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PubMed2003

A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort.

The CYP19 gene encodes for aromatase (P450arom), a key steroidogenic enzyme that catalyzes the final step of estrogen biosynthesis. Apart from rare mutations in CYP19 which result in severe phenotypes associated with estrogen insufficiency, little is known about whether common variation in CYP19 is associated with risk of hormone-related diseases. In this study, we employed a haplotype-based approach to search for common disease-associated variants in this candidate breast cancer susceptibility gene among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We utilized 74 densely spaced single-nucleotide polymorphisms (SNPs) (one every approximately 2.6 kb) spanning 189.4 kb of the CYP19 locus to characterize linkage disequilibrium (LD) and haplotype patterns among 69-70 individuals from each ethnic population. We detected four regions of strong LD (blocks 1-4) that were quite closely conserved across populations. Within each block there was a limited diversity of common haplotypes (5 to 10 with a frequency >/=5%) and most haplotypes were observed to be shared across populations. Twenty-five haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.92) and genotyped in a breast cancer case-control study in the MEC (cases, n=1355; controls, n=2580). We first performed global tests for differences in risk according to the common haplotypes and observed significant haplotype-effects in block 2 [P=0.01; haplotypes 2b (OR=1.23; 95% CI, 1.07-1.40), 2d (OR=1.28; 95% CI, 1.01-1.62)]. We also found a common long-range haplotype comprised of block-specific haplotypes 2b and 3c to be associated with increased risk of breast cancer (haplotype 2b-3c: OR=1.31; 95% CI, 1.11-1.54). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.

Adult↗

PubMed1993

Haplotype analysis at the low density lipoprotein receptor locus in normal and familial hypercholesterolemia Norwegian subjects.

We have performed haplotype analysis at the low density lipoprotein receptor (LDLR) locus in order to investigate the molecular genetics of familial hypercholesterolemia (FH) in Norway. Haplotypes were constructed using 7 restriction fragment length polymorphisms (RFLPs) in 194 subjects from 48 unrelated Norwegian FH families. Hypercholesterolemia co-segregated with haplotypes at the LDLR locus in all 48 families. Unambiguous haplotypes could be established for 190 independent chromosomes from 51 FH heterozygotes and 44 healthy normal subjects. A total of 20 different haplotypes was found. The most frequent haplotype was haplotype 3, which accounted for 32.4% or 43.1% of the normal and defective haplotypes, respectively. Haplotype 2 was significantly more frequent among the defective alleles than among the normal alleles (33.3% and 5.8%, respectively, p < 0.0001). Thus, haplotypes 2 and 3 accounted for 76.4% of the defective haplotypes. More data are needed to determine the possible existence of founder genes in the Norwegian population. Haplotypes 1, 2, 3, 5 and 8 accounted for 88.2% of the normal haplotypes. Based upon the cumulative heterozygosity index, the SphI, NcoI and 3' ApaLI RFLPs are the most informative markers in the Norwegian population.

Base Sequence↗

PubMed2005

Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population.

BACKGROUND: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). PATIENTS AND METHODS: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto's thyroiditis alone, and 15 patients with Graves' disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. RESULTS: In 13 APS III patients with both Hashimoto's thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto's thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves' disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves' disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves' disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. CONCLUSIONS: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.

Adult↗

PubMed1999

The presence or absence of a retroviral long terminal repeat influences the genetic risk for type 1 diabetes conferred by human leukocyte antigen DQ haplotypes. Belgian Diabetes Registry.

Major genetic susceptibility to type 1 diabetes mellitus maps to the human leukocyte antigen (HLA) region on chromosome 6p. During evolution, endogenous retroviral long terminal repeats (LTR) have been integrated at several sites within this region. We analyzed the presence of a solitary HERV-K LTR in the HLA DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from type 1 diabetes mellitus. Segregation analysis of 984 HLA DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P < 10(-6)), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P < 10(-6)) compared with 1 of 6 DR-DQ matched DQ-LTR3 negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3 negative haplotypes were also preferentially transmitted to patients (80%; P < 10(-6)), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). Other DQA1/B1 haplotypes did not differ for DQ-LTR3 between transmitted and nontransmitted haplotypes. Thus, the presence of DQLTR3 on HLA DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for type 1 diabetes.

Diabetes Mellitus, Type 1↗

PubMed2003

Haplotypes and the systematic analysis of genetic variation in genes and genomes.

Haplotypes have been used in various fields of genetics for a long time, in a variety of contexts, and for different purposes. Now, haplotype-based approaches to the analysis of candidate genes and genome-wide linkage disequilibrium (LD) mapping have gained center stage. It is time to explicitly distinguish the different concepts implied in the present haplotype approaches: haplotypes are not haplotypes, after all. The distinction of three different categories, ancestral, common haplotypes or haplotype blocks, gene-based haplotypes as complex genetic markers and gene-based functional haplotypes, is proposed. These categories serve as framework to review and analyze in particular the recent work suggesting evidence for a haplotype block structure of the human genome and the body of comparative sequencing studies addressing haplotype and LD structures at the gene level. Haplotype approaches will be evaluated along the dimensions preselection of variants versus complete DNA sequence information, role of LD and stages in the process of disease gene identification. Overall, the content of haplotypes is conceived as a function of available technologies to evaluate genetic variation and general advances in human genome research.

Genetic Predisposition to Disease↗

PubMed2001

Haplotype analysis at the FRAXA locus in Thai subjects.

The prevalence of fragile X syndrome (FXS) is approximately 7% in Thai boys with developmental delay of unknown cause. To determine if FXS might have a specific haplotype association, we analyzed 125 unrelated control subjects and 25 unrelated FXS patients using 3 microsatellites, DXS548, FRAXAC1 and FRAXE, and two single nucleotide polymorphisms, ATL1 and IVS10. FRAXAC1 and DXS548 are located approximately 7 kb and approximately 150 kb proximal to the CGG-FMR1 whereas ATL1, IVS10 and FRAXE are located approximately 5.6 kb, approximately 24.5 kb and approximately 600 kb distal to the CGG-FMR1. We found 40 haplotypes in the control group and 14 haplotypes in the FXS group. Of 14 haplotypes in the FXS group, 6 haplotypes were not found in the control group suggesting possible new mutations or admixture of immigrant haplotypes. We observed that most diverse haplotypes came from different FRAXE alleles. For this reason, we analyzed haplotypes composed from the remaining markers alone (DXS548-FRAXAC1-ATL1-IVS10). We found 2 major haplotypes (20-18-G-T and 20-19-A-C) with no significant haplotype differences between the control group (67/125 of 20-18-G-T and 25/125 of 20-19-A-C) and FXS group (16/25 of 20-18-G-T and 6/25 of 20-19-A-C). The other haplotypes found were 33/125 in the control group and 3/25 in the FXS group. The two major haplotypes associated FXS in Thai subjects were the two most common haplotypes in the normal Thai subjects. We could not prove, therefore, that there were founder effects at the FRAXA locus in Thailand. We could not, however, exclude it completely. These findings apparently contrast with most other reports on FXS founder effects in various ethnic groups.

Alleles↗

PubMed2003

[Study on HLA haplotypes in Jiangsu-Zhejiang-Shanghai Han population].

This study is to investigate HLA haplotypes in Jiangsu-Zhejiang-Shanghai Han population based on 166 families by serological and molecular biological HLA typing methods and to analyze the distribution characteristic of HLA haplotypes. The results showed that allele frequencies of more than 10% for HLA antigens were A2, A11, A24, B13, B46, B60, DRB1 *04, DRB1 *08, DRB1* 09, DRB1 * 12 and DRB1 * 15. In the analysis of HLA haplotypes, 128 kinds of A-B haplotypes and 182 kinds of B-DRB1 haplotypes were found, comprising 19.28% (128/664) and 27.41%(182/664) of total theoretical haplotypes, respectively. 18 kinds of A-B haplotypes and 23 kinds of B-DRB1 haplotypes occurred at frequencies of more than 0.5% (linkage disequilibrium value, delta > 0) .351 kinds of A-B-DRB1 haplotypes were found, comprising 52.86% (351/664) of total theoretical haplotypes, and 8 kinds of A-B-DRB1 haplotypes occurred at frequencies of more than 0.5% (delta > 0). The common A-B-DRB1 haplotypes were A30-B13-DRB1 * 07(4.22%), A2-B46-DRB1 * 09(3.77%), A33-B58-DRB1 * 17(3.01%), A33-B58-DRB1 * 13.1 (1.81%) and A11-B75-DRB1 * 12(1.51%). The HLA haplotype distribution of Jiangsu-Zhejiang-Shanghai Han population has its own genetic characteristics, so it suggests this population is between southern and northern Han population. The HLA polymorphism of Chinese Han population is more abundant in East Asian populations.

China↗

PubMed1989

Genealogical analysis of cystic fibrosis families and chromosome 7q RFLP haplotypes in the Hutterite Brethren.

In the 100-year period 1880-1980 the Hutterite population increased from about 442 to 23,000 individuals in North America. There are three endogamous subdivisions in this Caucasian genetic isolate. A total of 11 cystic fibrosis (CF) families from Canada and the United States were investigated, including at least two families from each of the three subdivisions, the Dariusleut, Lehrerleut, and Schmiedeleut. A study of RFLPs for the loci D7S8, D7S23, MET, and D7S18 (also called D7S16) in the region of the CF gene in 10 families shows considerable genetic variability. There were three different extended CF gene-region haplotypes on CF chromosomes (CF haplotypes), and there were 13 different extended CF gene-region haplotypes on normal chromosomes (normal haplotypes). The three CF haplotypes have different D7S23 and MET haplotypes. Parents who have the same CF haplotype are, on the average, more closely related than parents who have different haplotypes, but only within the same subdivision. A marriage node graph of 11 families illustrates the complexity of Hutterite genealogies. The frequency distribution of CF haplotypes in the Hutterite sample differs notably from those of larger agglomerates of family data from collaborative studies, with respect to D7S8, MET haplotypes, and D7S23 haplotypes. We propose that there were at least three CF carriers among the founders of the Hutterite population and that copies of a particular CF haplotype in current individuals are identical by descent. The alternative that one or more genetically distinguishable CF haplotypes resulted from recombination since the founding of the population is considered to be less likely.

Canada↗

PubMed1989

Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU).

DNA polymorphisms at the phenylalanine hydroxylase (PAH) locus have proved highly effective in linkage diagnosis of phenylketonuria (PKU) in Caucasian families. More than 10 RFLP sites have been reported within the PAH structural locus in Caucasians. With information from affected and unaffected offspring in PKU families it is often possible to reconstruct complete RFLP haplotypes in parents and to use these haplotypes to follow the segregation of PKU within families and to determine the distribution of PKU chromosomes within populations. To establish the utility of these RFLPs in characterizing Asian families with PKU, we typed eight DNA sites in 21 Chinese families and 12 Japanese families with classical PKU. The eight RFLPs were chosen for their informativeness in Caucasians. From these families we reconstructed a total of 91 complete PAH haplotypes, 44 from non-PKU chromosomes and 47 from PKU-bearing chromosomes. Although all eight marker sites are polymorphic in both Chinese and Japanese, there is much less haplotypic variation in Asians than in Caucasians. In particular, one haplotype alone, haplotype 4, accounts for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. Haplotype 4 is also relatively common in Caucasians. The next most common Asian haplotype is 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations the sum of the frequencies of the five most common haplotypes is still less than 80%, and several of the most common haplotypes are equally frequent. Even though the extent of haplotypic variation in Asians is severely limited, the few haplotypes that are found often differ at a number of RFLP sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1984

Study of alleles of the second complement component (C2) on Canadian HLA haplotypes.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2-1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2*1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B *2 whilst the Bw22 haplotypes mostly carry C4A *4, C4B *4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2 *2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2 *2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.

Alleles↗

PubMed1995

Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia.

In Africa, the beta-globin gene cluster haplotype may be associated with variation of Hb F levels in subjects with sickle cell anemia (SS). These observations have not yet been conclusively confirmed in SS out of Africa, perhaps because of small sample sizes, the predominance of haplotype heterozygotes, and diverse influences, including gender, upon Hb F levels. We studied 384 adult African-American SS patients (mean age, 31 years) and explored the relationship of gender, beta-globin gene cluster haplotype, and alpha thalassemia to hematological values and Hb F levels. Both haplotype and gender influenced Hb F concentration. In the total sample, Hb F was higher in females than in males (8.2 vs. 6.5%). In 35 males who were either homozygous for the Senegal chromosome or had the Senegal/Benin haplotype, the mean percent Hb F (8.0%) was equivalent to the Hb F level in females with Benin and Bantu haplotypes (approximately 7.5%). Both females and males homozygous for the Senegal haplotype chromosome or with the Senegal/Benin combination had a significant increase in Hb F compared to other groups. In 44 Senegal/Senegal or Senegal/Benin females the Hb F was 10.9%, or 1.0 g/dl, the highest value observed in all primary analysis groups. Preliminary analyses suggested that the presence of a Bantu chromosome blunted the gender-associated difference in Hb F, but Hb F differences between females with the Senegal/Benin haplotype (11.2%) and the Senegal/Bantu haplotype (8.8%) were not statistically significant. Hemoglobin concentrations were higher in males than in females except in subjects with at least one Senegal haplotype chromosome, where hemoglobin levels were equal. As expected, alpha thalassemia reduced the MCV, increased hemoglobin concentration, and lowered reticulocyte counts, regardless of haplotype. Hb F levels were not affected by the presence of alpha thalassemia in any group. We conclude that gender and beta-globin gene cluster haplotype interact significantly in the modulation of Hb F and anemia in adults with SS.

Adult↗

PubMed2007

Association of a TNAP haplotype with ankylosing spondylitis.

OBJECTIVE: To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS). METHODS: We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissue-nonspecific alkaline phosphatase, and performed family-based association analyses. RESULTS: In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) was significantly associated with AS (P = 0.032 by additive model). Haplotype-Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P = 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P = 0.001 by additive model). The HBAT -p option (haplotype permutation test) was used to compute the "exact" P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2-sided P value for haplotype rs3767155 [G]/rs3738099 [G]/rs1780329 [T] = 0.00059, the smallest observed P value among all the individual haplotype scores = 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families. CONCLUSION: Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.

Adolescent↗

PubMed1996

An approach to mapping haplotype-specific recombination sites in human MHC class III.

Studies of the major histocompatibility complex (MHC) in mouse indicate that the recombination sites are not randomly distributed and their occurrence is haplotype-dependent. No data concerning haplotype-specific recombination sites in human are available due to the low number of informative families. To investigate haplotype-specific recombination sites in human MHC, we here describe an approach based on identification of recombinant haplotypes derived from one conserved haplotype at the population level. The recombination sites were mapped by comparing polymorphic markers between the recombinant and assumed original haplotypes. We tested this approach on the extended haplotype HLA A3; B47; Bf*F; C4A*1; C4B*Q0; DR7, which is most suitable for this analysis. First, it carries a number of rare markers, and second, the haplotype, albeit rare in the general population, is frequent in patients with 21-hydroxylase (21OH) defect. We observed recombinants derived from this haplotype in patients with 21OH defect. All these haplotypes had the centromeric part (from Bf to DR) identical to the original haplotype, but they differed in HLA A and B. We therefore assumed that they underwent recombinations in the segment that separates the Bf and HLA B genes. Polymorphic markers indicated that all break points mapped to two segments near the TNF locus. This approach makes possible the mapping of preferential recombination sites in different haplotypes.

Alleles↗

PubMed1995

Primate DRB genes from the DR3 and DR8 haplotypes contain ERV9 LTR elements at identical positions.

The HLA-DRB genes of the human major histocompatibility complex constitute a multigene family with a varying number of DRB genes in different haplotypes. To gain further knowledge concerning the evolutionary relationship, the complete nucleotide sequence was determined for a region spanning introns 4 and 5 of the three DRB genes (DRB1*0301, DRB2, and DRB3*0101) from a DR52 haplotype and the single DRB gene (DRB1*08021) in the DR8 haplotype. These analyses identified as endogenous retroviral long terminal repeat element (ERV9 LTR3), inserted at identical positions in intron 5 of the functional DRB genes in these two haplotypes. Comparison of the nucleotide sequence from introns 4 and 5 including the ERV9 LTR elements revealed a strong similarity between the three expressed DRB genes. The DRB3*0101 and DRB1*08021 genes were most similar in this comparison. These findings provide further evidence for a separate duplication in a primordial DR52 haplotype followed by a gene contraction event in the DR8 haplotype. A homologous element was found in a chimpanzee DRB gene from a DR52 haplotype. This represents the first characterized ERV9 LTR element in a nonhuman species. The corresponding introns of the DRB genes in the DR4 haplotype contain no ERV9 LTRs. In contrast, these genes have insertions of distinct Alu repeats, implying distinct evolutionary histories of DR52 and DR53 haplotypes, respectively. Phylogenetic analyses of DRB introns from DR52, DR53, and DR8 haplotypes showed a close relationship between the DRB2 and DRB4 genes. Thus, the ancestral DR haplotype that evolved to generate the DR52 and DR53 haplotypes most likely shared a primordial common DRB gene.

Animals↗

PubMed1991

Association of polymorphisms in the HLA-B region with extended haplotypes.

Genomic probes from the HLA-B region of the major histocompatibility complex (MHC) were used to study the association of restriction fragment length polymorphisms (RFLPs) with various MHC alleles, complotypes, and extended haplotypes. The two DNA probes, M20A and R5A, were derived from previously cloned cosmids and are located 38 and 110 kilobases (kb) centromeric to HLA-B, respectively. Five different RFLP variants occurring in five different haplotypic combinations were detected within a panel of 40 homozygous-typing cells and cells from 21 families using Bst EII. In two informative families with HLA-B/DR recombinations the inheritance of the RFLP variants was consistent with their mapping between HLA-B and complotypes. The R5A/M20A haplotypic pattern 6.5 kb/3.0 kb (A) had a normal Caucasian frequency of approximately 0.43 and was found in all independent examples of the extended haplotypes [HLA-B8,SC01,DR3], [HLA-B18,F1C30,DR3], [HLA-Bw62,SC33,DR4], [HLA-B44,SC30,DR4], and [HLA-Bw47,FC91,0,DR7]. The patterns 6.9 kb/3.0 kb (B), 6.5 kb/4.7 kb (C), 1.45 kb/3.0 kb (D), and 6.9 kb/4.7 kb (E) had normal Caucasian frequencies of approximately 0.23, 0.15, 0.15, and 0.04 and were found on all independent examples of [HLA-B38,SC21,DR4], [HLA-Bw57,SC61,DR7], [HLA-B7,SC31,DR2], and [HLA-B44,FC31,DR7], respectively. Individual complotypes or HLA-B alleles which were markers of extended haplotypes showed variable associations. For example, HLA-B7 and the complotype SC31 were associated with all R5A/M20A RFLP haplotypes except haplotype E, although [HLA-B7,SC31,DR7] was associated exclusively with haplotype D. HLA-B27, not known to be part of an extended haplotype, was surprisingly exclusively associated with the 6.5 kb/4.7 kb or C haplotypic pattern in all five instances tested. These findings support the concept of regional conservation of DNA on independent examples of extended haplotypes. The results also further characterize these haplotypes.

Alleles↗

PubMed2004

High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: characterization of six new variants of PADI4 exons 2-4 by a novel haplotype-specific sequencing-based approach.

Seven single nucleotide polymorphisms (SNPs) of the peptidylarginine deiminase 4 (PADI4) gene have recently been reported to be strongly associated with rheumatoid arthritis in Japanese individuals. These SNPs are located in or close to exons 2-4 of PADI4 and are organized in at least four different haplotypes. However, a detailed sequencing-based characterization of the PADI4 gene in other populations is still lacking. We therefore analyzed exons 2-4 of the PADI4 gene in 102 healthy white Germans individuals by DNA sequencing and characterized new variants and haplotypes by a novel haplotype-specific sequencing-based approach. The haplotypes 2/3 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*T, padi4_95*C, padi4_96*C), and haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) conferring susceptibility to rheumatoid arthritis were detected at frequencies of 30.9% and 7.8%, respectively. In addition, three novel coding SNPs in exons 2, 3, and 4, and three SNPs in introns 2 and 3 located near the exon-intron boundaries were identified in 11 individuals (10.8%). The so-called nonsusceptibility haplotype 1 (padi4_89*A, padi4_90*C, padi4_92*C, padi4_94*C, padi4_104*C, padi4_95*G, padi4_96*T) occurred at a frequency of 58.3%. Additionally, we identified a closely related novel haplotype, haplotype 1B (2.9%), that differs from haplotype 1 only by padi4_92*G/padi4_96*C. This haplotype was not described in the Japanese population. Our results indicate that the PADI4 gene exhibits a remarkable variability and a rather complex haplotypic organization. Further studies on disease association of PADI4 should be performed by haplotype-specific sequencing-based approaches to identify the exact genotype of the PADI4 fragment of interest.

Exons↗

PubMed2005

Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo.

BACKGROUND AND OBJECTIVE: beta2-Adrenergic receptors (beta2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta2-AR variants; Thr164Ile beta2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta2-AR polymorphisms affect beta2-AR-mediated venodilation in healthy subjects in vivo. METHODS: We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common beta2-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile beta2-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily. RESULTS: Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous beta2-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile beta2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta2-AR subjects. CONCLUSION: beta2-AR-mediated dilation of human hand veins is influenced by the 3 most common beta2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta2-AR. Long-term terbutaline treatment desensitizes venous beta2-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).

Adrenergic beta-2 Receptor Agonists↗

PubMed2004

Direct determination of MUC5B promoter haplotypes based on the method of single-strand conformation polymorphism and their statistical estimation.

Haplotype-based human genome research is important in identifying disease susceptibility genes efficiently. Although haplotype reconstruction by statistical methods is widely used, direct haplotype determination by molecular techniques has also been developed as a complementary method for statistical estimation. In this study, we demonstrate a molecular haplotyping method making use of single-strand conformation polymorphism (SSCP) gels. We identified 10 common SNPs and a dinucleotide insertion/deletion polymorphism within 2-kb region upstream of the transcription initiation site of MUC5B and determined haplotype structure, dividing the region into two DNA fragments. Real haplotypes were determined unambiguously by our SSCP-based analysis with fragments longer than 1 kb. Haplotypes reconstructed from diploid genotypes in the same region by the statistical methods including EM algorithm were also evaluated. Direct comparison between statistical estimation and direct determination of haplotypes revealed that major haplotypes containing multiple marker sites showing strong LD are estimated in great accuracy but that a variety of haplotypes reflecting weak LD are not reconstructed precisely enough. Our data can be helpful in implementing molecular haplotyping or statistical estimation, since usage of these methods may be determined depending on the haplotype structures.

Base Sequence↗