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PubMed1994

Identification of two different HLA B49 DR4 extended haplotypes in the Sardinian population.

The HLA-B49 DR4 haplotype, which is rare in Caucasoid populations, has a frequency in Sardinia of approximately 6% and a very strong linkage disequilibrium (LD). To better understand its genetic structure, the Bf, C4A and C4B Class III alleles were studied in 56 healthy unrelated Sardinian subjects of B49 DR4 phenotype and in 24 of their families. Moreover, 14 sick subjects with the same phenotype were examined together with five of their families. A group of 285 haplotypes belonging to randomly selected individuals was used as a control population sampling. The distribution of the Bf, C4A and C4B alleles among the healthy probands revealed two main groups of association: one major group of 36 subjects (64.3%) with the BfF, C4A3 and C4B4 alleles and one minor group of 14 subjects (25%) with BfS, C4AQ0 and C4B1. A similar subdivision was also observed in the small group of patients. The family analysis confirmed these results and showed two different B49 DR4 extended haplotypes: one with the F34 complotype in 79.1% of the probands (delta x 1000 = 49.0) and the other with the S01 complotype in 20.8% of the probands (delta x 1000 = 17.3). The first one, in LD with the A1 and Cw7 alleles, has not yet been reported in other populations. The second one seems to be identical to a haplotype already reported in the Spanish population. The molecular analysis of the DRB1 locus carried out in 20 of the 70 probands demonstrated that, in both haplotypes, DR4 was represented by the DRB1*0405 allele.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1996

C4 polymorphism and extended HLA haplotypes in Namibian San and Khoi and in South African Xhosa.

We studied C4A and C4B polymorphisms and HLA-B and -DR associations in the San, Khoi and Xhosa. C4A and C4B alleles were determined using conventional protein allotyping methods. The C4A*3, C4B*1 haplotype had a high frequency (30-55%) in all populations. The frequency of C4A*3, C4B*Q0 was 7-19%. The C4A*Q0, C4B*1 haplotype was frequent (15%) in the Khoi but very rare in the San (P < 0.001). C4A*12 A*91, C4B*Q0 was frequent in the Xhosa (15%) but rare in the San and Khoi (P < 0.001). Alleles C4A*5 and C4A*6, and the C4B*2 B*92 duplication were only found in the Xhosa. C4A alleles A*4, A*45, A*58, A*12, A*14, A*19 and the C4A*3 A*91 duplication were only found in the San/Khoi population group. In the San, fourteen extended haplotypes were found in a relatively high frequency (2-7%). In the Xhosa, one extended haplotype (B42, C4A*12 A*91, C4B*Q0, DR18) was found in a very high frequency (13%) and was characteristic for this group; five other extended haplotypes were found with a low frequency (< 3%).

Complement C4a↗

PubMed1996

Complement C4A, C4B and BF haplotypes in Koreans.

Specific alleles at C4A, C4B and BF loci occur in populations and are inherited in complotypes, which are linked with particular HLA haplotypes. Considerable differences in complement allele and complotype frequencies have been observed among various ethnic groups. In the present study, 109 Korean families were analyzed for complement and complotype polymorphism. Thirty-four different complotypes were detected: the most common was BF*S-C4A*3-C4B*1 (S31) with a frequency of 42.2%, followed by S42 (14.3%) and F31 (13.8%). Three complotypes, S42, F31, and FQ01, showed positive linkage disequilibrium. Some of the complotypes were linked with characteristic HLA haplotypes. Two complotypes carrying duplicated C4A genes, S3+31(BF*S-C4A*3-C4A*3-C4B*1) and S3+2Q0(BF*S-C4A*3-C4A*2-C4B*Q0), were exclusively associated with HLA-A24-Cw7-B7-DR1-DQ1 and A24-CBL-B52-DR15-DQ1 haplotypes, respectively. Twelve families showed recombinant haplotypes, nine in the class I region, three between the HLA-B and HLA-DR loci, and none in the class III region. Maternal recombination occurred twice as frequently as paternal. The results obtained in this study represent the frequencies of complotypes and extended HLA haplotypes of well-defined Koreans, based on a family study.

Complement C4a↗

PubMed1996

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-DRB1*0402, DQA1*0301, DQB1*0302 and HLA-DRB1*1401, DQA1*0104, DQB1*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 DRB1*0402 and DQB1*0503 alleles. A genetic resistance to PV seems to be conferred by the HLA-DR3, DQ2 haplotype in the Sardinian population.

Alleles↗

PubMed1996

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India.

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.

Alleles↗

PubMed1997

HLA-B14 subtyping by semi-nested PCR-SSP and haplotype distribution in a Spanish population.

HLA-B14 serological subtyping is very limited probably due to the internal position of the unique amino acid residue that differentiates B64 and B65 molecules. In order to carry out an accurate B14 subtyping we have designed a semi-nested PCR-SSP procedure that can differentiate B*1401 and B*1402 in any HLA-A, -B or -C antigen combination. A panel of 133 B14-positive and 31 B14-negative healthy and unrelated Spanish individuals were studied. Additionally, 45 B14-bearing haplotypes (-A,-B,-C,-DRB1,-DRB3/DRB4/DRB5,-DQA1,- DQB1) were available through family studies. The relative frequencies of HLA-B14 subtypes were 74% for B*1402 and 26% for B*1401, in agreement with those found in other Central European populations, but differing from those in Wales, where the relative presence of B64 goes to 41%. A total of 11/17 and 18/28 different haplotypes for B*1401 and B*1402, respectively, were identified. Both alleles showed the strongest association to Cw8 (43/45), indicating a primary ancestral B14-Cw8 association. However, B14 subtypes evidenced very distinguishable haplotype distributions. B*1401 is strongly associated with the common HLA class II haplotype DRB1*0701-DQA1*0201-DQB1*02 (13/17), while B*1402 is mainly associated to DRB1*0102 (16/28). Three major haplotypes were identified: A32-Cw8-B*1401-DR7-DQ2 (5/17), A33-Cw8-B*1402-DRB1*0102-DQ5 (5/28) and A2-Cw8-B*1402-DRB1*0102-DQ5 (5/28).

HLA-B Antigens↗

PubMed1998

Polymorphism and distribution of HLA-DR2 alleles and haplotypes in a Greek population.

HLA-DR2 serological subtyping has indicated that the DR16 serotype appears at a higher frequency relative to the DR15 serotype in the Greek population, differing from the distribution observed in most other Caucasian groups. In this study, we have analyzed by the PCR-SSP technique a DR2-positive group of unrelated Greek individuals selected from our normal control panel for the different DRB1, DRB5, DQB1 and DQA1 DR2-associated alleles present. Six of the 50 individuals analyzed were homozygous for DR2, contributing a total of 56 haplotypes for DR2. The observed frequencies of the DR2-related DRB1 alleles were as follows: 58.9% for the DRB1*1601, 7.1% for the DRB1*1602, 25.0% for the DRB1*1501 and 7.1 % for the DRB1*1502 allele. The rare allele DRB1*1605 was detected in one heterozygous sample and its presence was definitively established by DNA sequencing. The alleles *1503, *1504, *1505, *1603 and *1604 were not detected. Three DRB5 alleles were identified: DRB5*0202 (67.8%), DRB5*0101 (25.0%) and DRB5*0102 (7.1%). Ten different DRB1/DQB1/ DQA1 DR2-associated haplotypes were defined. The most frequently observed haplotype was DRB1*1601-DQB1*0502-DQA1*0102 (relative frequency=57%) followed by DRB1*1501-DQB1*0602-DQA1*0102 (relative frequency=14.3%). In conclusion, the refined analysis of the DR2-associated DRB1 alleles in the Greek population revealed the prevalence of the DRB1*1601 allele. The rare allele DRB1*1605 was demonstrated once. A considerable variety of different DR2-related DR/DQ haplotypes was detected and the overall haplotypic frequencies in the Greek population are distributed differently compared to those reported for most other Caucasian populations.

Alleles↗

PubMed1998

Haplotypes comprising subtypes of the DQB1*06 allele direct the antibody response after immunisation with hepatitis B surface antigen.

Two HLA class II haplotypes, HLA-[DQB1*0602; DQA1*0102; DR15] and HLA-[DQB1*0603; DQA1*0103; DRB1*1301] were found to be less common in 52 nonresponders compared with 68 responders, P<0.025 and P<0.05 respectively, after vaccination with hepatitis B surface antigen (HBsAg). Another haplotype, HLA-[DQB1*0604; DQA1*0102; DRB1*1302], had a significantly higher frequency in the nonresponders (P<0.005). The nonresponders and responders were nonsmoking, healthy individuals with an antibody concentration of <10 IU/l and >100 IU/l respectively. The three haplotypes comprise either of three different DQB1*06 subtypes. Two of the seven amino acids that differ between the two responder alleles DQB1*0602 and *0603 and the nonresponder allele *0604 are located in the peptide-binding groove of the DQB1 molecule. In addition to this finding, amino acid 86 in the DRB1 molecule seems to determine the response against HBsAg. DRB1*1301 and DR15 in the responder haplotypes have a Val at this position while the nonresponder haplotype has a Gly. These results suggest a role for both the DQB1*06 alleles and the DRB1 alleles *1301, *1302 and DR15 to direct either a response or a nonresponse against HBsAg. Sixteen HLA class II genotypes were found to be shared by 25 nonresponders and 32 responders. This finding of HLA-identical nonresponders and responders indicates an influence of other genetic factors in addition to the HLA system in the response to HBsAg.

Adult↗

PubMed2004

Microgeographic variation of HLA-A, -B, and -DR haplotype frequencies in Tuscany, Italy: implications for recruitment of bone marrow donors.

HLA-A/B haplotype frequencies were estimated in a sample of 2355 bone marrow donors born in a subregion of Tuscany (Italy), and the HLA-A, -B, -DR haplotype frequencies were estimated in a subset of 809 individuals. This area was divided in 10 subsamples (two-locus haplotypes), or six subsamples (three-locus haplotypes), all with sample size >50, based on administrative boundaries. A considerable level of heterogeneity of haplotype frequency was present among subsamples; this heterogeneity was associated to a large variation (up to 4-fold) of the number of new donors that must be typed in order to reach 50% chance of finding an HLA-A, -B phenotype of intermediate frequency. Knowledge of the genetic structure of the population at a microgeographic level may be useful in directing the search of specific bone marrow donors.

Bone Marrow↗

PubMed2005

Haplotype analysis of the CD11 gene cluster in patients with chronic Helicobacter pylori infection and gastric ulcer disease.

Helicobacter pylori infection leads to a broad spectrum of disease manifestations such as gastritis, ulcer disease, and even gastric carcinoma. The genetically determined immune response and subsequent inflammation influence the degree of mucosal damage. Adhesion molecules of the CD11 cluster play an important role in adherence of neutrophils to endothelial cells in inflammation. We conducted a haplotype-based analysis of the CD11 cluster in a sample of 315 patients with H. pylori infection and investigated associations with gastric erosions and ulcer disease. Twelve single nucleotide polymorphisms (SNPs) covering the genes CD11a, CD11b, and CD11c were genotyped by Taqman technology. Linkage disequilibrium (LD) was assessed within the CD11 cluster and haplotype case-control analysis was conducted. Sliding window haplotype analysis identified a haplotype consisting of the markers CD11c exon 15 and intron 31 associated with gastric ulcer disease. Patients carrying the haplotype GA bear a 2.4-fold increased risk. No significant associations of single markers with disease outcome were found. High-density LD mapping and mutation detection of CD11c in larger samples will be necessary to confirm our findings and identify the causative variant. Thus, we conclude that genetic variants in the CD11 cluster may play a role in the development of gastric ulcer in chronic H. pylori infection presumably by influencing leukocyte adhesion. The biological effect of genetic variants of CD11c in gastric inflammation needs further clarification.

Adult↗

PubMed2005

Distributions of HLA class I alleles and haplotypes in Northern Han Chinese.

Human leukocyte antigen (HLA) class I allelic genotypes were determined in 105 unrelated Han ethnic individuals inhabiting the northern China area. A total of 19 HLA-A alleles, 49 HLA-B alleles and 24 HLA-Cw alleles were detected. Through the analyses of two and three loci haplotypes of HLA-A, HLA-B, and HLA-C loci, 11 HLA-A-B-Cw haplotypes, 19 HLA-A-B haplotypes, 18 HLA-A-Cw haplotypes, and 24 HLA-B-Cw haplotypes with the frequencies of higher than 0.01 were revealed. The Nei's genetic distance (GD) was estimated, and the NJ dendrogram showed that Northern Han had a higher GD to Southern Han (0.233) than those to the Korean (0.138) or other Northern ethnic groups, suggesting that Northern Han had more mixed blood with the ethnic groups originally in Northeast Asia. Our results provide useful information on the further study of evolution and relationships of Chinese ethnic groups and disease association in terms of HLA class I genes.

Alleles↗

PubMed2006

The association between HLA class II haplotype with Graves' disease in Thai population.

The distribution of HLA-DRB1, -DQA1 and -DQB1 alleles were analysed in 124 Graves' disease (GD) patients compared to 124 normal controls in order to identify the alleles/haplotypes associated with GD in Thai population. The DRB1*1602-DQA1*0102-DQB1*0502 haplotype was significantly increased in GD patients (P = 0.0209, OR = 2.55). DRB1*07-DQA1*0201-DQB1*0201 haplotype (P = 0.039, OR = 0.32) and HLA-DRB1*12-DQA1*0601-DQB1*0301 haplotype (P = 0.0025, OR = 0.28) were significantly decreased in GD patients. Interestingly, a protective DRB1*07 allele in Thai population lacks an arginine at position 74 similar to DRB1*0311 (a protective allele in Caucasians). A significant association of DRB1*1602-DQA1*0102-DQB1*0502 and HLA-DRB1*12-DQA1*0601-DQB1*0301 alleles and haplotypes with GD was recently reported in Korean but not in any Caucasian studies. Thus, DRB1*1602 allele and closely linked haplotype, DRB1*1602-DQA1*0102-DQB1*0502, might serve as a marker for genetic susceptibility to GD in Asian population.

Adolescent↗

PubMed2006

TNF-alpha SNP haplotype frequencies in equidae.

Tumour necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that plays a crucial role in the regulation of inflammatory and immune responses. In all vertebrate species the genes encoding TNF-alpha are located within the major histocompatability complex. In the horse TNF-alpha has been ascribed a role in a variety of important disease processes. Previously two single nucleotide polymorphisms (SNPs) have been reported within the 5' un-translated region of the equine TNF-alpha gene. We have examined the equine TNF-alpha promoter region further for additional SNPs by analysing DNA from 131 horses (Equus caballus), 19 donkeys (E. asinus), 2 Grant's zebras (E. burchellii boehmi) and one onager (E. hemionus). Two further SNPs were identified at nucleotide positions 24 (T/G) and 452 (T/C) relative to the first nucleotide of the 522 bp polymerase chain reaction product. A sequence variant at position 51 was observed between equidae. SNaPSHOT genotyping assays for these and the two previously reported SNPs were performed on 457 horses comprising seven different breeds and 23 donkeys to determine the gene frequencies. SNP frequencies varied considerably between different horse breeds and also between the equine species. In total, nine different TNF-alpha promoter SNP haplotypes and their frequencies were established amongst the various equidae examined, with some haplotypes being found only in horses and others only in donkeys or zebras. The haplotype frequencies observed varied greatly between different horse breeds. Such haplotypes may relate to levels of TNF-alpha production and disease susceptibility and further investigation is required to identify associations between particular haplotypes and altered risk of disease.

Animals↗

PubMed2006

Human leukocyte antigen class I and MICA haplotypes in a multicase family with Cladophialophora carrionii chromoblastomycosis.

Previous studies carried out in an endemic semiarid region northwest of Venezuela at Falcon State have shown a prevalence of 15.4/1000 of chromoblastomycosis following traumatisms with xenophile vegetation infected with Cladophialophora carrionii. We performed high-resolution DNA typing of human leukocyte antigen (HLA)-A, -B and -C and major histocompatibility complex class I chain related gene A (MICA) alleles and segregation analysis in 49 members of one extended family with 12 affected individuals, who have lived for approximately 70 years in this endemic zone. None of the alleles, haplotypes or genotypes is shared by all the patients. No deviation from the expected HLA haplotype distribution or association of chromoblastomycosis with HLA-A, -B and -C haplotypes was observed. Further, a haplotype-sharing transmission/disequilibria testing of 11 nuclear families did not give enough evidence to claim linkage (P = 0.398), suggesting that genes located in the short arm of chromosome 6 may not be relevant in the immune response toward infection with C. carrionii in this Venezuelan endemic zone. Deleted MICA alleles on HLA-B*4802 haplotypes were present among several members of the extended family, but only two of them were affected.

Alleles↗

PubMed1992

Genetic relationship between the 3'-VNTR and diallelic apolipoprotein B gene polymorphisms: haplotype analysis in individuals of European and south Asian origin.

The genetic relationship amongst apolipoprotein B (apo B) gene polymorphisms (signal peptide insertion/deletion (Leu-Ala-Leu-16/-14), XbaI (Thr2488), EcoRI (Glu4154----Lys), Asn4311----Ser, 3'-VNTR) has been investigated in samples of South Asian (Indian) and Swedish individuals. The frequency distribution of alleles at all these sites was found to be significantly different between the South Asian and the Swedish samples (deletion allele: 0.20 v. 0.31, X+ (presence of XbaI cutting site): 0.29 v. 0.55, R- (absence of EcoRI cutting site): 0.11 v. 0.19, Ser4311: 0.45 v. 0.19). The distribution of allele frequencies at the VNTR site was bimodal in both populations. However, in South Asians, the most common allele was a 35 repeat unit allele, whilst in the Swedish sample, and in all other reports from Caucasian samples the 37 repeat unit allele was the most frequent (South Asian v. Swedish: 35 allele: 0.36 v. 0.19, 37 allele: 0.25 v. 0.48). Furthermore, four new alleles at the apo B gene 3'-VNTR site (15, 17, 32, 38 repeat unit alleles) were observed in South Asians, of which two (15 and 17 repeat unit alleles) were well outside the bimodal distribution. In both samples, strong linkage disequilibrium and allelic association were detected between alleles at the 3'-VNTR and each of the other sites, and also between the ins/del and XbaI sites and between the XbaI and Asn4311----Ser sites. The same five common haplotypes as defined by ins/del, XbaI, EcoRI and Asn4311----Ser were found to be present in both samples comprising 97 and 99% of the haplotypes observed in the South Asian and Swedish samples respectively. Detailed analysis revealed the predominant occurrence of certain 3'-VNTR alleles on specific haplotypes and demonstrates the usefulness of the VNTR site for haplotyping and representative association studies. A model for the evolutionary relationship of the major haplotypes including the 3'-VNTR site is presented. These findings support a mechanism of replication slippage as a major factor for the generation of new alleles at the apo B 3'-VNTR locus rather than unequal crossing over.

Adult↗

PubMed1996

Geographic clustering of human Y-chromosome haplotypes.

Five polymorphic markers on the Y-chromosome (mostly microsatellites) were typed in 121 individuals from 13 populations around the world. With these markers 78 different haplotypes were detected. Haplotypes present more than once tend to be shared by individuals from the same population or continent. A reconstruction of haplotype phylogeny also indicates significant geographic structure in the data. Based on the similarity of the haplotypes, population relationships were examined and found to be largely concordant with those obtained with other markers. Even though the sample size and the number of markers are small, there is very signficant clustering of the haplotypes by continent of origin.

Alleles↗

PubMed2006

Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease in the Italian population derive from a single ancestral combination of alleles.

The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases. Several RET polymorphisms and haplotypes have been described in association with the disease, suggesting a role for this gene in HSCR predisposition, also in the absence of mutations in the coding region. Finally, the presence of a functional variant in intron 1 has repeatedly been proposed to explain such findings. Here we report a case-control study conducted on 97 Italian HSCR sporadic patients and 85 population matched controls, using 13 RET polymorphisms distributed throughout the gene, from the basal promoter to the 3'UTR. Linkage disequilibrium and haplotype analyses have shown increased recombination between the 5' and 3' portions of the gene and an over-representation, in the cases studied, of two haplotypes sharing a common allelic combination that extends from the promoter up to intron 5. We propose that these two disease-associated haplotypes derive from a single founding locus, extending up to intron 19 and successively rearranged in correspondence with a high recombination rate region located between the proximal and distal portions of the gene. Our results suggests the possibility that a common HSCR predisposing variant, in linkage disequilibrium with such haplotypes, is located further downstream than the previously suggested interval encompassing intron 1.

Alleles↗

PubMed2006

Patterns of genetic variation in the hypertension candidate gene GRK4: ethnic variation and haplotype structure.

Association studies using single nucleotide polymorphisms (SNPs) have the potential to help unravel the genetic basis of hypertension. Nevertheless, to date, association studies of hypertension have yielded ambiguous results. It is becoming clear that such association studies must be interpreted within the context of the genetic structure of the populations being studied, and patterns of variation within specific genomic regions. With this in mind we analyzed genetic variation in the G protein-coupled receptor kinase 4 (GRK4) gene, a gene whose product has recently been shown to inhibit the dopamine receptor D1 (DRD1) from increasing sodium excretion. We genotyped three previously identified GRK4 SNPs, as well as ten additional SNPs, over 71.6 kb of the GRK4 locus in four populations: African Americans, Asians, Hispanics and Caucasians. Haplotype structure varied among populations, with Hispanics and Caucasians having the most linkage disequilibrium (LD) among SNPs. African Americans had three shorter haplotype blocks, while patterns of markers in the Asian populations demonstrated less LD among markers, a pattern inconsistent with block structure. We observed limited haplotype diversity in each of the four populations, with differing haplotype frequencies among the ethnic groups. We also found substantial evidence for population differentiation, with the largest differences between the African-American and Asian samples with F(ST) values in the upper 90(th) percentile when compared to a genome-wide distribution. However, for all population comparisons, F(ST) values decreased sharply in the 3' region of the gene. This pattern of differentiation among populations is consistent with selection in this part of the gene maintaining similar patterns of variation among otherwise divergent populations. Our results document not only different allele frequencies between populations, but differences in haplotype structure that may be important in evaluating association studies between hypertension and GRK4.

Black or African American↗