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Results for “Haplotypes”

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PubMed2002

Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).

A psoriasis susceptibility locus has been mapped to the HLA region in the proximity of the HLA-C locus. This critical region also contains the CDSN gene coding for the corneodesmosin protein. In a case-control association study of psoriasis in the Sardinian population, we analyzed the allele distribution of eight intragenic SNPs (positions 619, 767, 1215, 1118, 1236, 1243, 1331, 1593) of the CDSN gene and the six haplotypes that are coded by these SNPs. Our study showed that these CDSN haplotypes are very stable and well-conserved in the Sardinian population. The CDSN2 haplotype was found to be associated with susceptibility to psoriasis. The association did not depend upon any one of the intragenic SNPs taken separately. At the HLA-C locus, the Cw6 and Cw7 alleles were dragged along by linkage disequilibrium with the CDSN2 haplotype and only revealed a trend towards association with the disease. Therefore, the intragenic SNPs of the CDSN gene and the HLA-Cw6 and Cw7 alleles are not directly involved in susceptibility to psoriasis. However, the strong association of the CDSN2 haplotype suggests a possible role for the CDSN gene and its chromosome region in susceptibility to psoriasis.

Female↗

PubMed2000

Association of the alpha-spectrin R28H mutation with allele alphaLELY and with alphaI/alphaII domain haplotypes in three Brazilian families.

We have studied three Brazilian kindreds presenting spectrin alpha/74 hereditary elliptocytosis (HE) due to a G-->A substitution, responsible for the R28H mutation. The mutant allele was associated with alphaI domain haplotype 1 (XbaI-/MspI-/PvuII+) in all three families and with two different alphaII domain haplotypes (1/RIT, 4/RVR). This result may reflect that this mutation occurs in a "hot spot" and may have arisen more than once or that a crossing over event may have occurred between the two domains studied. We detected one new haplotype in the alphaI domain (haplotype 3 -XbaI(+)/MspI(-)/PvuII(+)). The mutant allele was associated with the lack of the alphaII domain Alu insertion in all three cases. Allele alphaLELY, detected by PCR and restriction enzyme digestion, was present in the heterozygous form in patient 1 (alphaHE/alphaLELY) and in the homozygous form in patients 2 and 3(alphaHE-LEL/alphaLELY). It was found to be associated with domain haplotypes I (RIT) and 4 (RVR) and with the presence and absence of the Alu insertion. This may have arisen through recombination events, since this polymorphism is located in the alphaIV-alphaV domain junction, which is far distant from the alphaII domain.

Amino Acid Substitution↗

PubMedDate not supplied

An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2.

Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC 1.14.16.1). PKU is a common inborn error of amino-acid metabolism in caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele. To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes. We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles. We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele. This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes.

Alleles↗

PubMed2001

Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects.

Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom. Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor alpha-receptor (Pdgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 that have been associated with NTDs cause deregulated activation of the human PDGFRA promoter. There is an increasing awareness that genetic polymorphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, of which the two most abundant ones, designated H1 and H2 alpha, differ in at least six polymorphic sites. In a transient transfection assay in human bone cells, the five haplotypes differ strongly in their ability to enhance reporter gene activity. In a group of patients with sporadic spina bifida, haplotypes with low transcriptional activity, including H1, were under-represented, whereas those with high transcriptional activity, including H2 alpha, were over-represented. When testing for haplotype combinations, H1 homozygotes were fully absent from the group of sporadic patients, whereas H1/H2 alpha heterozygotes were over-represented in the groups of both sporadic and familial spina bifida patients, but strongly under-represented in unrelated controls. Our data indicate that specific combinations of naturally occurring PDGFRA promoter haplotypes strongly affect NTD genesis.

Genetic Predisposition to Disease↗

PubMed2001

High-resolution haplotype structure in the human genome.

Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non-monotonic picture, because the power to detect allelic associations depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has remained poorly understood. Here we report a high-resolution analysis of the haplotype structure across 500 kilobases on chromosome 5q31 using 103 single-nucleotide polymorphisms (SNPs) in a European-derived population. The results show a picture of discrete haplotype blocks (of tens to hundreds of kilobases), each with limited diversity punctuated by apparent sites of recombination. In addition, we develop an analytical model for LD mapping based on such haplotype blocks. If our observed structure is general (and published data suggest that it may be), it offers a coherent framework for creating a haplotype map of the human genome.

Base Sequence↗

PubMed2004

Gender-specific association of a perilipin gene haplotype with obesity risk in a white population.

OBJECTIVE: Perilipin is a class of protein-coating lipid droplets in adipocytes and steroidogenic cells. Our purpose was to examine the association between common single-nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus and obesity, as well as related phenotypes, in unrelated American adults. RESEARCH METHODS AND PROCEDURES: Four PLIN SNPs (PLIN 6209T>C, 11482G>A, 13041A>G, and 14995A>T) were typed in 734 white subjects (373 men and 361 women) attending a residential lifestyle intervention program. The baseline anthropometric and biochemical measures were used. Obesity was defined as BMI > or = 30 kg/m(2). RESULTS: Multivariate analysis demonstrated that, in women, two of the SNPs (13041A>G, and 14995A>T) were significantly associated with percentage body fat (p = 0.016 for 13041A>G and p = 0.010 for 14995A>T) and waist circumference (p = 0.020 for 13041A>G and p = 0.045 for 14995A>T). Moreover, haplotype analysis using these two SNPs indicated that haplotypes A/T and G/T were both associated with significantly increased obesity risk (odds ratio = 1.76, 95% confidence interval 1.07 to 2.90 for haplotype A/T, and odds ratio = 1.73, 95% confidence interval 1.06 to 2.82 for haplotype G/T) when compared with haplotype A/A. No significant associations between PLIN variations and obesity were found in men. DISCUSSION: Our data support the hypothesis that the PLIN locus may be a significant genetic determinant for obesity risk in whites and that women are more sensitive to the genetic effects of perilipin than men.

Adipose Tissue↗

PubMed2002

Non-invasive determination of the paternal HLA haplotype of a fetus using kinetic PCR to detect fetal microchimerism in maternal plasma.

Knowledge of fetal HLA type can be important if cord blood (CB) is being considered as a stem cell source for transplantation. The feasibility of determining the paternally inherited HLA haplotype of a fetus was explored through analysis of fetal DNA in the maternal circulation. A 5-year-old child with relapsed acute leukemia was a candidate for transplantation. The HLA type of the fetal sibling was needed to assist with evaluation of this potential cord blood donor. DNA was isolated from maternal plasma and whole blood. Kinetic PCR using sequence-specific primers for paternal HLA-A, -B, and -DRB1 alleles was performed. Alleles corresponding to one paternal haplotype were detectable in plasma, but not in whole blood. Alleles from the alternative haplotype were not detectable. This demonstrated that the fetus shared at least one haplotype with the patient and therefore arrangements were made to bank the CB. The maternal haplotype of the fetus could not be determined in the presence of maternal DNA. The prenatal fetal typing was confirmed by typing the newborn's CB. This rapid non-invasive technique may facilitate the selection of CB units for banking based on needed HLA types.

Acute Disease↗

PubMedDate not supplied

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance.

We report linkage of a family affected with autosomal dominant hereditary spastic paraparesis (HSP) and/or cognitive impairment to the HSP locus on chromosome 2p. To date all families linked to this locus have been affected with 'pure' HSP. The specific pattern of cognitive impairment in this family is characterised primarily by deficits in visuo-spatial functions. We also present genetic studies that indicate variable expression and low or delayed penetrance. We have constructed a haplotype flanked by polymorphic markers D2S400 and D2S2331 that was present in 12 individuals affected with spastic paraparesis. The severity of spasticity varied markedly among these individuals. In addition four of these individuals (aged 62-70) also had a specific form of cognitive impairment. The disease haplotype was also present in an individual (age 57) who had an identical pattern of cognitive impairment as the only sign of the disease supporting the hypothesis that spastic paraparesis and cognitive impairment are the result of variable expression of a single gene (rather than a co-incidental occurrence). Haplotype reconstruction for all participating family members revealed the presence of this disease haplotype in six individuals who had normal neurological and neuropsychological examinations. All six are below the maximal age of onset in the family--60 years. This is evidence for low or late penetrance of the AD HSP gene in this family. The identification of normal individuals carrying the disease haplotype demonstrates the importance of genetic studies in combination with clinical examination when counselling at risk family members.

Aged↗

PubMed2002

Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11.

Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.

Chromosomes, Human, Pair 17↗

PubMed2002

The impact of genotyping error on haplotype reconstruction and frequency estimation.

The choice of genotyping families vs unrelated individuals is a critical factor in any large-scale linkage disequilibrium (LD) study. The use of unrelated individuals for such studies is promising, but in contrast to family designs, unrelated samples do not facilitate detection of genotyping errors, which have been shown to be of great importance for LD and linkage studies and may be even more important in genotyping collaborations across laboratories. Here we employ some of the most commonly-used analysis methods to examine the relative accuracy of haplotype estimation using families vs unrelateds in the presence of genotyping error. The results suggest that even slight amounts of genotyping error can significantly decrease haplotype frequency and reconstruction accuracy, that the ability to detect such errors in large families is essential when the number/complexity of haplotypes is high (low LD/common alleles). In contrast, in situations of low haplotype complexity (high LD and/or many rare alleles) unrelated individuals offer such a high degree of accuracy that there is little reason for less efficient family designs. Moreover, parent-child trios, which comprise the most popular family design and the most efficient in terms of the number of founder chromosomes per genotype but which contain little information for error detection, offer little or no gain over unrelated samples in nearly all cases, and thus do not seem a useful sampling compromise between unrelated individuals and large families. The implications of these results are discussed in the context of large-scale LD mapping projects such as the proposed genome-wide haplotype map.

Diagnostic Errors↗

PubMed2004

Haplotype diversity and SNP frequency dependence in the description of genetic variation.

Haplotype diversity is controlled by a variety of processes, including mutation, recombination, marker ascertainment and demography. Understanding the extent to which genetic variation at physically linked loci is co-inherited is crucial for the design of the HapMap project and the correct interpretation of the resulting data. In the absence of an analytical theory extensive coalescent simulations are used to disentangle the influence of all of these factors on haplotype diversity. In addition to these qualitative insights, this study also demonstrates (i) that marker spacing and frequency profoundly influence observed levels of haplotype diversity; (ii) that the spectrum of haplotypes contains information about how exhaustively genetic variation in a region is described by a given marker set; and (iii) that so-called haplotype blocks can be generated due by the stochasticity inherent in the recombination process without having to assume variation in the recombination rate.

Computer Simulation↗

PubMed2004

Cox proportional hazards survival regression in haplotype-based association analysis using the Stochastic-EM algorithm.

It is now widely recognized that haplotype information inferred from genotypes can be of great interest to better characterize the role of a candidate gene in the etiology of a complex trait in the context of association studies. Several works have recently advocated the simultaneous estimation of haplotype frequencies and haplotype effects in order to get a better efficiency in parameter estimation. Most of the available models can deal with a binary or a quantitative phenotype, but none has yet discussed the application of haplotype-based association analysis to a survival outcome. We describe how the recently proposed Stochastic-EM (SEM) algorithm can be applied to estimate haplotype effects in censored data analysis using a standard Cox proportional hazards formulation. This model has been implemented in the THESIAS software freely available at http://www.genecanvas.org.

Algorithms↗

PubMed2005

Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans.

The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.

Black or African American↗

PubMed2005

X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations.

Linkage disequilibrium (LD) structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity -- Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) -- in 15 Eurasian populations. Demographic events predicted to increase the LD level -- genetic drift, bottleneck and admixture - had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasize the importance of understanding the history, structure and variation of a study population.

Asia↗

PubMed2004

Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans.

The major inflammatory cytokines interleukin(IL)1beta, IL6 and tumor necrosis factor alpha (TNFalpha) play a crucial role in infection, inflammation and stress responses. Previously, three coding genes were resequenced, identifying promoter polymorphisms that were used in association studies of neurodegenerative diseases, metabolic disorders and cancer. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: IL1B-511 C>T, IL6-174 G>C and TNF-308 G>A provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for IL1B, IL6 and TNF/LTA that included the known functional marker but also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 26 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations, a single block with little evidence of historical recombination was observed in IL1B, IL6 and TNF/LTA. For each gene, haplotypes captured the information content of each functional locus, even if that locus was not genotyped, and presumably haplotypes would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using gene haplotype maps and marker panels as tools for linkage studies on related phenotypes.

Black or African American↗

PubMed2005

Haplotype tagging efficiency in worldwide populations in CTLA4 gene.

The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.

Alleles↗

PubMed2005

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

Black or African American↗

PubMed2002

Linkage disequilibria between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura.

The association between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura from Calvia (Balearic Islands, Spain) was studied in order to search for linkage disequilibria, in an attempt to explain the populational dynamics of the mtDNA haplotypes of this species in nature. The presence of Wolbachia was not detected. Two main haplotypes (I and II) were found, as well as a series of less common ones. The Tajima D-test seemed to indicate some kind of seasonal population bottleneck. An analysis of linkage disequilibrium and factorial analysis of correspondences detected an association between haplotype I and the J(ST) inversion and haplotype II and the J(1) inversion.

Animals↗