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PubMed1991

Physical map of the 3' region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype.

We have constructed the physical map of the 3' region of the human immunoglobulin heavy chain variable region (VH) genes. DNA segments extending to 200 kb upstream of the JH segment were isolated in two YAC clones. Five VH segments were identified in this region in the 5' to 3' order, V(II-5), V(IV-4), V(I-3), V(I-2), and V(VI-1) segments which were all structurally normal and orientated in the same direction as the JH segments. From DNA of a different cell line we have isolated a cosmid contig containing the same DNA region which has extraordinary polymorphism. The YAC and cosmid DNAs were called haplotypes A and B, respectively. Haplotype B contained an additional VH-I segment (V(I-4.1b)) between the V(II-5) and V(IV-4) segments. V(I-4.1b) segment is almost identical to a previously published VH sequence encoding a rheumatoid factor. Another VH segment in the B haplotype (V(I-3b)) corresponding to the V(I-3) segment also showed 99.7% nucleotide sequence homology with an anti-DNA autoantibody VH sequence. However, none of the VH sequences in haplotype A showed such strong homology with autoantibody VH sequences. The results suggest that VH haplotypes may have linkage with autoantibody production.

Amino Acid Sequence↗

PubMed2005

Tests of trait-haplotype association when linkage phase is ambiguous, appropriate for matched case-control and cohort studies with competing risks.

The impact of competing risks on tests of association between disease and haplotypes has been largely ignored. We consider situations in which linkage phase is ambiguous and show that tests for disease-haplotype association can lead to rejection of the null hypothesis, even when true, with more than the nominal 5 per cent frequency. This problem tends to occur if a haplotype is associated with overall mortality, even if the haplotype is not associated with disease risk. A small simulation study illustrates the magnitude of bias (high type I error rate) in the context of a cohort study in which a modest number of disease cases (about 350) occur over time. The bias remains even if the score test is based on a logistic model that includes age as a covariate. For cohort studies, we propose a new test based on a modification of the proportional hazards model and for case-control studies, a test based on a conditional likelihood that have the correct size under the null even in the presence of competing risks, and that can be used when haplotype is ambiguous.

Aged↗

PubMed1992

A Tcra congenic mouse: V alpha epitope expression is influenced by both Tcra haplotypes and background genes.

A T-cell receptor alpha chain locus (Tcra) congenic mouse is described. The Tcraa haplotype of BALB/c (donor strain) was bred on to B10.D2 (background strain, Tcrab haplotype) by using a Bgl I Tcra-C restriction fragment length polymorphism. Tcraa/b heterozygous offspring from the eleventh backcross generation were brother-sister mated to obtain Tcra-Ca homozygous animals. The resulting congenic line, B10.D2.C-Tcraa/Bo carries a recombination between the Tcra and the hr loci; thus, the transferred differential segment is the centromeric 18-27 cM of the BALB/c chromosome 14. Analysis with a multitude of Tcra-V and Tcrd-V probes demonstrates that the complete Tcraa haplotype is contained within this differential segment. Lymph node T cells of BALB/c (Tcraa) B10.D2 (Tcrab) and B10.D2.C-Tcraa were stained with anti-V alpha 8 (KT50, KT65), anti-V alpha 3.2 (RR3-16) and anti-V alpha 11.1 and 2 (RR8-1) monoclonal antibodies. We find that the frequencies of V alpha epitope expression are highly Tcra haplotype-dependent even though an influence of background genes is also observed. Thus, Tcra-V germline differences may possibly influence the T cell repertoire, in addition to the already well known positive and negative thymic selections. Tcra haplotype does not influence the frequencies of V beta utilization. However, BALB/c mice have fewer V beta 11+ T cells than B10.D2 and B10.D2-Tcraa, therefore, the BALB/c genome must harbor a V beta 11 deleting gene(s) in addition to those described so far.

Animals↗

PubMed1991

The codon 408 mutation associated with haplotype 2 is predominant in Polish families with phenylketonuria.

The incidence of phenylketonuria (PKU) in the western part of Poland is 1 in 5000 live births. Restriction fragment length polymorphism (RFLP) haplotypes at the phenylalanine hydroxylase locus have been analysed in 46 Polish families with PKU. Among 43 fully-informative families 16 RFLP haplotypes were identified. Haplotype 2 is the most frequently (62%) associated with Polish PKU alleles, and the codon 408 mutation is in complete linkage disequilibrium with this haplotype in Poland. This finding is in agreement with observations in other eastern European countries (German Democratic Republic, Czechoslovakia, and Hungary) and in contrast to the genotype distribution observed in western European countries. The present observation suggests the spread of classical PKU, due to the codon 408 mutation associated with haplotype 2, from east to west in European populations. Perhaps more important for genetic counselling, 62% of all PKU chromosomes in the Polish population can now be detected using only one mutant-specific oligonucleotide probe.

Alleles↗

PubMed1991

Molecular analysis of PKU haplotypes in the population of southern Poland.

Out of a population of 138,598 infants born in southern Poland between 1987 and 1989, and screened for phenylketonuria (PKU), 28 cases were ascertained probands and their parents were isolated and eight polymorphic restriction sites were analyzed within the phenylalanine hydroxylase gene region. Twenty-one different haplotypes (HT) were revealed, five of them representing new categories. The most common haplotypes among those carrying normal alleles were: HT1 (27.3%) and HT4 (11.4%). Within the group of haplotypes with mutant alleles the most frequent was HT2 (56.8%), whereas the frequency of this haplotype in other European populations, such as French, Danish and German, ranged from 12% to 24%. HT3, being the most common in Danish (38%), and relatively frequent in the other western European (13-14%) populations, appeared to be very rare in our sample (2.3%). The mutation of codon 408 (exon 12, C----T, Arg----Trp), which has been described to be tightly linked to HT2, was tested on amplified DNA by dot-blot hybridization. This mutation was found in 25 out of 44 proband chromosomes. In one case it was linked to HT5, in the remaining 24 to HT2. Our results confirm molecular heterogeneity of PKU haplotypes, as well as their significant interpopulation variation.

Alleles↗

PubMed1990

HLA-DQ RFLP variants of five HLA-DQw2-bearing major histocompatibility complex extended haplotypes.

We have analyzed genomic DNA in a large number of independent examples of five HLA-DQw2-bearing extended haplotypes for their associated subtypes by restriction fragment length polymorphism (RFLP) using DRB, DQA, and DQB probes after Taq I and Pst I digestion and Southern blotting. In addition to three previously described HLA-DQw2 subtypes, DQw2a, DQw2b, and DQw2c, we observed a fourth subtype, HLA-DQw2d, characterized by 5.8 kilobase (kb) DRB/Taq I, 2.4, 2.3, and 1.8 kb DQB/Taq I, and 8.0 and 2.3 kb DQA/Pst I fragments. All 22 independent examples of the extended haplotype [HLA-B8, SC01, DR3] carried DQw2a and all 11 independent examples of [HLA-B18, F1C30, DR3] carried DQw2b. In addition, all independent examples (21 and 4, respectively) of two DR7-carrying extended haplotypes, [HLA-B44, FC31, DR7] and [HLA-Bw47, FC91,0,DR7], carried DQw2c and all independent examples of [HLA-Bw57, SC61, DR7] carried DQw2d. Our results show that the DNA in the DR/DQ region of extended haplotypes is relatively fixed and that different DQw2 subtypes characterize different DQw2-bearing extended haplotypes.

Blotting, Southern↗

PubMed1992

Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM.

The major histocompatibility complex (MHC) contains multiple and diverse genes which may be relevant to the induction and regulation of autoimmune responses in insulin dependent diabetes mellitus (IDDM). In addition to HLA class I and II, the possible candidates include TNF, C4, and several other poorly defined polymorphic genes in the central MHC region. This study describes two approaches which take advantage of the fact that the relevant genes are carried by highly conserved ancestral haplotypes such as 8.1 (HLA-B8, TNFS, C4AQ0, C4B1, DR3, DQ2). First, three "diabetogenic" haplotypes (two Caucasoid and one Mongoloid) have been compared and it has been shown that all three share a rare allele of BAT3 as well as sharing DR3, DQ2. In 43 sequential patients with IDDM the cross product ratio for BAT3S was 4.8 (p less than 0.01) and 6.9 for HLA-B8 plus BAT3S (p less than 0.001). Second, partial or recombinant ancestral haplotypes with either HLA class I (HLA-B8) or II (HLA-DR3, DQ2) alleles were identified. Third, using haplotypic polymorphisms such as the one in BAT3, we have shown that all the patients carrying recombinants of the 8.1 ancestral haplotype share the central region adjacent to HLA-B. These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes. By contrast, similar approaches suggest that protective genes map to the HLA class II region.

Adult↗

PubMed1993

Phenylketonuria in Spain: RFLP haplotypes and linked mutations.

In order to investigate the molecular basis of phenylketonuria (PKU) in Spain, we analyzed the restriction fragment length polymorphism (RFLP) haplotypes and common mutations in the phenylalanine hydroxylase (PAH) gene in 32 unrelated Spanish PKU families. The distribution of RFLP haplotypes differs from that of northern Europe. Mutant haplotypes 2 and 3 were completely absent in our sample. Approximately 65% of the mutant alleles are confined to three RFLP haplotypes, namely haplotypes 1, 6 and 9, also frequently found in other Mediterranean populations. We screened for previously described PKU mutations using the polymerase chain reaction and allele-specific oligonucleotides, and found IVS10, I65T, E280K and P281L as the major mutations, representing 41% of the PKU alleles. Other mutations found were Y414C, and a new one, P244L. Mutations R408W and IVS12, prevalent in northern Europe, as well as others present in southern European populations (R252W, R261Q, L249F) were not detected in our sample. Our results reveal the genetic heterogeneity present in the Spanish PKU population, which shows similarities to others of Mediterranean origin.

DNA Mutational Analysis↗

PubMed1988

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in type 1 (insulin-dependent) diabetes.

Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOB1,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DR beta and DQ beta DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n = 58), B18,DR3 (n = 62) or other DR3 haplotypes (Bx, DR3, n = 70), the haplotype segments C4AQOB1,DR3 (n = 41) or C4A3BQO,DR3 (n = 52) and the C4 null alleles C4AQO (N = 48) or C4BQO (n = 112) alone. The B8,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p less than 0.01, less than 0.08 and less than 0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (p less than 0.02, less than 0.01 and less than 0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former patients (p less than 0.02, less than 0.02 and less than 0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1989

DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population.

Thirty-nine Turkish phenylketonuria (PKU) families were investigated for their DNA haplotypes at the phenylalanine hydroxylase (PAH) locus. There was a threefold higher incidence of consanguinity in the population studied compared with the general Turkish population. The PAH DNA haplotype 6 was found to be almost exclusively associated not only with the mutant PAH genes but also with the classic phenotype in 39% of the Turkish patients. This haplotype was of not importance in northern European populations. The two DNA haplotypes (1 and 4) that were almost equally frequent among the normal and the mutant PAH genes in northern European populations show virtually the same distribution in Turkish individuals. In all populations studied, these haplotypes are associated with different phenotypes.

Blotting, Southern↗

PubMed1989

A cellular and functional split in the DRw8 haplotype is due to a single amino acid replacement (DR beta ser 57- asp 57).

The single DR beta chain gene of the DRw8 haplotype has been suggested to carry both the DRw8 and the DRw52 epitopes. Cellular typing has shown that the DRw8 haplotype can be split into three subtypes, Dw8.1, Dw8.2, and Dw8.3, presumably due to a polymorphism in the DRw8 beta chain. Furthermore, Dw8.1 and Dw8.2 cells present influenza virus antigen to different T-cell clones. In the present study, DRw8/Dw8.2 beta chain cDNA was cloned and characterized. A comparison of this sequence with a partial DRw8/Dw8.1 beta chain gene suggested that the DRw8 split is due to a single amino acid replacement of ser57-asp57 caused by three nucleotide substitutions in the same codon. In most DR haplotypes, two expressed DR beta chain genes exist. Comparing the nucleotide sequence of the single beta gene in the DRw8 haplotype to those of other DR beta genes revealed that the DRw8 beta gene sequence is most closely related to the DRB1 genes of the DR3, 5, and w6 haplotypes. However, the comparisons also showed that it was not possible from sequence similarities to divide the DR beta genes into two or more distinct allelic series.

Amino Acid Sequence↗

PubMed1992

The mouse plasminogen locus maps to the recombination breakpoints of the tLub2 and TtOrl partial t haplotypes but is not at the tw73 locus.

The mouse plasminogen (Plg) locus maps to a region of chromosome (Chr) 17 which is inverted in the t haplotype Chromosomal variant. Here we investigate the genomic organization of the Plg locus in structurally variant forms of Chr 17; wild-type (+), t haplotype (t), and two partial t haplotypes TtOrl and tLub2 which arose by recombination between + and t chromosomes. Our analysis suggests that the t haplotype chromosomal variant contains extra, inverted copies of the Plg locus, and that a single locus is present in the wild-type variant. Changes in the Plg locus in TtOrl and tLub2 suggest that they arose by homologous recombination across elements in the Plg locus having the same orientation in the wild-type and t haplotype chromosomes. One hundred ten kb around the wild-type Plg genomic locus have been cloned and the proximal breakpoint of a deletion in the tLub2 chromosome has been localized to a fragment 30 kb downstream of the Plg gene. The tLub2 deletion has been shown to delete a gene named tw73 that affects blastocyst implantation, a process probably requiring proteases such as plasminogen. However, the mapping of Plg relative to the tLub2 deletion and mRNA analysis of plasminogen in tw73 heterozygotes suggests that Plg does not lie at the tw73 locus.

Animals↗

PubMed1992

Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands.

Two steroid 21-hydroxylase genes are normally present within the human major histocompatibility complex near the genes encoding the fourth component of complement (C4A and C4B). Steroid 21-hydroxylase is encoded by the CYP21 gene, while the highly homologous CYP21P gene is a pseudogene. We studied steroid 21-hydroxylase and complement C4 haplotypes in 33 Dutch patients (29 families) suffering form classical congenital adrenal hyperplasia (CAH) and in their 80 family members, and also in 55 unrelated healthy controls, using 21-hydroxylase and complement C4 cDNA probes. Eleven different haplotypes, defined in terms of gene deletions, gene duplications, conversions of CYP21 to CYP21P, and "long" and "short" C4 genes, were found. In 23% of the patients' haplotypes, the CYP21 gene was deleted; in 12%, it was converted into a CYP21P pseudogene. In the remaining 65%, the defect was apparently caused by a mutation not detectable by this method. The most common haplotype (with one CYP21 and one CYP21P gene) was significantly more often observed in patients with simple virilizing CAH than in those with salt-losing CAH. Comparison of the 21-hydroxylase haplotypes found in CAH patients from several countries shows evidence for considerable genetic variation between the groups studied.

Adrenal Hyperplasia, Congenital↗

PubMed1992

Lung involvement, the delta F508 mutation and DNA haplotype analysis in cystic fibrosis.

Molecular studies of cystic fibrosis (CF) have allowed the genetic analysis of patients by means of DNA markers and the direct analysis of the CF gene. Some limited observations are available on the correlation between phenotype and genotype. Here, we report a study on the correlation of DNA haplotypes identified by KM-19 and XV-2c, the presence of the delta F508 mutation and lung involvement in 82 unrelated CF patients. Pulmonary involvement was defined by Chrispin's chest X-ray score, pulmonary function, sputum microbiology, serum immunoglobulin (SIg) levels and Shwachman's clinical score. Patients homozygous for haplotype B showed worse X-ray and clinical scores, more frequent sputum colonization by Pseudomonas aeruginosa and Staphylococcus aureus, lower spirometric values and raised concentrations of SIg G, A and M, compared with patients with other haplotypes. When lung involvement parameters were examined in patients homozygous, heterozygous or null for the delta F508 mutation, no difference was found among the three groups. Our data indicate a significant occurrence of severe pulmonary involvement in patients homozygous for the B haplotype; this is not influenced by the delta F508 mutation. We suggest that simple DNA haplotypes may provide data of both diagnostic and prognostic value, without the need for extensive and expensive molecular analyses.

Adolescent↗

PubMed1989

The D17Tu5 locus in the t complex: implications for the origin of t haplotypes and inbred strains.

The mouse x Chinese hamster cell line R4 4-1 contains only one mouse chromosome, the bulk of which corresponds to Mus musculus chromosomes 17 and 18 (MMU17 and MMU18, respectively). A genomic library was prepared from the R4 4-1 DNA, and a mouse clone was isolated from the library, which-with the help of somatic cell hybrids-could be mapped to the MMU17. A locus defined by a 2.7-kb long Bam HI probe from this clone was designated D17Tu5 (Tu for Tübingen). The locus proved to be polymorphic among inbred strains and wild mice. By testing of recombinant inbred strains and partial t haplotypes, the D17Tu5 locus could be mapped to a position between the D17Leh66E and D17Rp17 loci within the t complex. Two alleles were found at this locus, D17Tu5a and D17Tu5b, defined by Taq I restriction fragment length polymorphism. Both alleles are present among inbred strains and wild mice of the species M. domesticus. All complete t haplotypes tested carry the D17Tu5a allele and all tested wild mice of the species M. musculus, with the exception of those bearing t haplotypes, carry the D17Tu5b allele. Additional alleles are found in some populations of wild mice and in other species of the genus Mus. The distribution of the two alleles among the inbred strains correlates well with their known or postulated genealogy. Their distribution between the two species of Mus and among the mice with T haplotypes suggests a relatively recent origin of the t haplotypes.

Alleles↗

PubMed1991

Molecular organization of the D-Qa region of t-haplotypes suggests that recombination is an important mechanism for generating genetic diversity of the major histocompatibility complex.

We have determined the molecular maps of the H-2D and Qa regions of the t-complex haplotypes t12 and tw5 by chromosomal walking. Analysis with class I probes and other probes unique to the H-2D:Qa subregion indicates that the class I gene organization of t12 is: D1-D2-Q1-Q2-Q3-Qx-Q4-Q5-Q10, while that of tw5 is: D1-D2-Q1-Q2-Q4-Q5-Q10. Thus, the absence of the Q6-Q9 genes suggested previously in t-haplotypes was confirmed. A comparison of the molecular maps of the t12 and tw5 chromosomes revealed an extremely mosaic pattern of diversity: The regions between D1 and D2, and between Q4 and Q10, are very similar in both chromosomes. However, their Q1 to Q3 regions are strikingly different. Further comparisons of wild-type chromosomes and additional t-haplotypes by molecular mapping and genomic Southern blot hybridization with probes to the Q1-Q3 region showed a high level of polymorphism among both wild-type chromosomes and among t-haplotypes. The characteristics of the polymorphisms suggest that recombination may play an important role in generating this genetic diversity. Furthermore, recombination between wild-type and t-haplotype chromosomes may be involved.

Animals↗

PubMed1996

HLA risk haplotype Cw6,DR7,DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris.

Psoriasis vulgaris has HLA associations. We have previously defined HLA-Cw6,DR7,DQA1*0201 as the central element of the risk haplotypes for psoriasis. On the other hand, Cw6 as a single gene has the strongest association with psoriasis. The aim of this study was to determine whether the risk haplotype and Cw6 correlate with the clinical parameters of the disease. The series consisted of 64 patients and the clinical parameters were age at onset, family history of psoriasis, arthritis and the frequency of inpatient treatment. The HLA risk haplotype Cw6,DR7,DQA1*0201 had previously been found in 30% and Cw6 alone in 54% of the patients. The presence of Cw6 correlated with early age at onset (Pc = 0.01). The presence of the risk haplotype correlated with a positive family history of psoriasis among the first-degree relatives (Pc = 0.02) and an overall positive family history (Pc = 0.04), but Cw6 had a stronger correlation with an overall positive family history (Pc = 0.01). There were no positive correlations with arthritis or the number of inpatient treatment periods. Only type I psoriasis was associated with Cw6 (Pc = 0.0006). In conclusion, Cw6 and the haplotype Cw6,DR7,DQA1*0201 are important in the heredity of psoriasis vulgaris, but the presence of Cw6 alone is sufficient to indicate a clinically significant risk for psoriasis.

Adult↗

PubMed2003

Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease.

Matrix metalloproteinase-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis, the pathology underlying the majority of coronary artery disease. We previously identified several polymorphisms in the gene encoding MMP-9. In this study we tested the hypothesis that variation in the matrix metalloproteinase-9 gene influences the development of atherosclerosis. Three common polymorphisms, i.e. -1562C>T, R+279Q and +6C>T, were analysed in 1510 white subjects undergoing coronary angiography. Analyses of individual polymorphisms showed that the frequencies of the C/T and T/T genotypes of the -1562C>T polymorphism were significantly higher in patients with coronary stenosis than in those with a normal angiogram. Logistic regression analyses indicated that individuals carrying the -1562T allele had an approx. 1.5-fold higher risk of developing coronary stenosis (OR 1.49, 95% CI 1.039-2.144), which was equivalent to an over 30% reduction in risk of coronary stenosis in individuals not carrying this allele (OR 0.670, 95% CI 0.467-0.963). The three polymorphisms studied were found to be in strong linkage disequilibrium. Haplotype analyses showed that the C-G-C haplotype (-1562C, +279Q and +6C) was associated with a protective effect against atherosclerosis. Individuals carrying this haplotype were at reduced risk of developing coronary stenosis (OR 0.695, 95% CI 0.530.92). Furthermore, the C-G-C haplotype was associated with less severe coronary atherosclerosis, i.e. carriers of this haplotype were at a lower risk of having coronary stenosis in more than one coronary artery (OR 0.796, 95% CI 0.640.99). These data, together with the previous finding that the -1562T allele has a higher transcriptional activity than the -1562C allele, support the notion that genetic variation with an effect on MMP-9 expression influences the development and progression of atherosclerosis.

Case-Control Studies↗