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PubMed2000

Beta-thalassemia mutations and haplotype analysis in Lebanon.

The molecular basis of beta-thalassemia in Lebanon reflects the heterogeneity of the Lebanese population. Eighteen different mutations were identified among a total of 277 chromosomes. There is evidence of clustering of some mutations in particular geographic regions or among specific religious groups. Haplotype analysis, using seven restriction sites was performed on a total of 110 samples and 11 different haplotypes were identified. The five most common mutations were each found on two different haplotypes, and most linkages were as previously reported in other Mediterranean populations, with a few exceptions, also showing some clustering.

Genetic Linkage↗

PubMed1996

Haplotype analysis of the Mexican frameshift Cd 11 (-T) and -28 A->C beta-thalassemia alleles.

The origins of the -28 A->C and frameshift Cd 11 - T(Fs CD 11-T)alleles were investigated by beta-globin cluster haplotype analysis. These alleles were found in a Mexican mestizo family with beta-thalassemia (beta-thal). The -28 A->C mutation was described previously in Kurdish Jews linked to the most common haplotype in the world(+----++),the same haplotype observed in this Mexican family. Therefore, it is not possible to assess a new origin of the -28 A->C mutation in our population. The Fs Cd 11 -T allele, not reported to date in any other populations, was linked to the -++--+-haplotype (sixth in frequency in the world). This haplotype has not been reported in association with any beta-thal mutant, suggesting a Mexican origin for the Cd 11 -T mutation.

Adolescent↗

PubMed1984

Genetic polymorphism of complement C6 and haplotype analysis between C6 and C7 in a Japanese population.

Genetic polymorphism of C6 in the Japanese population has been described using polyacrylamide gel isoelectric focusing electrophoresis followed by the electrophoretic blotting technique, and haplotype analysis between C6 and C7 has also been investigated. In 565 plasma samples five different common patterns and three rare variant patterns were observed, and these were controlled by autosomal codominance at a single locus with three common and one rare alleles. These alleles were designated C6*B, C6*A, C6*B2, and C6*M, and gene frequencies were estimated to be 0.50265, 0.43186, 0.06018, and 0.00531 for C6*B, C6*A, C6*B2, and C6*M, respectively. It is noteworthy that C6*B2 has a polymorphic frequency in the Japanese population. The distribution of phenotypes fitted the Hardy-Weinberg equilibrium. Two combinations between C6 and C7 alleles, namely C6B-C7B and C6M-C7B, were shown to be in significant positive linkage disequilibrium. The presence of allelic combinations showing linkage disequilibrium suggests the close proximity between the C6 and C7 loci.

Complement C6↗

PubMed1999

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.

Alleles↗

PubMed2005

Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates.

The human killer immunoglobulin-like receptors (KIR) are encoded within the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4. Here we report the comparative genomic analysis of single KIR haplotypes in two other primates. In the common chimpanzee (Pan troglodytes), seven KIR genes (ptKIRnewI, ptKIRnewII, ptKIR2DL5, ptKIRnewIII, ptKIR3DP1, ptKIR2DL4, ptKIR3DL1/2) have been identified, and five KIR genes (mmKIRnewI, mmKIR1D, mmKIR2DL4, mmKIR3DL10, mmKIR3DL1) are present in the haplotype sequenced for the rhesus macaque (Macaca mulatta). Additional cDNA analysis confirms the genes predicted from the genomic sequence and reveals the presence of a fifth novel KIR gene (mmKIRnewII) in the second haplotype of the rhesus macaque. While all known human haplotypes contain both activating and inhibitory KIR genes, only inhibitory KIR genes (characterized by long cytoplasmic tails) were found by in silico and cDNA analyses in the two primate haplotypes studied here. Comparison of the two human and the two non-human primate haplotypes demonstrates rapid diversification of the KIR gene family members, many of which have diverged in a species-specific manner. An analysis of the intronic regions of the two non-human primates reveals the presence of ancient repeat elements, which are indicative of the duplication events that have taken place since the last common ancestor.

Amino Acid Sequence↗

PubMed2001

Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families.

The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.

BRCA2 Protein↗

PubMed1995

Haplotype analysis in gelsolin-related amyloidosis reveals independent origin of identical mutation (G654A) of gelsolin in Finland and Japan.

Familial amyloidosis, Finnish type (FAF) (gelsolin-related amyloidosis) is an autosomal dominant form of systemic amyloidosis characterized by corneal lattice dystrophy and peripheral polyneuropathy. The accumulating protein in FAF consists of fragments of gelsolin, an actin-modulating protein. The gelsolin mutation G654A has been found in both Finnish and Japanese patients. To study the origin of the gelsolin mutation in these patients we performed haplotype analysis in 10 Finnish and 2 Japanese FAF families. Poymorphic DNA markers GSN, D9S103, AFMa061xd9, and AFMa139xb9 revealed a uniform disease haplotype in all the disease-associated chromosomes of the Finnish FAF families, which was different from the one observed in the Japanese families. The present results and the previously detected gelsolin mutation G654T in Czech and Danish FAF patients suggest that nucleotide 654 may represent a mutation hot spot in the gelsolin gene. The DNA markers studied here will be useful in future genealogical analyses of FAF.

Amyloid Neuropathies↗

PubMed2007

Pattern-recognition techniques with haplotype analysis in pharmacogenomics.

Single nucleotide polymorphisms (SNPs) can be used in clinical association studies to determine the contribution of genes to drug efficacy. However, it would be extremely inefficient to test all the 10 million common SNPs for an association study. Here we review haplotype analysis and pattern-recognition techniques to systematically select candidate SNPs for candidate-gene association studies in pharmacogenomics. First, we survey linkage disequilibrium methods to identify tag SNPs and explore the use of haplotypes as genetic markers that are correlated and associated with drug efficacy. Secondly, we investigate pattern-recognition algorithms and statistical analyses to assess drug efficacy based on SNPs and other factors. Finally, we study pattern-recognition approaches to evaluate the epistasis among genes and SNPs. These techniques may provide tools for clinical association studies and help find genes/SNPs involved in responses to therapeutic drugs or adverse drug reactions.

Animals↗

PubMed2006

Haplotype analysis of UDP-glucuronocyltransferase 2B7 gene (UGT2B7) polymorphisms in healthy Japanese subjects.

OBJECTIVES: UDP-glucuronocyltransferase 2B7 (UGT2B7) catalyzes glucuronidation of various types of endogenous compounds and drugs, but the genetic basis of interindividual variation in the metabolism of these substances has not yet been sufficiently elucidated. In addition, information about single nucleotide polymorphisms (SNPs) and haplotypes of the UGT2B7 gene that encode the enzyme in the Japanese population is still far from sufficient. DESIGN AND METHODS: We paid special attention to and performed an investigation on -327A > G, -161T > C, -138G > A, and -125T > C in the proximal promoter region, which is regarded as being important for the transcription of the UGT2B7 gene, and also on 211G > A and 802C > T, i.e., non-synonymous SNPs of exon 1 and exon 2 that encode the substrate binding domain. Their genotypes were determined by PCR-direct sequencing. RESULTS: As a result of genotyping, the minor allele frequencies in 160 Japanese individuals were found to be as follows: -327SNP A allele, 0.244; -161SNP T allele, 0.244; -138SNP A allele, 0; -125SNP C allele, 0.078; 211SNP T allele, 0.148 and 802SNP T allele, 0.244. By computational haplotype analysis, it was found that these regions formed a linkage disequilibrium block, and the presence of five haplotypes was demonstrated. CONCLUSIONS: These results suggest that the haplotype structure in the Japanese population is different from that of other ethnic groups.

Asian People↗

PubMed2001

Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom.

Genetic factors are important in the pathogenesis of osteoporosis and the estrogen receptor has been suggested as a possible candidate gene for regulation of bone mineral density (BMD). We investigated the relationship between PvuII, XbaI, and dinucleotide (TA)n repeat polymorphisms of the estrogen receptor alpha (ER-alpha) gene and BMD in a study of women from northeast Scotland in the United Kingdom. No significant association was observed between BMD values at the lumbar spine (LS) and femoral neck (FN) in relation to PvuII and XbaI polymorphisms individually, but haplotype analysis showed that BMD values (Z score) were significantly lower in those who carried the Px haplotype (n = 36) compared with those who did not (n = 170) at both the LS (mean +/- SEM; -0.775 +/- 0.125 vs. -0.285 +/- 0.082;p = 0.002) and the FN (-0.888 +/- 0.130 vs. -0.335 +/- 0.083; p = 0.0006). In keeping with this, the Px haplotype also was found to be an independent predictor of LS BMD (p = 0.019) and FN BMD (p = 0.005) in a multiple regression analysis model that included other possible predictors of BMD including age, years since menopause (YSM), hormone-replacement therapy (HRT) use, weight, and height. This model explained 15.7% and 23.4% of the total observed variance in LS and FN BMD, respectively, with the Px haplotype accounting for approximately 3% of the variance at both sites. Although the TA repeat polymorphism was in strong linkage disequilibrium (LD) with the PvuII (chi2 = 109.8; p < 0.0001) and XbaI (chi2 = 97.2; p < 0.0001) polymorphisms, there was no overall association between TA repeat number and BMD. We conclude that polymorphisms of the ER-alpha gene are significantly related to BMD in our population and that this association is dependent on the Px haplotype, suggesting that it is the Px haplotype, or a linked polymorphism, that confers risk.

Alleles↗

PubMed1999

Intron 22 inversions in the Turkish haemophilia A patients: prevalence and haplotype analysis.

In about half of the severe haemophilia A cases, the disease is caused by an inversion that split the F.VIII gene into two parts separated by approximately 300-400 kb. Herein, we show that in the Turkish population this inversion mutation accounts for 29% of 141 haemophilia A cases and 42% of severe cases. Most of the inversions are of the distal type (72%) whereas nine were of the proximal type (28%). Haplotype analysis using 4 markers in the F.VIII gene did not reveal a single haplotype associated with the inversion. However, the pre- valence of one haplotype: HindIII (-) - Int13 (CA)20 - Int22 (CA + CT)26 - XbaI (-) is higher in the inversion patients. Since founder effect is excluded for the inversion patients, our results suggest that some as yet unknown factor(s) may make these alleles more prone for the inversion. However, a bias due to the low number of studied cases cannot be excluded.

Factor VIII↗

PubMed1999

Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene.

Ferrochelatase, the enzyme that catalyzes the terminal step in the heme biosynthetic pathway, is the site of the defect in the human inherited disease erythropoietic protoporphyria. Molecular genetic studies have shown that the majority of erythropoietic protoporphyria cases are transmitted in dominant fashion and that mutations underlying erythropoietic protoporphyria are heterogeneous. We performed haplotype analysis of American families that shared recurrent ferrochelatase gene mutations yet had forbearers from several European countries. This was to gain insight into whether these mutations represent mutational hotspots at the ferrochelatase gene, or propagation of ancestral alleles bearing the mutations. Two recurrent mutations were found to occur on distinctive chromosome 18 haplotypes, consistent with being hotspot mutations. On the other hand, we found three sets of two unrelated families that shared the same haplotypes bearing these mutations, which could reflect geographic dispersion of ancestral mutant alleles. In addition, we report novel mutations associated with erythropoietic protoporphyria: g(+ 1)-->t transversion of the exon 4 donor site, g(+ 1)-->a transition of the exon 6 donor site, and t(+ 2)-->a substitution at the exon 9 donor site; these mutations are predicted to cause splicing defects of the associated exons. We also identified a g(+ 5)-->a transition of the exon 1 donor site in four unrelated families with erythropoietic protoporphyria, and a G(- 1)-->A substitution at the exon 9 donor site in an additional family. The probability that these sequence changes are normal polymorphisms was virtually excluded (p < 0.0001) by their absence in 120 ferrochelatase alleles from 30 normal subjects and 30 individuals with manifested erythropoietic protoporphyria with or without a known mutation.

Alternative Splicing↗

PubMed2000

Stability and haplotype analysis of the FRAXE region.

FRAXE full mutations are rare and appear to be associated with mild mental retardation. As part of a screening survey of boys with learning difficulties to determine the frequency of full and premutations, we have collected data on the frequency of instability at FRAXE for about 4000 transmissions and the haplotype for over 7000 chromosomes. The distribution of FRAXE repeats was similar to other English populations but differed from two North American Caucasian series. Observed instability at FRAXE was rare but increased with increasing repeat number, and there were no expansions into the full mutation range, except in pedigrees ascertained through a full mutation. Haplotype analysis suggested division into five groups with each group having a characteristic distribution of FRAXE repeats. Fourteen of the 15 full mutations occurred on a single haplotype and this haplotype also had a significant excess of intermediate-sized alleles, suggesting that full mutations originate from large normal alleles. However, a related haplotype also had a significant excess of intermediates but we observed no full mutations on this haplotype, suggesting either loss or gain of stability determinants on it. We suggest that whilst triplet repeat size is a significant predisposing factor for expansion at FRAXE other genetic determinants are also likely to be important.

Alleles↗

PubMed2006

Haplotype analysis of tumour necrosis factor receptor genes in 1p36: no evidence for association with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with partially understood aetiology. The 1p36 region has been previously linked with SLE and harbours tumour necrosis factor receptor (TNFR) genes. Functional and genetic data implicate their gene products in SLE and other autoimmune diseases. In all, single-nucleotide polymorphisms (SNPs) across TNFRSF14 (HVEM), and 43 SNPs across the TNFRSF8 (CD30) and TNFRSF1B (CD120B) locus were investigated for linkage disequilibrium (LD) and haplotype analysis in European-Caucasians. Strong LD was observed across HVEM and CD120B, and little LD and recombination across CD30. We also examined the association of SNPs and haplotypes in HVEM, CD30 and CD120B with SLE in European-Caucasians. There was no evidence of association for these genes in 456 European-Caucasian families with SLE from UK. Haplotype tagging SNPs are made known across areas of strong LD, which will facilitate analysis for susceptibility in other diseases.

Chromosomes, Human, Pair 1↗

PubMed1993

Familial Mediterranean fever (FMF) in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis.

Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The FMF gene (designated "MEF") is on 16p, with the gene order 16cen-D16S80-MEF-D16S94-D16S283-D16S291-++ +16pter. Here we report the association of FMF susceptibility with alleles as D16S94, D16S283, and D16S291 among 31 non-Ashkenazi Jewish families (14 Moroccan, 17 non-Moroccan). We observed highly significant associations at D16S283 and D16S291 among the Moroccan families. For the non-Moroccans, only the allelic association at D16S94 approached statistical significance. Haplotype analysis showed that 18/25 Moroccan FMF chromosomes, versus 0/21 noncarrier chromosomes, bore a specific haplotype for D16S94-D16S283-D16S291. Among non-Moroccans this haplotype was present in 6/26 FMF chromosomes versus 1/28 controls. Both groups of families are largely descended from Jews who fled the Spanish Inquisition. The strong haplotype association seen among the Moroccans is most likely a founder effect, given the recent origin and genetic isolation of the Moroccan Jewish community. The lower haplotype frequency among non-Moroccan carriers may reflect differences both in history and in population genetics.

Alleles↗

PubMed2004

[Long QT syndrome gene diagnosis by haplotype analysis].

OBJECTIVE: Three long QT syndrome(LQTS) pedigrees were brought together for genetic diagnosis by using short tandem repeat(STR) markers. METHODS: Genomic DNA was extracted from blood samples. STR markers (D7S1824, D7S2439, D7S483, D3S1298, D3S1767, D3S3521) in or spanning the HERG and SCN5A gene were amplified; the haplotype analysis for LQTS was performed. RESULTS: Clinical diagnosis showed that 15 are LQTS patients (3 died) and 11 are probable patients. Linkage analysis showed that LQTS patients are linked with the SCN5A gene in family 1, HERG is linked with the disease in family 2 and 3. Fourteen gene carriers were identified, 2 patients and 7 probable patients were excluded. CONCLUSION: Linkage analysis using STR markers can serve as useful tool for presymptomatic diagnosis.

ERG1 Potassium Channel↗

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↗

PubMedDate not supplied

Haplotype analysis enables the diagnosis of Marfan syndrome.

Marfan syndrome is an inherited disorder of connective tissue associated with aneurysmal rupture of the ascending aorta. Timely and accurate diagnosis has reduced the mortality and morbidity associated with this disorder through expectant observation and implementation of appropriate prophylactic therapy. To this end, haplotype analysis using polymorphic genetic markers in close proximity to the Fibrillin-1 gene (FBN1) were employed to aid in the diagnosis of two individuals who did not meet the clinical diagnostic criteria.

Child↗