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PubMed2004

Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study.

Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy.

Algorithms↗

PubMed2004

Haplotype block partitioning and tag SNP selection using genotype data and their applications to association studies.

Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed by regions of low LD. A small fraction of SNPs (tag SNPs) is sufficient to capture most of the haplotype structure of the human genome. In this paper, we develop a method to partition haplotypes into blocks and to identify tag SNPs based on genotype data by combining a dynamic programming algorithm for haplotype block partitioning and tag SNP selection based on haplotype data with a variation of the expectation maximization (EM) algorithm for haplotype inference. We assess the effects of using either haplotype or genotype data in haplotype block identification and tag SNP selection as a function of several factors, including sample size, density or number of SNPs studied, allele frequencies, fraction of missing data, and genotyping error rate, using extensive simulations. We find that a modest number of haplotype or genotype samples will result in consistent block partitions and tag SNP selection. The power of association studies based on tag SNPs using genotype data is similar to that using haplotype data.

Algorithms↗

PubMed1997

Molecular characterization of major histocompatibility complex (B) haplotypes in broiler chickens.

In Leghorn (laying) chickens, susceptibility to a number of infectious diseases is strongly associated with the major histocompatibility (B) complex. Nucleotide sequence data have been published for six class I (B-F) alleles and for class II (B-L beta) alleles or isotypes from 17 Leghorn haplotypes. It is not known if classical B-L or B-F alleles in broilers are identical, at the sequence level, to any Leghorn alleles. This report describes molecular and immunogenetic characterization of two haplotypes from commercial broiler breeder chickens that were originally identified by serology as a single haplotype, but were differentiated serologically in the present work. The two haplotypes, designated BA4 and BA4variant, shared identical B-G restriction fragment length polymorphism patterns, but differed in one B-L beta fragment that cosegregated with the serological B haplotype. Furthermore, the nucleotide sequences of the highly variable exons of an expressed B-L beta II family gene and B-F gene from the two haplotypes were markedly different from each other. Both the B-L beta II family and B-F gene sequences from the BA4 haplotype were identical to the sequences obtained from the reference B21 haplotype in Leghorns; however, in the BA4 haplotype the B-L beta 21 and B-F21 alleles were in linkage with B-G alleles that were not G21. The nucleotide sequences from BA4variant were unique among the reported chicken B-L beta II family and B-F alleles.

Animals↗

PubMed2004

Regulation of glucocorticoid receptor gamma (GRgamma) by glucocorticoid receptor haplotype and glucocorticoid.

OBJECTIVE: To measure glucocorticoid receptor gamma (GRgamma) expression in transformed lymphocytes from individuals of known GR gene haplotype. Recently, a glucocorticoid receptor haplotype (GAT) has been described that associates with increased sensitivity to dexamethasone. As there is strong linkage disequilibrium across the gene, this haplotype is likely to extend through exon 3, altered splicing of which generates the GRgamma isoform, a splice variant with impaired transactivation activity. Therefore we proposed that the GR haplotype affects glucocorticoid sensitivity either by influencing GRgamma expression basally, or in response to Gc exposure. DESIGN: We have measured expression of GRgamma, using a validated RT-PCR assay in human B lymphoblast cells of known haplotype under basal conditions, and after dexamethasone treatment. PATIENTS: The A549 human lung cell line and normal volunteers, five with the GAT GR haplotype and three with the CGA haplotype. MEASUREMENTS: Relative expression of GRgamma compared to total GR mRNA. RESULTS: GRgamma made up 5-6% of all the GR transcripts. There was no effect of carriage of the GR gene GAT haplotype on this expression. There was no effect of dexamethasone on relative expression of GRgamma. CONCLUSIONS: We propose that the GRgamma isoform is a product of constitutive splicing, that it does not explain the GR haplotype association with altered glucocorticoid sensitivity, and is unlikely to play an important physiological role in affecting glucocorticoid sensitivity. As glucocorticoids do not affect GRgamma expression, relative to total GR, this splice variant is unlikely to influence glucocorticoid treatment response.

Adult↗

PubMed1992

Tumour necrosis factor-beta gene RFLP alleles in Finnish IDDM haplotypes. The Childhood Diabetes in Finland (DiMe) Study Group.

The genes located between class II and class I HLA genes including polymorphic tumour necrosis factor (TNF) genes may contribute to the disease susceptibility in IDDM. Restriction fragment polymorphisms of the TNF-beta gene have been found to be fixed in the major IDDM susceptibility haplotypes, the B62,DR4 haplotype being associated with the 10.5-kb fragment and the B8,DR3 haplotype with a 5.5-kb fragment. We studied this TNF polymorphism in a sample of diabetic families. In all IDDM-associated haplotypes (n = 129) the 5.5-kb allele was more frequent than in haplotypes found only in healthy family members (n = 112) (58.1% versus 40.2%, P < 0.01). Among IDDM haplotypes the B62,DR4 haplotype was characterized by the 10.5-kb TNF fragment, whereas two other common Finnish IDDM-associated DR4 haplotypes--A24,B39,DR4 and A2,B56,DR4--had the 5.5-kb TNF fragment. Both IDDM-associated and non-associated DR3 positive haplotypes were linked to the 5.5-kb fragment. The distribution of various combinations of TNF alleles in IDDM probands (n = 63) did not differ from that expected according to the Hardy-Weinberg distribution. Our results indicate that the 10.5-kb allele of TNF-beta gene as such is not a risk factor contributing to DR4/DQ8-associated susceptibility. Alternatively, there may be heterogeneity in pathogenetic effector mechanisms.

Alleles↗

PubMed1993

HLA-DQA1, DQB1 and DPB1 alleles on HLA-DQ2- and DQ9-carrying extended haplotypes.

DQA1, DQB1 and DPB1 alleles were investigated in a large panel of samples carrying HLA-DQ2- and HLA-DQ9-bearing extended haplotypes. Every instance of the [HLA-B8, SCO1, DR3, DQ2a] and [HLA-B18, F1C30, DR3, DQ2b] extended haplotypes carried the DQA1*0501 allele, while every instance of [HLA-B44, FC31, DR7, DQ2c], [HLA-B47, FC91,0, DR7, DQ2c] and [HLA-B57, SC61, DR7, DQ2d] carried the DQA1*0201 allele. All HLA-DR3, DQ2 and HLA-DR7, DQ2 extended haplotypes carried the DQB1*0201 allele. Every example of [HLA-B57, SC61, DR7, DQ9] carried the DQB1*0303 allele. Several associations between the DPB1 alleles and some HLA-DQ2- and DQ9-carrying extended haplotypes were identified. HLA-DPw2-encoding alleles, DPB1*0202 (50%, p < 0.001) and 0201 (30%), were found on the [HLA-B18, F1C30, DR3, DQ2b] extended haplotype. Every instance of the [HLA-B57, SC61, DR7, DQ9] extended haplotype carried the DPB1*0401 allele. Also, we have confirmed the associations of the DPB1*0101 and DPB1*0401 alleles with the [HLA-B8, SC01, DR3, DQ2a] extended haplotype. The analysis of homozygous typing cells carrying the [HLA-B44, FC31, DR7, DQ2c] extended haplotype showed that the DPB1*0401 and 0201 alleles were present at similar frequencies (37.5%), while the DPB1*1101 allele was found in only 25% of these haplotypes analyzed. Our results suggest that the constancy of the DNA of the HLA-B, DR, DQ regions may extend to the DP region and that the extent of such fixity varies, perhaps as the result of ethnic variability of the population studied.

Alleles↗

PubMed2004

TNF-alpha promoter polymorphisms and extended HLA and TNF-alpha haplotypes in Koreans based on 100 families.

We investigated five single-nucleotide polymorphism (SNP) sites of tumor necrosis factor-alpha (TNF-alpha) promoter, the distribution of five-locus TNF-alpha haplotypes, and extended human leukocyte antigen (HLA)/TNF-alpha haplotypes in 200 parents from 100 unrelated Korean families. TNF-alpha SNPs were typed using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and PCR restriction fragment length polymorphism (PCR-RFLP) methods. The frequencies of -1031C, -863A, -857T, -308A, and -238A alleles were 0.185, 0.145, 0.140, 0.060, and 0.040, respectively. The allele frequencies in Koreans were similar to those of Japanese. A total of five TNF-alpha haplotypes (-1031/-863/-857/-308/-238) were detected in 196 parents: TCCGG (frequency 0.617), CACGG (0.143), TCTGG (0.143), TCCAG (0.061), and CCCGA (0.036). Five most common extended HLA/TNF-alpha haplotypes (frequencies >0.020) accounted for 16% (63/392) of the total haplotypes. A total of 223 HLA haplotypes and 239 HLA/TNF-alpha haplotypes were detected, indicating that most HLA haplotypes are exclusively associated with particular TNF-alpha haplotypes.

Family↗

PubMed2005

Analysis of 250 HLA-B44 genotypes in European Caucasoids: high diversity and preferential ABCDRB1 associations in B4402, B4403, and B*4405 haplotypes.

Based on high-resolution DNA typing within 235 pedigrees, a total of 250 HLA-A/B/C/DRB1/DRB3 genotypes have been characterized. These comprise 129 different B44 haplotypes, of which 73.6% occurred only once. Only four different B*44 alleles were identified: B*4402-4405, with B*4402 and B*4403 haplotypes accounting for 57.6 and 36.8%, respectively, of all haplotypes. Although the relative numbers of different A/B/C/DRB1/B3 haplotypic associations were similar in both B*4402 and B*4403 haplotypes, the genotypic profiles were quite different in the two groups. When associated with the A*0101, A*0201, A*2402, A*3201, and A*6801 alleles, a much more extensive polymorphism of B*4402 haplotypes with respect to HLA-C and DRB1 associations was disclosed. On the other hand, B*4403 haplotypes were more diverse in the A23-B44 and A29-B44 groups with respect to DRB1 associations. Considering B-C linkage, B*4402-Cw*0501, B*4402-Cw*0704, B*4402-Cw*1604, B*4403-Cw*0401, B*4403-Cw*1601, B*4404-Cw*1601, and B*4405-Cw*0202 accounted for 98% of all genotypes. Eight A/B/C/DRB1 haplotypes occurred at a relative genotypic frequency of >0.015, with A*2902-B*4403-Cw*1601-DRB1*0701 (11.2%) and A*0201-B*4402-Cw*0501-DRB1*0401 (8.4%) as the two most frequent genotypes. Some A and DRB1 alleles were predominantly, if not exclusively, associated with specific B-C pairs: A*0301 with B*4402-Cw*0501 and B*4403-Cw*0401; A*2301 with B*4403-Cw*0401; A*2608 with B*4402-Cw*0501; A*2902 with B*4403-Cw*1601; DRB1*0101/0401/0403/0404/1101/1104/0801/1301/1302 with B*4402-Cw*0501; and DRB1*0701 with B*4403-Cw*1601. On the basis of this dataset and our experience with searches for phenotypically matched unrelated stem cell donors, several ABDR haplotypes were identified that would confer a higher probability of B44- and C-incompatibility. The analysis of 112 consecutive unrelated stem cell donor searches revealed that 24% of the 400 tested donors were B44-mismatched, and that no single B44 allele- matched donor could be identified for only 7% of the patients. HLA-C incompatibility rate was 22.2% for the patients with > or =1 B44 allele-matched donor(s). This dataset can therefore be used as a predictive tool for B44- and C-disparities in unrelated stem cell transplantation.

Alleles↗

PubMed2006

Association of HLA haplotype with alopecia areata in Chinese Hans.

BACKGROUND: Some studies have shown discrepancies in human leucocyte antigen (HLA) associated with alopecia areata (AA) between different ethnic populations. OBJECTIVE: To investigate whether HLA-I, -DQA1 and -DQB1 alleles and the HLA haplotype are associated with AA, and the correlation between the HLA haplotype profile, age of onset and severity of AA in Chinese Hans. METHODS: The polymerase chain reaction-sequence specific primer (PCR-SSP) method was used to analyse the frequencies of HLA class I, -DQA1 and -DQB1 alleles in 192 patients with AA and 252 controls in Chinese Hans. The linkage disequilibrium was calculated using the 2 x 2 table. RESULTS: The 24 two-locus haplotypes [including A*02-B*18, A*02-B*27, A*02-B*52, A*02-Cw*0704, A*02-DQA1*0104, A*02-DQB1*0604, A*02-DQB1*0606, B*18-Cw*0704, B*18-DQA1*0104, B*18-DQA1*0302, B*18-DQB1*0606, B*27-Cw*0704, B*27-DQA1*0104, B*27-DQA1*0302, B*52-Cw*0704, B*52-DQA1*0104, B*52-DQA1*0302, B52-DQB1*0606, Cw*0704-DQA1*0104, Cw*0704-DQA1*0302, Cw*0704-DQB1*0606, DQA1*0104-DQB1*0604, DQA1*0104-DQB1*0606, DQA1*0302-DQB1*0606 (P<0.05)] were associated with AA, while eight extended haplotypes (A*02-B*18-DQA1*0104, A*02-B*27-DQA1*0104, A*02-B*52-DQA1*0104, A*02-B*52-DQA1*0302, A*02-B*52-DQB1*0606, B*52-Cw*0704-DQA1*0104, B*52-Cw*0704-DQA1*0302, A*02-B*52-DQA1*0302-DQB1*0606) were found to be related to AA in Chinese Hans. Through stratified analysis, we found that the extended haplotype B*52-Cw*0704-DQA1*0302 was related to early onset of AA, and no haplotype was only associated with severe AA. CONCLUSION: This is the first detailed report to elucidate HLA haplotypes associated with AA and that demonstrates the significant HLA haplotypes in Chinese Hans AA. The haplotype B*52-Cw*0704-DQA1*0302 was identified to be related to early onset of AA. Our results provide some information for future research on predisposing genes in HLA regions in Chinese Hans.

Adolescent↗

PubMed2006

Power and sample size for testing associations of haplotypes with complex traits.

Evaluation of the association of haplotypes with either quantitative traits or disease status is common practice, and under some situations provides greater power than the evaluation of individual marker loci. The focus on haplotype analyses will increase as more single nucleotide polymorphisms (SNPs) are discovered, either because of interest in candidate gene regions, or because of interest in genome-wide association studies. However, there is little guidance on the determination of the sample size needed to achieve the desired power for a study, particularly when linkage phase of the haplotypes is unknown, and when a subset of tag-SNP markers is measured. There is a growing wealth of information on the distribution of haplotypes in different populations, and it is not unusual for investigators to measure genetic markers in pilot studies in order to gain knowledge of the distribution of haplotypes in the target population. Starting with this basic information on the distribution of haplotypes, we derive analytic methods to determine sample size or power to test the association of haplotypes with either a quantitative trait or disease status (e.g., a case-control study design), assuming that all subjects are unrelated. Our derivations cover both phase-known and phase-unknown haplotypes, allowing evaluation of the loss of efficiency due to unknown phase. We also extend our methods to when a subset of tag-SNPs is chosen, allowing investigators to explore the impact of tag-SNPs on power. Simulations illustrate that the theoretical power predictions are quite accurate over a broad range of conditions. Our theoretical formulae should provide useful guidance when planning haplotype association studies.

Computer Simulation↗

PubMed1996

Analysis of HLA haplotypes in families with type 1 diabetes mellitus in La Réunion island.

To analyse HLA and insulin-dependent diabetes mellitus (IDDM) association in the ethnically mixed population of La Réunion island, we carried out a family study on 70 diabetic subjects. HLA-DQA1, -DQB1 and -DRB1 typing was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), completed by PCR-sequence-specific oligonucleotide (SSO) and PCR-sequence-specific priming (SSP). Haplotype-relative risks (HRR) were determined with the non-transmitted parental haplotypes as controls, and relative risks (RR) were calculated with a classical case-control study. The most significant risks were found for the cis and trans combinations between DQA1*03 or *0501 (Arg52+) and DQB1*02 or *0302 (Asp57-) alleles, suggesting a direct role for the HLA-DQ heterodimer in IDDM susceptibility. Interestingly, due to the mixed origin of the population, the trans-encoded DQ molecules in the (DR3)-DQA1*0501-DQB1*02/(DR4)-DQA1*03-DQB1*0302 subjects were also found cis-encoded in patients with the (DR7 or 9)-DQA1*03-DQB1*02 haplotype and in a patient with the rare (DR11)-DQA1*0501-DQB1*0302 haplotype. A relative predispositional effect (RPE) analysis gave significant haplotype-IDDM+ associations in the following order: (DR3)-DQA1*0501-DQB1*02 > (DR4)-DQA1*03-DQB1*0302 > (DR9)-DQA1*03- DQB*02 > (DR7)-DQA1*03-DQB1*02 > (DR2)-DQA1*01-DQB1*0502. No protective effect remained significant once the susceptible haplotypes were removed. A stratification study showed a stronger influence of the DQ genes than DRB1 alleles within the DR7 haplotypes. On the other hand, IDDM subjects with only one susceptible haplotype had inherited this haplotype more often from their father than from their mother. This paternal effect could be related to the greater risk of IDDM in offspring of diabetic fathers than the risk in offspring of diabetic mothers.

Adult↗

PubMed2004

Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults.

BACKGROUND: Several studies have shown linkage of chromosome 12q 13-24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. METHODS: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation-time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE>53 kU/l, 66% IgE>99 kU/l and 90% IgE>307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. RESULTS: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. CONCLUSION: The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases.

Adult↗

PubMed2004

Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer.

Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer development and aggression. Our previous studies revealed a strong association between the MMP-2 -1306C/T polymorphism and risk of several cancers. A novel -735C/T polymorphism in MMP-2 promoter has been identified but the function is undefined. This study examined our hypothesis that these two polymorphisms might have functional relevance and impact on risk of esophageal squamous cell carcinoma in the context of haplotype. Genotypes and haplotypes were analyzed in 527 cases and 777 controls and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The function of the polymorphisms was examined by electrophoretic mobility shift assays, luciferase gene expression assays, and reverse transcriptase-PCR analyses. It was found that the -735C-->T transition disrupts an Sp1 site and displays a lower promoter activity. The C(-1306)-C(-735) haplotype had 7-fold increased luciferase expression and 3.7-fold increased MMP-2 mRNA levels in esophageal tissues compared with the T(-1306)-T(-735) haplotype. A case-control analysis revealed a 1.52-fold (95% CI = 1.17-1.96) or 1.30-fold (95% CI = 1.04-1.63) excess risk of developing esophageal squamous cell carcinoma for the -1306CC or -735CC genotype carriers compared with noncarriers, respectively. A greater association was observed between elevated risk of developing esophageal squamous cell carcinoma and C(-1306) or C(-735) allele containing haplotypes, with the risk being highest for the C(-1306)-C(-735) haplotype compared with the T(-1306)-T(-735) haplotype (OR = 6.53; 95% CI = 2.78-15.33). The C(-1306)-C(-735) haplotype was also associated with increased risk for distant metastasis of esophageal squamous cell carcinoma (OR = 3.34; 95% CI = 1.16-9.63). These findings suggest that the C(-1306)-C(-735) haplotype in the MMP-2 promoter contributes to risk of the occurrence and metastasis of esophageal squamous cell carcinoma by increasing expression of MMP-2.

Alleles↗

PubMed2005

Estimating haplotype relative risks on human survival in population-based association studies.

Association-based linkage disequilibrium (LD) mapping is an increasingly important tool for localizing genes that show potential influence on human aging and longevity. As haplotypes contain more LD information than single markers, a haplotype-based LD approach can have increased power in detecting associations as well as increased robustness in statistical testing. In this paper, we develop a new statistical model to estimate haplotype relative risks (HRRs) on human survival using unphased multilocus genotype data from unrelated individuals in cross-sectional studies. Based on the proportional hazard assumption, the model can estimate haplotype risk and frequency parameters, incorporate observed covariates, assess interactions between haplotypes and the covariates, and investigate the modes of gene function. By introducing population survival information available from population statistics, we are able to develop a procedure that carries out the parameter estimation using a nonparametric baseline hazard function and estimates sex-specific HRRs to infer gene-sex interaction. We also evaluate the haplotype effects on human survival while taking into account individual heterogeneity in the unobserved genetic and nongenetic factors or frailty by introducing the gamma-distributed frailty into the survival function. After model validation by computer simulation, we apply our method to an empirical data set to measure haplotype effects on human survival and to estimate haplotype frequencies at birth and over the observed ages. Results from both simulation and model application indicate that our survival analysis model is an efficient method for inferring haplotype effects on human survival in population-based association studies.

Aged↗

PubMed1986

Studies of HLA, factor B (Bf), complement C2 and C4 haplotypes in type 1 diabetic and control families from northern Sweden.

The HLA-A,-B,-C,-DR antigens and the complement factors C2, C4 and Bf were determined in 30 insulin-dependent diabetes mellitus (IDDM) patients and 30 healthy controls from northern Sweden. Family studies allowed the deduction of extended haplotypes in the HLA and complement systems. Phenotype studies revealed significant associations between IDDM and HLA-DR4 (p less than 0.001), HLA-DR3 (p less than 0.05), HLA-DR3/4 (p less than 0.025), C4-B3 (p less than 0.001) and Bf-S (p less than 0.025). Haplotype studies showed that the extended haplotype [HLA-B15, C2-1, C4-A3B3, Bf-S, HLA-DR4] had a particularly strong association to IDDM. This haplotype was found in 10 out of 30 IDDM probands but in none of 30 control children and accounts for practically all the C4-B3 allotypes among the 30 IDDM probands. The C4-B3 gene therefore seems to be a valuable marker for IDDM. No haplotype containing HLA-DR3 was increased in frequency among the IDDM probands. The extended haplotype [HLA-B7, C2-1, C4-A3B1, Bf-S, HLA-DR2] present among the controls was absent in the IDDM probands. The frequency of the extended haplotype [HLA-B15, C2-1, C4-A3B3, Bf-S, HLA-DR4] was increased also among the parents to the IDDM probands compared to those of the control parents, whereas the frequency of [HLA-B7, C2-1, C4-A3B1, Bf-S, HLA-DR2] was decreased. The extended haplotype [HLA-B8, C2-1, C4-B1, Bf-S, HLA-DR3] was more common among the males (p less than 0.05) compared to the females in the total material. The family analysis showed that 3 out of 5 affected sibs shared both haplotypes with their IDDM proband. This was the case for only 3 out of 35 unaffected sibs.

Adolescent↗

PubMedDate not supplied

Analysis of HLA haplotype segregation in the Schmiedeleut Hutterites of South Dakota.

HLA data from 1,085 South Dakotan Schmiedeleut Hutterites were examined for evidence of nonrandom transmission of haplotypes. The inheritance of haplotypes was viewed as a series of genetic contests between competing pairs of parental haplotypes using a maximum likelihood approach first put forward by Carlisle and Woodbury. Haplotype transmission probabilities were expressed in terms of weights, and the null hypothesis that the inheritance pattern was a random stochastic process, equivalent to the equality of the weights, was tested via the likelihood ratio. A total of 1,517 competitions was subjected to analysis, first globally using all data, and then for particular haplotypes of interest. Transmission of haplotype observed to compete with only a single other haplotype was also assessed using an exact procedure. No evidence of preferential transmission of HLA haplotypes was found. These results do not rule out transmission biases that may arise because of selection against homozygotes, mechanisms specifically affecting particular alleles or haplotypes not considered in the present study, or biases arising from maternal-fetal interactions.

Consanguinity↗

PubMed1991

Certain mutations observed in the 5' sequences of the G gamma- and A gamma-globin genes of beta S chromosomes are specific for chromosomes with major haplotypes.

In this paper we describe the distribution of some specific sequence differences in the 5' flanking regions of the A gamma- and G gamma-globin genes from 100 Black adult and 57 newborn SS patients from the southeastern United States, from 76 individuals with AS, S-beta-thal, SC, AC, or A-beta-thal, and from 31 normal individuals. Haplotypes for all adult individuals have been previously determined using various restriction endonucleases. The DNA samples were amplified, dot blotted, and hybridized with 32P-labeled specific oligonucleotide probes. All 134 chromosomes with haplotype 19 were positive for the G----T substitution at position -657 (A gamma), while 132 were also positive for the C----G mutation at -369 (G gamma). The three specific changes for the chromosome with haplotype 20 were found on all 54 chromosomes with this haplotype. The C----T mutation at -158 5' to G gamma was present on all 41 chromosomes with haplotype 3, and on two chromosomes with a related atypical haplotype. Normal and beta-thal chromosomes with each of these substitutions had the same 5' subhaplotype as beta S haplotypes 19 or 20, respectively. The close relationship between the occurrence of specific mutations and the haplotype of beta S chromosomes makes the determination of these haplotypes with specific oligonucleotide probes attractive with respect to time and expense.

Adult↗

PubMed1995

Convergent myotonic dystrophy (DM) haplotypes: potential inconsistencies in human disease gene localization.

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease which has been shown to be caused by an unstable trinucleotide repeat located on chromosome 19q. We have conducted extensive haplotype analysis on 105 DM chromosomes using twelve 19q13.2 loci identifying 18 RFLPs, spanning a physical distance of 1.3 Mb containing the DM gene. Three major haplotypes (H1, H2 and H3) comprising 46.7% of the DM chromosomes in our population, were observed. With the exception of H1 and H2 derivatives (H4, H5 and H6), the remainder of the DM chromosomes analyzed were found to have unique haplotypes. Haplotypes H2 and H3 observed exclusively on DM chromosomes of French-Canadian origin contain identical 500-kb core regions. The low frequency of this core haplotype in normal chromosomes (0.8%) is consistent with a mapping of the DM gene within this region. However, the DM mutation is found 160 kb distal to the point of divergence between the two haplotypes. In contrast, the 450-kb region shared by haplotypes H1 and H2 contains the DM mutation. Further analysis of the DM region using a polymorphic microsatellite (GJ-VSSM2; D19S207) located 15 kb distal to the DM mutation revealed strong allelic association of one of the (CA)n repeat alleles to DM; allele 5 was observed on 88.2% of DM chromosomes and 6% of normal chromosomes. The fact that the (CA)n allele 5 was found on all 56 DM chromosomes containing the three major haplotypes indicates that DM chromosomes in our population, including the two French-Canadian haplotypes which have a common region outside the DM gene, are probably derived from the same mutational event.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗