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PubMed2004

Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis.

In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.

DNA Primers↗
PubMed2006

Molecular-based haplotype analysis of the beta 2-adrenergic receptor gene (ADRB2) in Japanese asthmatic and non-asthmatic subjects.

BACKGROUND: The beta2-adrenergic receptor gene (ADRB2) is a target molecule of beta2-agonists. Single nucleotide polymorphisms (SNPs) in the ADRB2 are related to the effectiveness of beta2-agonists. However, there are some discrepancies in the results of pharmacogenetic studies of ADRB2 among different ethnic groups. The aims of this study were to determine the ADRB2 haplotypes and diplotypes in Japanese asthmatic and non-asthmatic subjects and to examine their relation to asthma and to compare these results with previous studies done in other ethnic groups. METHODS: Complete sequences for 3 kb promoter and 1.2 kb structural regions of ADRB2 were analyzed in 48 Japanese asthmatics and 100 controls, and haplotypes and diplotypes of SNPs were analyzed. RESULTS: Fifteen SNPs including a novel one in -839 were observed. Allele frequencies for all SNPs were similar between asthmatics and controls. We also identified 42 haplotypes and 54 diplotypes of ADRB2 in a Japanese population. The frequencies were similar between the two groups. They were classified into 17 and 23 types, respectively, according to Drysdale's haplotype-organization system, and a significant ethnic difference was observed between the Japanese and Caucasian populations. CONCLUSIONS: The frequencies of SNPs and ADBR2 haplotypes in Japanese are different from those in Caucasians and African Americans. These divergences might imply the need for independent pharmacogenetic studies for ADBR2 in each ethnic group.

Black or African American↗
PubMed2004

Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11.

Members of the apolipoprotein gene cluster (APOA1/C3/A4/A5) on human chromosome 11q23 play an important role in lipid metabolism. Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. The close genomic locations of these two genes as well as their functional similarity have hindered efforts to define whether each gene independently influences human triglyceride concentrations. In this study, we examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. We identified a total of five common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein gene in the cluster by a region of significantly increased recombination. Furthermore, one previously identified triglyceride risk haplotype of APOA5 (APOA5*3) showed no association with three APOC3 SNPs previously associated with triglyceride concentrations, in contrast to the other risk haplotype (APOA5*2), which was associated with all three minor APOC3 SNP alleles. These results highlight the complex genetic relationship between APOA5 and APOC3 and support the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans.

Apolipoproteins↗
PubMed2006

Sequencing and haplotype analysis of the activator of CREM in the testis (ACT) gene in populations of fertile and infertile males.

cAMP-responsive element modulator (CREM) is a key transcription factor in the differentiation of round spermatids into mature spermatozoa. During spermiogenesis, CREM is regulated in part by activator of CREM in the testis (ACT), which activates CREM in a phosphorylation-independent fashion. We hypothesized that the ACT gene, which is expressed exclusively in the testis, could be involved in male factor infertility in patients with idiopathic-impaired spermatogenesis. To test this hypothesis, we sequenced the coding regions and flanking intronic regions of the ACT gene in 96 azoo- or oligospermic patients and 69 fertile controls. A total of 12 single-nucleotide polymorphisms (SNPs) was identified, and four of them leading to amino acid substitutions. An association study was performed based on calculated haplotype frequencies, and statistically significant differences were found between the patient and control populations for some haplotypes. To help establish the evolutionary relationships between the haplotypes, the coding regions of both the chimpanzee and the gorilla ACT gene were sequenced and evaluated. To test whether the different haplotypes conferred a functional change to the ACT protein, a yeast two-hybrid assay was designed to test the interaction between the two most divergent ACT haplotypes and their known binding partners, CREM and KIF17b. We identified one ACT haplotype that had a 45% reduction in its interaction with CREM. Our results suggest that different haplotypes within the ACT gene may contribute to male factor subfertility.

Animals↗
PubMed1998

Fine localization of the CMT4A locus using a PAC contig and haplotype analysis.

Charcot-Marie-Tooth disease type 4A (CMT4A) is a severe, autosomal recessive peripheral neuropathy linked to chromosome 8q13-q21. We have previously constructed a YAC contig across the CMT4A region and narrowed the disease-flanking interval to approximately three megabases. Subsequently, we constructed a PAC/BAC contig made of 44 clones and mapped 44 new and 30 previous STSs, ESTs, and polymorphic makers to the region. Using 13 polymorphic markers, we have now identified an ancestral haplotype segregating in three families, indicating a common founder mutation. Two ancestral recombination events in this haplotype significantly reduce the minimal candidate region to a minimal trailing path of five PAC/BAC clones, which will now allow direct investigation of candidate genes for CMT4A.

Alleles↗
PubMed2004

Genetic evidence for recombination in Candida albicans based on haplotype analysis.

The possibility of sexual reproduction in the human pathogenic fungus Candida albicans is a question of great interest in medical mycology. Not only is it a fundamental biological issue, but it is also a potential mechanism for contributing to the phenotypic plasticity (and hence the virulence) of the organism. Molecular genotyping methods such as multi-locus sequence typing (MLST) are generating data that can shed light on this question. In the present study we have used MLST information to generate haplotypes that identify many different homologues of a chromosome within a collection of strains. Particular combinations of these haplotypes provide evidence for chromosomal segregation and intra-chromosome recombination. All of our observations of haplotype diversity could also be explained by other mechanisms, such as gene conversion or mitotic recombination, and the resolution of these issues will require a denser map of accurately localised markers. A common event observed in strain evolution is loss of heterozygosity at a particular marker. Our results contribute to the emerging picture of C. albicans as an organism whose primary means of reproduction is clonal, but with a small but important contribution from sexual reproduction, occurring in nature but not under commonly used laboratory conditions.

Alleles↗
PubMed2005

Linkage disequilibrium and haplotype analysis of two single nucleotide polymorphisms in STK15 in Chinese.

STK15 (Serine/Threonine protein kinase 15) is a serine/threonine kinase encoding gene, whose overexpression in mammalian cells leads to centrosome amplification, chromosomal instability, and oncogenic transformation. 91A-->T, a single nucleotide polymorphism (SNP) in exon 3 of STK15, has recently been shown to be associated with human cancer susceptibility. Within exon 3 of STK15, there are three nonsynonymous SNPs: 91 A-->T, 169G-->A and 311C-->T. We have determined STK15 genotypes and haplotypes composed of 91A-->T and 169G-->A by PCR-RFLP in a randomly sampled cohort of 193 normal individuals from Northeast China. DNA samples from all individuals were subjected to first round of PCR using a pair of specific primers. For the subsequent nested PCR,a mismatch forward primer, which could introduce an EcoR I restriction site to the 91A allele, was included. The nested PCR products were digested with the restriction endonucleases EcoRI and AccII. The double restriction digests were separated by polyacrylamide gel electrophoresis. Three haplotypes,91A-169G, 91T-169A and 91T-169G, were detected and their frequencies were 68.65%, 10.88% and 20.47%, respectively. Six genotypes composed of the above three haplotypes were found,and their frequencies were 91A-169G/91 A-169G (46.11%), 91A-169G/91 T-169A (14.51%), 91A-169G/91T-169G (30.57%), 91T-169G/91T-169G (3.11%), 91T-169G/91T-169A (4.15%), 91T-169A/91T-169A (1.55%). Whereas no 91A-169A haplotype was detected in all individuals examined in the current study, linkage disequilibrium (LD) between the two SNPs was found.

Alleles↗
PubMed2006

Detection of parent-of-origin effects in nuclear families using haplotype analysis.

Despite the potential pitfalls of stratification, population-based association studies nowadays are being conducted more often than family-based association studies. However, the mechanism of genomic imprinting has lately been implicated in the etiology of genetic complex diseases and can be detected using statistics only in family-based designs. Powerful tests for association and imprinting have been proposed previously for case-parent trios and single markers. Since the power of association studies can be improved if multiple affected children and haplotypes are considered, we extended the parental asymmetry test (PAT) for imprinting to a test that is suited for both general nuclear families and haplotypes, called HAP-PAT. Significance of the HAP-PAT is determined via a Monte-Carlo simulation procedure. In addition to the HAP-PAT, we modified a haplotype-based association test, proposed by us before, in such a way that either only paternal or maternal transmissions contribute to the test statistic. The approaches were implemented in FAMHAP and we evaluated their performance under a variety of disease models. We were able to demonstrate the usefulness of our haplotype-based approaches to detect parent-of-origin effects. Furthermore, we showed that also in the presence of imprinting it is more reasonable to consider all affected children of a nuclear family, than to randomly select one affected child from each family and to conduct a trio study using the selected individuals.

Computer Simulation↗
PubMed2004

Haplotype analysis of the matrix metalloproteinase 3 gene and myocardial infarction in a Chinese Han population. The Beijing atherosclerosis study.

Matrix metalloproteinase (MMP) 3 plays an important role in the pathogenesis of myocardial infarction (MI). Up to now, there has been conflicting data regarding the possible contribution of the MMP3 -1612 5A/6A promoter polymorphism to MI. In this study, we have investigated the possible association of three polymorphisms (-1612 5A/6A, -376C/G, Glu45Lys) in the MMP3 gene with MI in a Chinese Han population. The polymorphisms were analyzed in 509 patients with MI, and in 518 healthy controls. The frequency of the 5A allele was 14% in the healthy controls, which is less than in Western populations (40%-52%). Logistic regression analyses of individual polymorphisms indicated that individuals carrying the -1612 5A allele had an increased risk of MI (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.28 to 2.40), as did those carrying the -376 G allele (OR 1.78, 95% CI 1.33 to 2.38). The three polymorphisms studied were found to be in strong linkage disequilibria. Haplotype analyses showed that the 5A-G-Lys haplotype (-1612 5A, -376G and 45Lys) was independently associated with susceptibility to MI. Taken together, the effect of the MMP3 polymorphisms studied may be attributable to the -1612 5A/6A polymorphism. We conclude that the MMP3 -1612 5A/6A polymorphism is associated with MI in our population, implying that individuals of the 5A allele carriers have an increased risk of suffering MI.

Case-Control Studies↗
PubMed2006

Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance.

BACKGROUND: The ATP-binding cassette (ABC) proteins are a superfamily of efflux pumps implicated as a mechanism for multidrug resistance in cytotoxic chemotherapy, immunosuppressive therapy, HIV and epilepsy. Genetic variation in P-glycoprotein, the product of the ABCB1 gene, is proposed to mediate de novo drug resistance, but associations between polymorphisms in ABCB1 and pharmacoresistance have produced conflicting results. Potential explanations for the inconsistency of results include inadequate characterization of gene structure, variation and linkage disequilibrium (LD) in ABCB1, as well as overlap in substrate specificity between ABCB1 and the various other drug transporters. METHODS AND RESULTS: We undertook a fundamental analysis of gene structure, variation and LD in ABCB1 and four other drug transporter genes implicated in pharmacoresistance: ABCC1, ABCC2, ABCC5 and ABCB4. Manual annotation of the five genes revealed nine shorter alternative transcripts with new untranslated regions and one novel region of coding sequence, demonstrating that on-line annotations are incomplete. Sequencing of exons in 47 Caucasian individuals identified 75 novel single nucleotide polymorphisms (SNPs) previously undescribed in any public database, including 14 new coding sequence SNPs. Genotyping of 502 SNPs in 842 Caucasian individuals across the five genes revealed large blocks of high LD, and low haplotype diversity across all five genes that could be characterized by between 67 and 114 tagging SNPs, depending on the tagging criteria. CONCLUSION: The study illustrates that publicly available data resources on genomic organization of genes and common variation can have important gaps and limitations, and establishes a comprehensive set of tagging SNPs for future association studies in pharmacoresistance.

ATP-Binding Cassette Transporters↗
PubMed2002

H intragenic polymorphisms and haplotype analysis in the ornithine transcarbamylase (OTC) gene and their relevance for tracking the inheritance of OTC deficiency.

The "private" nature of most mutations causing ornithine transcarbamylase (OTC) deficiency makes mutation identification in the patients difficult. Further, the PCR-amplification technology generally used for the genetic diagnosis of the deficiency misses large deletions in carrier females. Intragenic OTC polymorphisms may allow detection of these deletions and may represent an alternative to mutation detection for prenatal diagnosis and carrier identification in families with a history of inherited OTC deficiency. A new highly informative polymorphism (allele frequencies, 0.66/0.34) in intron 3 of the OTC gene (IVS3-39_40insT) is reported here, and allelic frequencies of 16 additional intragenic OTC polymorphisms are determined in 133-35 (average per polymorphism, 72) unrelated chromosomes. In addition to the novel polymorphism, only three of the studied polymorphisms (Lys46Arg, allelic frequency 0.68/0.32; IVS3-8A>T, 0.34/0.66; Gln270Arg, 0.97/0.03) are confirmed to be informative. These provide, together with another reported polymorphism (IVS4-7A>G; reported allelic frequency 0.71/0.29; Plante and Tuchman, 1998), a set of highly valuable markers of the OTC gene. Nevertheless, the combined informativity of the studied polymorphisms is limited by their distribution in only four haplotypes with one of them predominating (65% of the sampled chromosomes). Although this haplotype composition may be restricted to the Iberian peninsula (the origin of the samples), more informative polymorphisms are required to increase the diagnostic potential and, particularly, to identify large deletions affecting OTC gene exons 5-10, where only one polymorphism of weak diagnostic value is known.

Base Sequence↗
PubMed2002

Haplotype analysis and phylogeny of ornithine transcarbamylase polymorphisms.

Ornithine transcarbamylase (OT2, EC 2.1.3.3) deficiency, the most common inborn error of urea cycle, is caused by a vast number of point mutations, deletions and insertions in the respective gene. Furthermore, 12 single nucleotide polymorphisms (NSPs) have been described in the OTC gene, four of them causing an amino acid change. We have studied the frequency of these markers in two populations: Portuguese and Mozambican. No significant differences were observed between populations, except for Lys --> Arg in codon 46. Allelic associations between polymorphisms were used to define haplotypic patterns. The three common haplotypes (H1, H2 and H3) show a combined frequency of 95% in Portugal and 87% in Mozambique. One haplotype was found only in Portugal and three are only present in Mozambique, resulting in a higher haplotype diversity. The combined information from the SNPs and the DXS1068 (CA)n repeat was used to outline OTC haplotype phylogeny, which, in conjunction with the population data, allowed us to sketch possible evolutionary pathways although some haplotypes could have arisen by either repeated mutation or recombination.

Alleles↗
PubMed2006

Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.

The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Haplotype analysis of the human endogenous retrovirus locus HERV-K(HML-2.HOM) and its evolutionary implications.

We and others recently identified an almost-intact human endogenous retrovirus (HERV), termed HERV-K(HML-2.HOM), that is usually organized as a tandem provirus. Studies on HERV proviral loci commonly rely on the analysis of single alleles being taken as representative for a locus. We investigated the frequency of HERV-K(HML-2.HOM) single and tandem alleles in various human populations. Our analysis revealed that another HERV-K(HML-2) locus, the so-called HERV-K(II) provirus, is also present as a tandem provirus allele in the human population. Proviral tandem formations were identified in various nonhuman primate species. We furthermore examined single nucleotide polymorphisms (SNPs) within the HERV-K(HML-2.HOM) proviral gag, prt, and pol genes, which all result in nonsense mutations. We identified four proviral haplotypes displaying different combinations of gag, prt, and pol SNPs. Haplotypes harboring completely intact proviral genes were not found. For the left provirus of the tandem arrangement a haplotype displaying intact gag and prt genes and a mutated pol was found in about two-thirds of individuals from different ethnogeographic origins. The same haplotype was always found in the right provirus. The various haplotypes point toward multiple recombination events between HERV-K(HML-2.HOM) proviruses. Based on these findings we derive a model for the evolution of the proviral locus since germ line integration.

Alleles↗
PubMed1999

Haplotype analysis of a de novo allele at a vWF STR locus using flanking STR loci.

We have detected an unusual allele at the vWF-Kimpton (vWF-K) loci in the DNA of a child (genotype: 1415) in a paternity trio case. One allele of the child's DNA was found to derive neither from the mother (1214) nor from the putative father (1314), whose paternity was established not only by conventional polymorphic markers (probability 0.99999) but also by the other 10 STRs and the D1S80 and HLA DQ alpha loci. Two STRs flanking vWF-K comprise vWF haplotypes, which allow the parental origin of the unusual allele to be determined. Sequencing of clones encompassing the three STRs showed that the unusual allele segregated with the paternal haplotype. The de novo allele of the child thus seemed to be generated from the longer allele (14) by gaining a single unit (TCTA) through slippage replication.

Journal Article↗
PubMed1997

Mutation-haplotype analysis of steroid 21-hydroxylase (CYP21) deficiency in Finland. Implications for the population history of defective alleles.

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common inherited defect of adrenal steroid hormone biosynthesis. Unusually for genetic disorders, the majority of mutations causing CAH apparently result from recombinations between the CYP21 gene encoding the 21-hydroxylase enzyme and the closely linked, highly homologous pseudogene CYP21P. The CYP21 and CYP21P genes are located in the major histocompatibility complex class III region on chromosome 6p21.3. We analyzed the mutations and recombination breakpoints in the CYP21 gene and determined the associated haplotypes in 51 unrelated Finnish families with CAH. They represent no less than half of all CYP21 deficiency patients in Finland. The results indicate the existence of multiple founder mutation-haplotype combinations in the population of Finnish CAH patients. The three most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represented single cases. Each of the common haplotypes was shown consistently to carry a typical CYP21 mutation and only in some cases was additional variation observed. Surprisingly, comparisons with previous published data revealed that several of the frequent mutation-haplotype combinations in Finland are in fact also found in many other populations of patients of European origin, thus suggesting that these haplotypes are of ancient origin. This is in clear contrast to many reports, including the present one, where a high frequency of de novo mutations in the CYP21 gene has been reported. In addition, two unique sequence aberrations in CYP21 (W302X and R356Q), not known to exist in the CYP21P pseudogene, were detected.

Adrenal Hyperplasia, Congenital↗