids and 10% with mongoloids. The distribution of the A, B, Cw, DR haplotypes is shown with 673 of them represented only once or twice, and 10 (1.2%) 14-322 times each. Of the latter, 8 are extended haplotypes, 6 of which characterize the Sardinian population. The analysis of our data suggests that the present-day Sardinian population is the result of a superposition of different populations, mainly consisting of caucasoids on a pre-caucasoid paleo-Mediterranean substratum.     

HLA sharing in multiplex sibships

For an arbitrary number of affected sibs with unaffected parents, the proportion that share both marker haplotypes identical by descent is derived for the generalized single locus model. This proportion is shown to depend on the underlying parameters of the disease transmission model, on the total sibship size and on the number of sibs who are affected. The variety of identity by descent patterns suggests that any attempt to infer the presence of other independent disease susceptibility loci solely on the basis of an observed inverse relationship between the degree of haplotype sharing and the number of affected sibs, is liable to result in spurious conclusions.     

HLA class II allele and haplotype frequencies in Koreans based on 107 families

We have investigated the distribution of HLA class II alleles and haplotypes in 107 Korean families (207 parents and 291 children) for the HLA-DRB1, DRB3/B4/B5, DQA1, DQB1 and DPB1 loci. Numbers of alleles observed for each locus were DRB1: 25, DQA1: 14, DQB1: 15, and DPB1: 13. Only two to three alleles were observed for the DRB3 (*0101, *0202, *0301), DRB4 (*0103, * 0103102 N), and DRB5 (*0101, *0102) loci. These alleles showed strong associations with DRB1 alleles: DRB3*0101 with DRB1*1201, *1301 and *1403; DRB3*0301 with DRB1*1202 and *1302; DRB3*0202 with DRB1*0301, *1101, *1401 and *1405; DRB5*0101 and *0102 were exclusively associated with DRB1*1501 and *1502, respectively. The seven most common DRB1-DQB1 haplotypes of frequencies > 0.06 accounted for 52% of the total haplotypes. These haplotypes were exclusively related with the seven most common DRB1-DRB3/B4/B5-DQA1-DQB1 haplotypes: DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 (0.085), DRB1*0405-DRB4*0103-DQA1*0303-DQB1*0401 (0.082), DRB1*09012-DRB4*0103-DQA1*0302-DQB1*03032 (0.082), DRB1*0101-DQA1*0101-DQB1*0501 (0.075), DRB1*0701-DRB4*0103-DQA1*0201-DQB1*0202 (0.065), DRB1*0803-DQA1*0103-DQB1*0601 (0.065), and DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0604 (0.065). When these haplotypes were extended to the DPB1 locus, much diversification of haplotypes was observed and only one haplotype remained with a frequency of > 0.06: DRB1*0405-DRB4*0103-DQA1*0303-DQB1*0401-DPB1*0501 (0.062). Such diversification would have resulted from cumulated events of recombination within the HLA class II region, and the actual recombination rate observed between the HLA-DQB1 and DPB1 loci was 2.3% (10/438 informative meioses, including 2 recombinants informative by analysis of TAP genes). Comparison of the distribution of DRB1-DQB1 haplotypes with other populations revealed that Koreans are closest to Japanese people. However, Koreans share a few haplotypes with white people and Africans, which are rare in Japanese: DRB1*0701-DQB1*0202 and DRB1*1302-DQB1*0609. The results obtained in this study will provide useful information for anthropology, organ transplantation and disease association studies.     

HLA haplotypes and class II molecular alleles in Sardinian and Italian patients with pemphigus vulgaris

HLA class II antigens and DRB1, DQA1, DQB1 alleles were studied in 16 Italian and in 16 Sardinian patients with pemphigus vulgaris (PV). In the last group the complete HLA A-DQ haplotypes, including the complotypes, were defined by family studies. As in other populations, two PV susceptibility haplotypes were found: HLA-DRB 1*0402, DQA1*0301, DQB1*0302 and HLA-DRB 1*1401, DQA1*0104, DQB 1*0503. The first haplotype was largely prevalent in the Sardinian patients and was a part of the extended haplotype HLA-A2, Cw4, B35, S31, DR4, DQ8. The strength of the allele associations to PV is in agreement with the view that the main PV susceptibility genes are the DRB 1*0402 and DQB 1*0503 alleles. A genetic resistance to PV seems to be conferred by the HLA-DR3, DQ2 haplotype in the Sardinian population.     

HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis

ProblemThe aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM).Method of studyA systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated.ResultsWe included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05–1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15–2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20–1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45–0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31–0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11–1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10–1.25) were both associated with the occurrence of RM.ConclusionAlthough the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully.     

Association between HLA genes and dust mite sensitivity in a Brazilian population

Background

Type I hypersensitivity, also known as IgE-mediated allergy, is a complex, multifactorial condition whose onset and severity are influenced by both genetic and environmental factors. Mite allergens stimulate the production of humoral response (IgE), especially in children, which is closely involved in atopic asthma and rhinitis.

Segregation of HLA in families with oral clefts: Evidence against linkage between isolated cleft palate and HLA

In an earlier study of amilies with two or more sibs affected with a cleft of the lip with or without clefts of the palate, we found no evidence for close linkage of HLA with this malformation. In the present study, we confime our attention to isolated cleft palate, an entity that is genetically distinct from clet palate associated with cleft lip. In 15 sibships with two or more effected sibs, cleft palate, and parental HLA haplotypes assorted independently in the affected sibs, providing evidence against close linkage of this phenotype.     

HLA gene and haplotype frequencies in Dutch blood donors

We analyzed the HLA-A, -B, -C, -DR and -DQ phenotypes of 2,440 healthy, unrelated, Dutch Caucasoid blood donors and of 20, 814 Dutch blood donors who were registered as volunteer bone marrow or platelet donors. Phenotype and gene frequencies, Hardy-Weinberg equilibrium fit and homozygosity were calculated as well as 2- and 3-locus haplotype frequencies, deltas, relative deltas and significance levels of the deltas. The population appears to be in Hardy-Weinberg equilibrium. Many haplotypes are in strong positive linkage disequilibrium. A phylogenetic tree, based on the HLA-A, -B and -DR gene frequencies of blood donors in different Dutch regions, reflects the limited but manifest heterogeneity of the Dutch population. Additionally we introduce a stepwise test for Hardy-Weinberg equilibrium and discuss the applicability of this test and of the single test for Hardy-Weinberg equilibrium for tissue typing quality control and for selection of split antigens prior to gene and haplotype frequency analyses.     

The Yin and Yang of HLA and KIR in human disease

Killer cell immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and subsets of T cells. The KIR genes are polymorphic and the KIR gene complex is polygenic with varying numbers of inhibitory and activating receptors. HLA class I molecules serve as ligands for the KIR. Interactions of the independently segregating KIR and HLA loci are important for recognition of targets by NK cells as well as NK cell ‘licensing’. Several disease association studies indicate a role for interactions between these loci in infectious diseases, autoimmune/inflammatory disorders, cancer and reproduction. Emerging functional data supports a mechanism based on a continuum of inhibition to activation through various compound KIR–HLA genotypes in diseases.     

HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families

The diabetes predisposing effect of HLA genes is defined by a complex interaction of various haplotypes. We analyzed the disease association of HLA DRB1-DQA1-DQB1 genotypes in a large nuclear family cohort (n = 622) collected in Finland. Using the affected family based artificial control approach we aimed at characterizing all detectable disease-specific HLA haplotype and genotype effects. The DRB1*0401-DQB1*0302 haplotype was the most prevalent disease susceptibility haplotype in the Finnish population followed by (DR3)-DQA1*05-DQB1*02 and DRB1*0404-DQB1*0302. DRB1*0405-DQB1*0302 conferred the highest disease risk, although this haplotype was very rare. The DRB1*04-DQB1*0304 was also associated with increased disease risk, an effect detected for the first time in the Finnish population. The following haplotypes showed significant protection from the disease and are listed in decreasing order of the strength of their effect: (DR7)-DQA1*0201-DQB1*0303, (DR14)-DQB1*0503, (DR15)-DQB1*0602, DRB1*0403-DQB1*0302, (DR13)-DQB1*0603, (DR11/12/13)-DQA1*05-DQB1*0301, (DR1)-DQB1*0501. In addition to the DRB1*0401/0404-DQB1*0302/(DR3)-DQA1*05-DQB1*02 genotype and DRB1*04-DQB1*0302 homozygous genotypes, heterozygous combinations DRB1*0401-DQB1*0302/(DR13)-DQB1*0604, approximately /(DR8)-DQB1*04, approximately /(DR9)-DQA1*03-DQB1*0303, approximately /(DR1)-DQB1*0501 and approximately /(DR7)-DQA1*0201-DQB1*02 were also disease-associated. As a new finding in this population, the (DR3)-DQA1*05-DQB1*02 homozygous and (DR3)-DQA1*05-DQB1*02/(DR9)-DQA1*03-DQB1*0303 heterozygous genotypes conferred disease susceptibility. Similarly, the DRB1*0401-DQB1*0302/(DR13)-DQB1*0603 genotype was disease predisposing, implying that DQB*0603-mediated protection from diabetes is not always dominant. Comparison of our findings with published data from other populations indicates a significant disease-specific heterogeneity of the (DR8)-DQB1*04, (DR7)-DQA1*0201-DQB1*02 and (DR3)-DQA1*05-DQB1*02 haplotypes.     

HLA class II disease associations in southern Africa

Southern Africa harbors several population groups representing a diversity of gene pool origins. This provides a unique opportunity to study genetic disease predisposition in these populations against a common environmental background. Human leukocyte antigen (HLA) association studies of these populations could improve knowledge on inter-population variation and HLA-related disease susceptibility. The aim of this paper is to review HLA class II disease associations reported for southern African population groups, compare them with findings in other populations and identify those unique to southern Africa. A number of HLA class II disease associations appear to be unique to southern African populations. These include DRB1*14011 association with insulin-dependent diabetes mellitus susceptibility in the Xhosa and DRB1*10 and DQB1*0302 with rheumatoid arthritis susceptibility in the South African (SA) Indian and SA Coloreds, respectively. A noteworthy similarity in class II disease association was observed among southern African Caucasoid and their European parental populations. Unique HLA class II disease associations observed in southern Africa are consistent with the notion that unique environmental and natural selective factors have resulted in certain ethnic-specific HLA class II disease associations, while common HLA class II disease associations found across different populations support the notion that common diseases are caused by common, ancient alleles present in indigenous African populations.     

HLA DPA1/DPB1 genotype and haplotype frequencies, and linkage disequilibria in Nigeria, Liberia, and Gabon

Abstract: The frequencies of DPA1 and DPB1 alleles and their occurrence in haplotypic linkage were assessed and compared in Nigerian, Liberian, and Gabonese individuals. Differences were seen in the distribution patterns; these differences were more pronounced between the Gabonese and the other two populations than between Liberians and Nigerians. Several haplotypic DPA1-DPB1 combinations could be verified by homozygosity. Linkage disequilibria of DPA1-DPB1 combinations, indicating further probable haplo-types, were estimated. Although different allele and haplotype frequencies were recognized in the three subgroups, the linkage disequilibria were mostly either positive or negative in all populations.