Association Of HLA Haplotypes Research Articles

HLA Haplotype Association with Celiac Disease in Albanian Pediatric Patients from Kosovo.

Genetic predisposition to celiac disease (CD) is strongly associated with the presence of HLA alleles in the individual genotype encoding HLA-DQ2 and/or HLA-DQ8 heterodimers. The main aim of this study was to analyze the HLA-A, -B, -DRB1, and -DQ allele and five-locus haplotype frequencies in 60 Albanian pediatric CD patients and 124 non-CD children from Kosovo. The most prevalent haplotype in patients was the ancestral AH 8.1 haplotype present in 22.5% of the cases compared to 2.8% of the controls (P < 0.0001). Additionally, two other haplotypes were also overrepresented in patients (HLA-A∗02~B∗50~DRB1∗07~DQA1∗02:01~DQB1∗02:02 and HLA-A∗68~B∗44~DRB1∗07~DQA1∗02:01~DQB1∗02:02). Analysis showed that 95.0% of CD patients and 43.3% of controls were carriers of HLA-DQ2 and/or HLA-DQ8 heterodimers. The most frequent CD-predisposing HLA-DQ haplotypes in patients were HLA-DQ2.5 (46.7%) and HLA-DQ2.2 (11.6%), while the most prevalent genotypes were HLA-DQ2.5/DQX (58.3%) and HLA-DQ2.5/DQ2.2 (20.0%). The frequency of the HLA-DQ8 heterodimer among CD patients (4.2%) compared to the control group (8.1%) was without statistical significance. The given data demonstrate differences in the distribution of HLA haplotypes among Albanian CD patients from Kosovo in comparison to other European and non-European populations, as well as provide additional population data to supplement the thus far undisputed importance of the role of HLA-DQ2 and HLA-DQ8 heterodimers in the development of CD.

Association of HLA Haplotypes with Paroxysmal Nocturnal Hemoglobinuria

The pathologies of paroxysmal nocturnal hemoglobinuria (PNH) are primarily caused by somatic mutation in the PIG-A gene in hematopoietic stem cells resulting in glycosyl phosphatidylinositol deficiency and accumulation of phosphatidylinositol (PI) in plasma membranes. The mechanism of pathologic clone domination over normal hematopoietic clones in PNH patients is not yet understood. Forty-four PNH patients, including 9 with aplastic anemia traits (AA/PNH), 31 without full aplasia in bone marrow (de novo PNH, or dn/PNH), and 4 with unclassified PNH, and 200 ethnically matched controls were tested for the HLA A, B, C, DRB1, and DQB1 alleles and haplotype associations. The top block association analysis showed the primary association of PNH with 3 haplotype fragments: the class I fragment A*2501-Cw*1203-B*1801 (risk ratio [RR], 6.64; P = .00012), and 2 class II fragments: DRB1*1501-DQB1*0602 (RR, 7.09; P = .0000015) and DRB1*0401-DQB1*0301 (RR, 6.76, P = .0093). The stratified analysis revealed that the A*2501-Cw*1203-B*1801 haplotype associated preferentially with AA/PNH, and its component HLA molecule showed immunodominant antiapoptotic peptides derived from PI-activated phospholipase D; whereas the DRB1*1501-DQB1*0602 haplotype was associated strongly with dn/PNH and presented immunodominant class II–derived autopeptides. We concluded that certain HLA haplotypes were associated with PNH much more strongly than their allelic components. At least 3 HLA haplotype blocks ( A*2501-Cw*1203-B*1801, DRB1*1501-DQB1*0602, and DRB1*0401-DQB1*0301) were primarily associated with PNH. Our results supported the hypothesis of the roles in AA/PNH of antiapoptotic and in dn/PNH of autoimmune mechanisms.

Drug Hypersensitivity: Epidemiology and Risk Factors

Drug allergies are heterogeneous and multifactorial diseases and are always the consequence of an exaggerated immune-mediated reaction. Previously described models of immunologic mechanisms (mainly based on Gell and Combs' classification) cannot fully explain the physiopathology of these diseases; it seems therefore important to identify risk factors. Clinical and biologic tests are helpful diagnostic tools but are limited in their sensitivity and reliability and are certainly not predictive. Epidemiologic data supply information concerning the prevalence of drug hypersensitivity: female gender, concomitant infections (HIV, herpes) and concurrent illnesses (systemic lupus erythematosus) are all significant risk factors. Another host-related factor is the genetic predisposition of patients and is currently under investigation in our laboratory. Most genetic studies concern HLA haplotype association or polymorphism in genes encoding drug-metabolising enzymes. A current study by our group seems to implicate polymorphisms within the promoter of IL-10, a cytokine with anti-inflammatory properties. The chemical properties of the drug and the treatment regimen also influence the development of drug allergies.

A Case‐Control Study to Examine HLA Haplotype Associations in Patients with Posttreatment Chronic Lyme Disease

In a comparison of 95 patients with systemic symptoms that persisted after antibiotic treatment for acute Lyme disease (posttreatment chronic Lyme disease) and 104 control subjects without such symptoms after antibiotic treatment, we sought associations between human leukocyte antigen class II (DRB1 and DQB1) markers and posttreatment chronic Lyme disease. No strong association between posttreatment chronic Lyme disease and any class II allele or genotype was found.

Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population.

In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.

The association of HLA haplotypes in liver transplant donors and recipients on biochemical and histologic recurrence of hepatitis C

The association of HLA haplotypes in liver transplant donors and recipients on biochemical and histologic recurrence of hepatitis C

Familial occurrence and inheritance studies in inflammatory bowel disease

A number of studies have demonstrated aggregation of cases of ulcerative colitis or Crohn's disease in families, and of cases of both diseases within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patients, study design and diagnostic criteria, different patterns of occurrence of inflammatory bowel disease (IBD) have been found among relatives of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to reveal (1) the frequency of familial occurrence of IBD among patients with ulcerative colitis and Crohn's disease, and (2) the prevalence of IBD among 10 relatives to patients with these diseases. Results from these studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, and a prevalence among 10 relatives of about 10 times that of the background population. A twin study reported a significantly higher concordance rate for Crohn's disease than for ulcerative colitis in monozygotic twins. By use of complex segregation analyses in 3 different studies, a very similar model of inheritance was found to fit for ulcerative colitis, namely a major dominant or additive gene with a low penetrance. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the concept of ulcerative colitis and Crohn's disease as two separate disease entities. The occurrence of both diseases within the same families in certain members of the affected families is difficult to explain. The search for distinct associations of HLA genes with inflammatory bowel disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with ethnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been revealed from studies of association of HLA-A or -B antigens or blood group and serum protein markers. In two French families with several members affected with Crohn's disease no evidence for an HLA haplotype association could be revealed. Possible inherited markers of ulcerative colitis or Crohn's disease have been sought but without convincing success. Increased intestinal permeability, presence of anticolon antibodies and presence of antineutrophil leukocyte antibodies have been proposed, but not proved. Thorough studies are now needed of multimember families with disease for linkage studies to identify loci which contribute to increased liability. Such studies are in progress in different centres.

Genetic polymorphism of the human tumor necrosis factor region in insulin-dependent diabetes mellitus linkage disequilibrium of TNFab microsatellite alleles with HLA haplotypes

The TNF region within the MHC includes a number of immunologically important genes. Microsatellites TNFa and TNFb adjacent to TNF exhibit extensive polymorphism. Employing a PCR-based technique, we identified TNFab haplotypes and defined their distribution in 97 controls and 48 diabetics of Caucasoid origin in a search for other genes within the MHC potentially associated with IDDM. Twenty-five different TNFab haplotypes were identified. A significant difference ( p < 0.0005) in frequency between patients and controls was found for TNFa1b5 (relative risk 53). However, no other TNFab microsatellites demonstrated significantly different frequencies. Among diabetics TNFa1b5 was found to be in linkage disequilibrium with HLA-DR3-B18, a haplotype known to be associated with IDDM. Thus the increased frequency of TNFalb5 among diabetics could reflect a linkage disequilibrium with a gene within the TNF region or with other genes, including the HLAs, which characterize this haplotype. In both controls and diabetics TNFa2b3 and TNFa7b4 were in linkage disequilibrium with DR3-B8 and DR7, respectively. Among diabetics, TNFa2b1 and TNFa6b5 were in linkage disequilibrium with DR4-B62 and DR4-B44, respectively. It is intriguing that TNFab haplotypes, represented by a short piece of about 200 nucleotides in the untranslated region upstream of TNFβ gene, maintain strong linkage disequilibria with different HLA haplotypes extending over 1 million base pairs. The identification of TNFab microsatellites exhibiting a high polymorphic index in a region lacking known polymorphic markers may provide potentially important information regarding the association of HLA haplotypes with autoimmune diseases, as they are in close proximity to other genes of immunologic importance.

Immunogenetics of Diabetes Mellitus in Chinese

Diabetes Mellitus is a syndrome of hyperglycemia with heterogeneous etiology. Previous reports from population, migration and twin studies suggested that both genetic and environmental factors are all important in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Among the genetic factors, HLA is the most important and extensively studied. As far as the non-insulin-dependent diabetes mellitus (NIDDM), the etiology remains obscure, though polygenetic factors had been mentioned. Our studies were mainly focused on the assessment of BLA association with diabetes mellitus in Chinese. Preliminary results were shown below: (A)Phenotype association of HLA with IDDM, NIDDM & Maturity-onset diabetes of the young (MODY). There was no significant association of HLA-AB,C alleles with IDDM. DR3 is better associated with IDDM than is DR4 (RR=10.25 vs 3.56) which is the reverse in Caucasian. DR6 is negatively associated with IDDM. No significant association of HLA with NIDDM & MODY. (B)DR heterozygotes association with DM and non-diabetic diseases. Both DR3/4 and 3/9 are significantly associated with juvenile-onset IDDM (RR=47.1 &15.9) and adult-onset IDDM (RR=27.5 &202). The association of DR3/4 is stronger than that DR/9 in both groups. There is no significant association of DR3/4 with NIDDM, MODY and other non-diabetic diseases. (C)Association of BlA-DQαRFLP’S with IDDM. Genomic DNA from patients and controls were digested with EcoRI, Pstl, BamHI and Hindlll and then hybridized with DQα cDNA probe. The results showed 1)significantly increased frequency of EcoRI 13.0 kb, PstIl 9.0 & 4.1 kb and HindIII 4.6 kb in patients 2)significantly decreased frequency of EcoRI 17.0 kb, PstI 17.0 & 10.0 kb, and Hindlll 9.0kb in patients 3)no significant difference in BamHI fragments between IDDM patients and controls. (D)HLA haplotype association with IDDM. IDDM patients are highly associated with DR3 haplotype but not with DR4 haplotype. AW33Bl7CW3DR3DQW2DRW52 may be a high risk haplotype for IDDM in Chinese. (E)Association of non-aspartic acid at position 57 of the HLA-DQβ chain with IDDM and NIDDM. The presence of an amino acid other than aspartic acid at position 57 of the HLA-DQB chain (NA) is highly associated with susceptibility to IDDM in Caucasion but not in Japanese. In Chinese, we demonstrated that HLA-DQB non-ASP-57 allele is significantly associated with IDDM, but not with NIDDM.

Distribution of alleles at D6S105 and D6S265 with possible HLA haplotype associations.

Distribution of alleles at D6S105 and D6S265 with possible HLA haplotype associations.

Genetic Predisposition of Autoimmune Disease and B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Autoimmune disease is a polygenic disease in which various genetic factors play crucial roles. The familial clustering and the association of HLA haplotypes have been well-recognized. There is a close association between chronic lymphocytic leukemia (CLL) and autoimmune disease. Like autoimmune diseases, CLL is the type of leukemia most often occurring among close relatives. The patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. As the majority of CLL is of CD5+ B-cell type, and as CD5+ B cells are suggested to be involved in autoimmunity, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells may be involved in both B-CLL and autoimmune disease. I discuss here the possibility that different, but related, MHC haplotypes would predispose either to autoimmune disease or to B-CLL, based on our findings obtained from MHC (H-2)-congenic New Zealand mouse strains.

HLA and genetics of IDDM. Holism vs. reductionism?

Analysis of HLA-associated susceptibility to insulin-dependent diabetes mellitus (IDDM) has largely focused on identifying the susceptibility gene. Adherents of a countertrend have long suggested the importance of analysis of HLA haplotypes (combinations of alleles on 1 chromosome) rather than individual genes. Accumulating data suggest that the relationship between IDDM susceptibility and HLA is much more complex than a single susceptibility gene. Consideration of this question should include the possibilities that 1) more than one HLA gene is involved in determining susceptibility or resistance; 2) different alleles of the same gene may be associated with different pathogenetic mechanisms; and 3) different susceptibility-associated haplotypes, even if they share an allele at an IDDM-relevant locus, may behave differently in IDDM. A better understanding of the genetics, and perhaps the pathogenesis, of IDDM may be obtained by following up the clues offered by analysis of the association of HLA haplotypes (rather than individual alleles) with one another, with clinical features of IDDM, and with possible non-HLA-linked susceptibility factors.

Late-Onset 21-Hydroxylase Deficiency Is an Allelic Variant of Congenital Adrenal Hyperplasia Characterized by Attenuated Clinical Expression and Different HLA Haplotype Associations

Three families with late-onset 21-hydroxylase deficiency were studied. Homozygous females presented with symptoms of mild hyperandrogenism such as acne, hirsutism, oligomenorrhea and menometrorrhagia. A homozygous male was asymptomatic and had reached normal adult height. The diagnosis of 21-hydroxylase deficiency was based upon markedly elevated responses of plasma 17-hydroxyprogesterone during a short (30-min) ACTH infusion test. The propositi of two of the families were diagnosed despite long-standing glucocorticoid therapy and adrenal suppression by using a prolonged (48-hour) ACTH infusion. Heterozygotes of late-onset 21-hydroxylase deficiency had mildly elevated 17-hydroxy-progesterone responses to ACTH. Late-onset 21-hydroxylase deficiency was inherited as an autosomal recessive trait with close linkage to the histocompatibility leukocyte antigens. The B14 haplotype was present in all affected members. One affected female had a daughter with classic, salt-losing 21-hydroxylase deficiency. Mixed heterozygosity of this patient for a classic and a late-onset 21-hydroxylase deficiency allele may have caused the classic phenotype in her daughter (homozygote for 2 classic alleles).

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

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.

No significant HLA haplotype association in nickel contact sensitivity: a family study.

No significant HLA haplotype association in nickel contact sensitivity: a family study.

Detection of HLA haplotype associations with disease.

In a recent paper, Thomson & Bodmer (1979) explored several conceptual and analytic issues involved in studying the association of HLA haplotypes with disease. One key problem they emphasized was the assessment of the statistical significance of the third order linkage disequilibrium between two HLA genes and a disease susceptibility gene. We have formulated an approach to this problem and illustrate this approach by deriving such statistical tests of true haplotype associations for two models of disease susceptibility previously studied by Terasaki & Mickey (1975) and by Thomson & Bodmer (1977). A numerical example using actual phenotypic data is then presented to demonstrate the practicality of the methods.

HLA haplotype associations with disease.

Interest recently has extended to the problem of looking for HLA haplotype associations with particular diseases. Higher order interactions, that is to say of particular haplotypes with a disease, are much more complicated than individual antigen associations, with which most disease studies have so far been concerned. Our aim in this work is to explain the concept of higher order interactions and to discuss the difficulties involved when trying to measure such haplotype associations. The main emphasis is to point out that it is not easily possible to detect haplotype associations if an individual antigen association with the disease exists.