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PubMed2004

Relationship between beta-2 adrenoceptor gene haplotypes and adipocyte lipolysis in women.

BACKGROUND AND AIMS: The beta(2)-adrenergic receptors are important for adipocyte lipolysis regulation by catecholamines in humans. The beta(2)-adrenoceptor gene is highly polymorphic. The role of these genetic variations for adipocyte lipolysis was investigated. DESIGN AND METHODS: Six single-nucleotide polymorphisms (SNPs) in the promotor region and four SNPs in the coding region (leading to amino-acid substitution) of the beta(2)-adrenoceptor gene were determined in 141 overweight or obese, but otherwise healthy women. Lipolysis experiments were performed on isolated subcutaneous adipocytes. RESULTS: Three homozygous haplotypes (6/6, 4/4 and 2/2) were found that differed about 500-fold in noradrenaline sensitivity or beta(2)-adrenoceptor sensitivity (6/6>2/2>4/4, P=0.01). The haplotypes also differed by 100% in maximum noradrenaline-induced lipolysis rates (6/6>2/2>4/4). However, there was no influence on beta(1)-, beta(3)- or alpha(2)A-adrenoceptor sensitivity. Heterozygosity at one or several SNPs in the haplotypes influenced the beta(2)-adrenoceptor sensitivity significantly. CONCLUSION: Multiple SNPs in the beta(2)-adrenoceptor gene form several haplotypes that markedly influence beta(2)-receptor function- and catecholamine-induced lipolysis in fat cells. These haplotypes may be important genetic factors behind impaired lipolysis in obesity.

Adipocytes↗

PubMed2003

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Carrier Proteins↗

PubMed2004

Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population.

The role of the serotonin transporter (5-HTT) in the development of neuropsychiatric disorders has been widely investigated. Two polymorphisms, an insertion/deletion in the promoter region and a 12 repeat allele in a variable nucleotide tandem repeat (VNTR) in intron 2, drive higher expression of the 5-HTT gene. Four studies have shown nominally significant excess transmission of alleles of the 5-HTT gene in autism, while three studies have reported no excess transmission. This present study investigates the role of 5-HTT in the genetically homogenous Irish population. In all, 84 families were genotyped for five polymorphisms (three SNPs, a VNTR and an in/del). The analysis of allele transmissions using the transmission disequilibrium test (TDT) was undertaken and indicated preferential transmission of the short promoter allele (TDT P-value=0.0334). Linkage disequilibrium between markers was calculated and haplotypes were assessed for excess transmission and odds ratios (ORs) to affected children. A number of haplotypes, especially those involving and surrounding SNP10, showed evidence of association. The ORs ranged from 1.2 to 2.4. The most significant haplotype associated with transmission to affected probands was the SNP10-VNTR-SNP18 haplotype (chi(2)=7.3023, P=0.0069, odds ratio=1.8). This haplotype included the 12 repeat allele of the VNTR, which is associated with increased expression and may play a subtle role in the early development of the brain in affected probands.

Autistic Disorder↗

PubMed2004

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans.

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.

Adult↗

PubMed2001

Frequency and distribution of t-haplotypes in the Southeast Asian house mouse (Mus musculus castaneus) in Taiwan.

t-haplotypes are a meiotic drive system found on the 17th chromosome of the house mouse (Mus musculus). They can be found in wild populations of all four genetically differentiated subspecies. The drive phenomenon is male-specific, such that heterozygous males (+/t) show non-Mendelian transmission and transmit the t-chromosome to > 90% of their offspring. So far the most comprehensive studies on the frequencies of t-haplotypes in natural populations have been on just one of the subspecies (M. musculus domesticus). We applied molecular methods to accurately screen t-haplotypes in a large number of populations of a second subspecies (M. musculus castaneus) distributed in Taiwan. We found that the overall t-haplotype frequency is low in M. m. castaneus (0.108), and the chromosomes are patchily distributed among its populations, closely resembling the situation found in M. m. domesticus. Further, we found the frequencies of t-haplotypes in our sample did not differ in relation to the sex or age of mice. This resemblance in the frequency and distribution among populations of the two distinct subspecies suggests that similar general mechanisms might be responsible for the low frequencies in both subspecies.

Age Factors↗

PubMed1998

Variable number of pig MHC class I genes in different serologically defined haplotypes identified by a 3'-untranslated region probe.

To estimate the number of porcine class I major histocompatibility genes, a short class I cDNA probe from the 3'-untranslated region was developed to be used in restriction fragment length polymorphism analysis. Six clones isolated from a pig spleen cDNA library were sequenced from their 3'-untranslated region. Three different transcripts were identified, one probably derived from the class I PD7 locus and two showing highest homology to the PD1 and the PD14 genes, respectively. Class I typing was performed both by restriction fragment length polymorphism and serology. Segregation of class I haplotypes was followed in one three-generation family (European Wild Boar x Large White: Swedish Yorkshire) and in six two-generation families (Duroc, Yorkshire and Chester White), for a total of 266 pigs. Twenty different class I haplotypes were identified either with restriction fragment length polymorphism and/or serological typing. Furthermore, previously unpublished serological haplotypes H62, H67 and H68 were identified. Two to seven polymorphic and three monomorphic fragments were detected in different restriction fragment length polymorphism haplotypes indicating that the number of class I genes in the investigated haplotypes varies.

Animals↗

PubMed2004

Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27.

AIMS: The relationship between beta2-adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic beta2-adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous beta2-adrenoceptor haplotypes on the acute systemic beta2-adrenoceptor effects following inhaled salbutamol in asthmatic subjects. METHODS: An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16-Gln27 (12%) and Gly16-Glu27 (19%). After a 1-week washout period where all beta2-adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16-Gln27: n = 8 and Gly16-Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 microg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5-min intervals for 20 min. RESULTS: The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16-Gln27 vs Gly16-Glu27. The mean +/- SEM maximum serum potassium change from baseline over 20 min was significantly greater (P = 0.04) for Arg16-Gln27: -0.37 +/- 0.05 mmol l(-1) vs Gly16-Glu27: -0.23 +/- 0.04 mmol l(-1); 95% CI for difference: -0.01 to -0.28 mmol l(-1). The maximum diastolic blood pressure change from baseline over 20 min was significantly greater (P = 0.0008) for Arg16-Gln27: -13 +/- 1 mmHg vs Gly16-Glu27: -4 +/- 2 mmHg; 95% CI for difference: -5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16-Gln27: 10 +/- 3 beats min(-1) vs Gly16-Glu27: 10 +/- 3 beats min(-1). CONCLUSIONS: Caucasian asthmatic subjects with the Arg16-Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16-Glu27 haplotype. The attenuated beta2-adrenoceptor response in the Gly16-Glu27 haplotype would be in keeping with increased susceptibility to prior down-regulation by endogenous catecholamines.

Administration, Inhalation↗

PubMed1999

Immunogenetics of atopic asthma: association of DRB11101 DQA10501 DQB1*0301 haplotype with Dermatophagoides spp.-sensitive asthma in a sample of the Venezuelan population.

BACKGROUND: Genes linked to the major histocompatibility complex (MHC), have been implicated in atopic asthma. Asthma is highly prevalent in the Venezuelan population (estimated at 20%) and genetic markers are needed to identify populations at risk and plan intervention strategies. OBJECTIVE: To study the influence of the MHC class I and class II genes in the susceptibility to atopic asthma. METHODS: MHC-class I HLA-A, -C, -B and MHC-class II HLA-DR, -DQ, -DP gene haplotype frequencies were determined in 135 Venezuelan mestizos, 71 belong to 20 atopic asthmatic families and 64 unrelated controls. The index cases were 20 atopic asthmatics with positive skin-prick tests and specific serum immunoglobulin E (IgE) for Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f). To ascertain the genes associated with susceptibility to atopy and/or asthma, two control groups were studied, 41 non-atopic subjects with skin-prick negative test, and undetectable levels of specific IgE and 23 non-asthmatic atopic subjects with detectable specific IgE to Der p and Der f. A linkage analysis was performed in those families with two or more atopic siblings (with or without asthma). RESULTS: MHC-class I genes analysis showed that HLA-Cw7 was absent in the asthmatic patients studied, whereas the frequency of this allele was 14.3% in non-atopic controls (P = 0.0 17, PC = 0.19) and 20.8% in the atopic controls (P = 0.0066, PC = 0.07). MHC-class II gene analysis showed a significant increase of the HLA-DRB1*11 in the asthmatic patients compared with non-atopic controls (allele frequencies of 25.6 vs 4.4% P = 0.0017, PC = 0.02). There were no significant differences among asthmatic and atopic controls in the frequency of HLA-DRB1*11 (25.6 vs 17.4%). In contrast, the HLA-DRB1*1101+ haplotypes were significantly higher in asthmatics compared with atopic and non-atopic controls (19.6% vs 2.2% vs 2.3%, PC<0.05). The HLA-DRB1*1101, DQA1*0501, DQB1*0301 haplotype was found significantly increased in the patients vs non-atopic controls (15.4 vs 1.1%, PC< 0.01). The serum levels of specific IgE were detectable in both atopic asthmatics and atopic controls; however, it was higher in atopic asthmatics vs atopic controls Der p (median, 58.7 vs 2.7 kU/L, P<0.001) and Der f (median, 46.9 vs 2.7 kU/L, P<0.001). No linkage between MHC genes and mite-atopy could be documented on informative families with two or more atopic siblings. CONCLUSIONS: We have identified an association between the haplotype HLA-DRB1*1101, DQA1*0501, DQB1*0301 and atopic asthma that confers susceptibility to develop mite-sensitive asthma to atopics (relative risk, RR 8.2), and to non-atopic controls (RR = 15.8) that carry this haplotype. Conversely, the allele HLA-Cw7 was absent in the asthmatics studied and had higher frequencies in the atopic (RR = 0.05) and non-atopic (RR = 0.08) controls. Thus, it may have a protective role for developing atopic asthma in the population studied.

Adolescent↗

PubMed1997

Hierarchy of SPEA presentation to T cells by mouse MHC haplotypes.

The ability of splenic antigen-presenting cells (APC) from nine independent mouse major histocompatibility complex (MHC) haplotypes to present recombinant streptococcal exotoxin A (rSPEA) to heterogeneous T cells and mouse T cell clones were compared using proliferation assays. We report that there is marked variation between MHC haplotypes, which can be ranked as follows: H2z > H2s = H2f = H2p = H2r = H2k > H2d > H2b = H2q. In some haplotypes both A and E molecules bind rSPEA with low affinity. In addition, we show that presentation is preferentially by E molecules in haplotypes where A and E are coexpressed, but that A alleles also bind and present rSPEA, based on inhibition of responses by anti-E and anti-A mAbs. Furthermore, using strains of mice which fail to express E, we demonstrate that A(s) and Af present rSPEA with high efficiency, whereas Aq and Ab are the least efficient of all haplotypes. The results suggest that there is significant variation in the ability of different alleles of both E and A molecules to bind and present rSPEA.

Animals↗

PubMed2001

Haplotype frequency distribution and discriminatory power of two mtDNA fragments in a marine pelagic teleost (Atlantic herring, Clupea harengus).

Two regions of the mtDNA of Atlantic herring (Clupea harengus), ND3/4 and ND5/6, were surveyed by RFLP analysis to assess the effects of marker variability on the power of statistical tests. Although haplotype diversity was similar, marked differences in the number of common haplotypes were observed between the two regions, with ND3/4 having a more even distribution of haplotype frequencies. ND3/4 also revealed higher differentiation among samples than ND5/6, similar to previously published microsatellite data of the same samples. The data suggested that the highly skewed haplotype distribution of many mtDNA markers may be one of the reasons for the less frequent detection of population differentiation compared to microsatellites. Pooling ('binning') of related haplotypes did not increase differentiation revealed by each mtDNA region individually, but greatly strengthened geographical patterns shown by both regions combined. The data provided evidence for genetic differentiation of Icelandic herring from other north-eastern Atlantic stocks, and indicated genetic differences between Baltic and Celtic Sea herring. However, mtDNA data failed to confirm previously reported differences between Barents Sea herring, Norwegian fjord populations and Norwegian spring spawners.

Animals↗

PubMed2000

Mitochondrial haplotype diversity among Portuguese brown trout Salmo trutta L. populations: relevance to the post-pleistocene recolonization of northern Europe.

Mitochondrial haplotype diversity in seven Portuguese populations of brown trout, Salmo trutta L., was investigated by sequencing the 5' end of the mitochondrial DNA (mtDNA) control region. Five new haplotypes were described for this species, each two to three mutational steps distant from the common north Atlantic haplotype. Significant population subdivision of mtDNA haplotypes was also apparent. Based on these results, as well as on published data describing the distribution of both mtDNA haplotypes and allozyme alleles throughout Europe, the postglacial recolonization of northern Europe was re-evaluated. It is argued that the available data do not support the contribution of two major glacial refugia (southwest Atlantic and Ponto-Caspian Basin) to this postglacial recolonization, as proposed in a recently published model. The unique genetic architecture of Portuguese brown trout within the Atlantic-basin clade of this species represents a highly valuable genetic resource that should be protected from introgression with nonendemic strains of hatchery fish.

Animals↗

PubMed2003

Variation of haplotype distributions of two genomic regions of Citrus tristeza virus populations from eastern Spain.

Genetic variation in natural populations of Citrus tristeza virus (CTV) was studied using haplotypes detected by single-strand conformation polymorphism (SSCP) analysis of two genomic regions (p20 gene and segment A, located in ORF1a). Analysis of 254 samples from 125 trees, collected at 12 different sites, yielded 8 different haplotypes for p20 and 5 for segment A. The most frequent haplotype of p20 was predominant at all sites, but several sites differed in the predominance of segment A haplotypes. At most sites, the homozygosity observed for the p20 gene tended to be higher than expected in a neutral evolution, whereas the opposite was true for segment A. Comparison of the populations at different sites showed that 44 of the 66 possible population pairs were genetically distinct for segment A, but only six pairs differed for the p20 gene. Analysis of molecular variance grouping trees by site, scion variety, rootstock or age, showed that variation in segment A was significantly affected by site, tree age and rootstock, and that variation between trees in each group and within trees was even more important. In contrast, variation in p20 was affected only by site and rootstock, each factor contributing to < 2% of the variation. The data suggest that sequence variations in segment A must be functionally less important and that it has less evolutionary constraints than p20. Detection of different haplotypes in neighbour trees or in samples from the same tree may help explain part of the variability observed in CTV symptom expression.

Analysis of Variance↗

PubMed2001

Haplotype (mtDNA) diversity of brown trout Salmo trutta in tributaries of the Austrian Danube: massive introgression of Atlantic basin fish--by man or nature?

Mitochondrial haplotype diversity in 27 populations of brown trout, Salmo trutta L., in Austria was investigated by sequencing the 5' end of the mitochondrial DNA (mtDNA) control region. Although all populations are within the Danube drainage, 44% of all individuals carried Atlantic basin haplotypes. It is argued that the presence of these haplotypes in Austria primarily reflects introgression stemming from the stocking of hatchery-reared fish. However, several lines of evidence suggest that some natural colonization from Atlantic lineages may have contributed to the present haplotype diversity. Nonetheless, the more diverse Danubian clade is represented by regionally distinct haplotype diversity that should be protected from the continued introduction of domesticated strains of exogenous fish

Animals↗

PubMed2001

Haplotype variation in a mitochondrial tandem repeat of Norway spruce (Picea abies) populations suggests a serious founder effect during postglacial re-colonization of the western Alps.

Populations from 13 elevational transects of Norway spruce [Picea abies (L.) Karst] across the Alpine range were sampled to elucidate the geographical pattern of genetic variation in relation to postglacial re-colonization and to study elevational effects on haplotypic diversity. We assessed fragment length variation in a tandem repeat region of the mitochondrial (mt) nad1 intron 2. This maternally inherited genetic marker is suited to infer migration as it is dispersed by seed only. A total of 10 haplotypes was found, most of which were due to repeat copy number variation. An analysis of molecular variance (amova) showed that overall population differentiation was high (F(ST)=0.41), and it revealed a significant differentiation between monomorphic western and moderately to highly variable eastern Alpine populations. This phylogeographic pattern may be explained by a founder effect during postglacial re-colonization. An early arriving haplotype, assumed to originate from a western Carpathian refugium, could expand into suitable habitats, reducing the chances for establishment of subsequently arriving haplotypes. On the other hand, the high variation in populations within an Italian transect of the south-eastern Alps may be the consequence of merging migration pathways from and close distance to putative glacial refugia, most likely those assumed in the Carpathian mountains and on the Balkan peninsula or possibly in the central plains of Italy. An effect of elevation on haplotypic diversity was not evident, though a low, but significant, partition of total genetic variation was attributed to among-population variation in one Italian transect. Various factors, such as vertical seed dispersal and forest management, may account for blurring an otherwise established pattern of genetic variation on a small geographical scale.

Analysis of Variance↗

PubMed1999

Comparative analysis of S haplotypes with very similar SLG alleles in Brassica rapa and Brassica oleracea.

Self-incompatibility in Brassica is controlled by a single multi-allelic locus (the S locus) which harbors at least two highly polymorphic genes, SLG and SRK. SRK is a putative transmembrane receptor kinase and its amino acid sequence of the extracellular domain of SRK (the S domain) exhibits high homology to that of SLG. The amino acid sequences of the SLGs of S8 and S46 haplotypes of B. rapa are very similar and those of S23 and S29 haplotypes of B. oleracea were also found to be almost identical. In both cases, SLG and the S domain of SRK of the same haplotype were less similar. This seems to contradict the idea that SLG and SRK of the same haplotype have the same self-recognition specificity. In the transmembrane-kinase domain, the SRK alleles of the S8 and S46 haplotypes had almost identical nucleotide sequences in spite of their lower homology in the S domain. Such a cluster of nucleotide substitutions is probably due to recombination or related events, although recombination in the S locus is thought to be suppressed. Based on our observations, the recognition mechanism and the evolution of self-incompatibility in Brassica are discussed.

Alleles↗

PubMed2001

Haplotype analyses with the human leucocyte antigen and tumour necrosis factor-alpha genes in narcolepsy families.

Our previous study suggested that the tumour necrosis factor-alpha gene with thymine residue at position -857 in its promoter region [TNF-alpha(-857T)] could be associated with human narcolepsy independently of a strong association of the human leucocyte antigen (HLA)-DRB1*1501 with the disorder. To understand the relationship of DRB1*1501 with TNF-alpha(-857T) in narcoleptic patients, we investigated 28 members of four Japanese narcolepsy families and determined the haplotypes with the HLA-B, TNF-alpha(-857C/T) and HLA-DRB1 in the members. The resultant haplotypes indicated that not only the DRB1*1501-TNF-alpha(-857C) haplotype but also the DRB1*1501-TNF-alpha(-857T) haplotype, which is rare in healthy individuals and may have a strong predisposition to the disorder, were present in the affected members. From the chromosomal recombination observed in a few members, it is possible that chromosomal recombination could play a role in the generation of the rare DRB1*1501-TNF-alpha(-857T) haplotype.

Adult↗

PubMed2003

Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing.

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 1 (MCKD1) [OMIM 174000] is a hereditary nephropathy that leads to renal salt wasting and end-stage renal failure at a median age of 62 years. In a Welsh MCKD1 kindred we have recently demonstrated linkage to the MCKD1 locus on chromosome 1q23.1 and refined the critical MCKD1 region to <3.3 Mb. METHODS: In order to refine the candidate gene region for MCKD1, high-resolution haplotype analysis in three large kindreds with MCKD1 was performed. RESULTS: We report here on high-resolution haplotype analysis in this Welsh kindred, as well as in the Arizona kindred, which was used for the first definition of MCKD as a disease entity, and in a kindred from the Dutch/German border. We detected extensive haplotype sharing among all affected individuals of all three kindreds. Scrutinization of the genealogy of the Arizona kindred revealed an origin from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. CONCLUSION: Under the hypothesis of haplotype sharing by descent, we refined the critical genetic interval to <650 kb, thus enabling candidate gene analysis.

Haplotypes↗

PubMed2004

Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population: implications for pharmacogenomic association studies.

Information about linkage disequilibrium (LD) patterns and haplotype structures for candidate genes is instructive for the design and analysis of genetic association studies for complex diseases and drug response. ABCC1 and ABCG2 are genes coding for two multidrug resistance (MDR) associated transporters; they are also related to some pathophysiological traits. To pinpoint the LD profiles of these MDR genes in Chinese, we systemically screened 27 unrelated individuals for single nucleotide polymorphisms (SNPs) in the coding and regulatory regions of these genes, and thereby characterized their haplotype structures. Despite marked variations in haplotype diversity, LD pattern and intragenic recombination intensity between the two genes, both loci could be partitioned into several LD blocks, in which a modest number of haplotypes accounted for a high fraction of the sampled chromosomes. We concluded that each locus has its own genomic LD profile, but that they still share a common segmental LD architecture with low haplotype diversity. Our data will benefit genetic association studies of complex traits and drug response possibly related to these genes.

ATP Binding Cassette Transporter, Subfamily G, Mem↗