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PubMed2005

Beta-fibrinogen haplotypes and the risk for cardiovascular disease in a dialysis cohort.

BACKGROUND: Elevated plasma fibrinogen levels are common in dialysis patients and may be related to an elevated risk for cardiovascular disease (CVD). We tested the hypothesis that genetic variation in the beta-fibrinogen ( FGB ) gene, shown to explain 1% to 5% of fibrinogen level variation in the general population, has an important role in elevated fibrinogen levels and excess CVD risk in dialysis patients. METHODS: Plasma fibrinogen was measured in 735 dialysis patients a median of 3 months from the start of dialysis therapy by using an automated clot-rate assay. Seven polymorphisms of the FGB gene were determined. Haplotype analysis was conducted using the Phase program to estimate haplotypes, with stratification for race. CVD events were ascertained from medical records. RESULTS: During a median follow-up of 2.1 years, 279 CVD events occurred. Genotype frequencies were in Hardy-Weinberg equilibrium. Four common haplotypes identified were not associated with fibrinogen levels or CVD risk in the entire cohort or after stratification by race. The -455A allele, known to increase gene expression in vitro, was marginally associated with fibrinogen levels only in patients without diabetes (regression coefficient [beta], 20 mg/dL [for +1 copy of the A allele; P = 0.06]), adjusted for age, sex, race, smoking, baseline dialysis modality, comorbidity, and history of diabetes and CVD. Post hoc analysis showed that -249C-->T (defining haplotype 3) was associated with greater fibrinogen levels and CVD risk among patients without diabetes and current smokers. CONCLUSION: The FGB gene likely does not have an important role in determining the variation in elevated plasma fibrinogen levels or excess CVD risk in dialysis patients.

Adult↗
PubMed2004

Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.

Aged↗
PubMed2004

Comparison of haplotype inference methods using genotypic data from unrelated individuals.

OBJECTIVE: Haplotypes are gaining popularity in studies of human genetics because they contain more information than does a single gene locus. However, current high-throughput genotyping techniques cannot produce haplotype information. Several statistical methods have recently been proposed to infer haplotypes based on unphased genotypes at several loci. The accuracy, efficiency, and computational time of these methods have been under intense scrutiny. In this report, our aim was to evaluate haplotype inference methods for genotypic data from unrelated individuals. METHODS: We compared the performance of three haplotype inference methods that are currently in use--HAPLOTYPER, hap, and PHASE--by applying them to a large data set from unrelated individuals with known haplotypes. We also applied these methods to coalescent-based simulation studies using both constant size and exponential growth models. The performance of these methods, along with that of the expectation-maximization algorithm, was further compared in the context of an association study. RESULTS: While the algorithm implemented in the software PHASE was found to be the most accurate in both real and simulated data comparisons, all four methods produced good results in the association study.

Algorithms↗
PubMed2006

Toward understanding MHC disease associations: partial resequencing of 46 distinct HLA haplotypes.

We carried out a resequencing project that examined 552 kb of sequence from each of 46 individual HLA haplotypes representing a diversity of HLA allele types, generating nearly 27 Mb of fully phased genomic sequence. Haplotype blocks were defined extending from telomeric of HLA-F to centromeric of HLA-DP including in total 5186 MHC SNPs. To investigate basic questions about the evolutionary origin of common HLA haplotypes, and to obtain an estimate of rare variation in the MHC, we similarly examined two additional sets of samples. In 19 independent HLA-A1, B8, DR3 chromosomes, the most common HLA haplotype in Northern European Caucasians, variation was found at 11 SNP positions in the 3600-kb region from HLA-A to DR. Partial resequencing of 282 individuals in the gene-dense class III region identified significant variability beyond what could have been detected by linkage to common SNPs.

Cell Line, Transformed↗
PubMed2006

Association of haplotypes of beta2-adrenoceptor polymorphisms with lung function and airway responsiveness in a pediatric cohort.

We evaluated the influence of haplotypes of beta(2)-adrenergic receptor (ADRB2) polymorphisms on lung function and airway responsiveness (AR) in a pediatric cohort recruited before birth and followed up to 11 years of age. The subjects (180) were the participants in a prospective study of lung function and AR. They have been assessed five times (at 1 month, 6 months, 12 months, 6 and 11 years of age) for lung function and AR. The two ADRB2 single nucleotide polymorphisms (SNPs): Arg16Gly and Gln27Glu were genotyped by PCR-RLFP and their haplotypes inferred using the program PHASE. An association between the haplotype arg16gln27 and the prevalence of positive AR was found at age 6 years (P = 0.009). The gly16gln27 haplotype was associated with higher FEV1 (P = 0.015) at age 6 and both higher FEV1 and FVC (P = 0.018 and P = 0.001, respectively) at age 11. In contrast, arg16gln27 was associated with both lower FEV1 and FVC (P = 0.028 and P = 0.011, respectively) at age 11. Children with the gly16gln27 haplotype were less likely to have asthma-ever or doctor-diagnosed asthma at age 11 (OR: 0.38; P = 0.019 and OR: 0.31; P = 0.041, respectively). In conclusion, haplotypes of beta(2)-adrenoceptor polymorphisms are associated with lung function, AR, and asthma susceptibility in childhood.

Airway Resistance↗
PubMed2004

The reliability of haplotyping inference in nuclear families: misassignment rates for SNPs and microsatellites.

Single nucleotide polymorphisms (SNPs) are widely used when investigators try to map complex disease genes. Although biallelic SNP markers are less informative than microsatellite markers, one can increase their information content by using haplotypes. However, assigning haplotypes (i.e., assigning phase) correctly can be problematic in the presence of SNP heterozygosity. For example, a doubly heterozygous individual, with genotype 12, 12, could have haplotypes 1-1/2-2 or 1-2/2-1 with equal probability; in the absence of additional information, there is no way to determine which haplotype is correct. Thus an algorithm that assigns haplotypes to such an individual will assign the wrong one 50% of the time. We have studied the frequency of haplotype misassignments, i.e., haplotypes that are misassigned solely because of inherent marker ambiguity (not because of errors in genotyping or calculation). We examined both SNPs and microsatellite markers. We used the computer programs GENEHUNTER and SIMWALK to assign the haplotypes. We simulated (a) families with 1-5 children, (b) haplotypes involving different numbers of marker loci (3, 5, 7 and 10 loci, all in linkage equilibrium), and (c) different allele frequencies. Misassignment rates are highest (a) in small families, (b) with many SNP loci, and (c) for loci with the greatest heterozygosity (i.e., where both alleles have frequency 0.5). For example, for triads (i.e., one-child families with both parents genotyped), misassignment rates for SNPs can reach almost 50%. Family sizes of 4-5 children are required in order to ensure a misassignment frequency of < or = 5% for ten-SNP haplotypes with allele frequencies of 0.25-0.5. For microsatellites, a family size of at least 2-3 children is necessary to keep haplotyping misassignments < or = 5%. Finally, we point out that it is misleading for a computer program to yield haplotype assignments without indicating that they may have been misassigned, and we discuss the implications of these misassignments for association and linkage analysis.

Chromosome Mapping↗
PubMed2001

A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes.

A stepwise logistic-regression procedure is proposed for evaluation of the relative importance of variants at different sites within a small genetic region. By fitting statistical models with main effects, rather than modeling the full haplotype effects, we generate tests, with few degrees of freedom, that are likely to be powerful for detecting primary etiological determinants. The approach is applicable to either case/control or nuclear-family data, with case/control data modeled via unconditional and family data via conditional logistic regression. Four different conditioning strategies are proposed for evaluation of effects at multiple, closely linked loci when family data are used. The first strategy results in a likelihood that is equivalent to analysis of a matched case/control study with each affected offspring matched to three pseudocontrols, whereas the second strategy is equivalent to matching each affected offspring with between one and three pseudocontrols. Both of these strategies require you be able to infer parental phase (i.e., those haplotypes present in the parents). Families in which phase cannot be determined must be discarded, which can considerably reduce the effective size of a data set, particularly when large numbers of loci that are not very polymorphic are being considered. Therefore, a third strategy is proposed in which knowledge of parental phase is not required, which allows those families with ambiguous phase to be included in the analysis. The fourth and final strategy is to use conditioning method 2 when parental phase can be inferred and to use conditioning method 3 otherwise. The methods are illustrated using nuclear-family data to evaluate the contribution of loci in the HLA region to the development of type 1 diabetes.

Alleles↗
PubMed2002

An MLH1 haplotype is over-represented on chromosomes carrying an HNPCC predisposing mutation in MLH1.

BACKGROUND: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in white populations. These are referred to as A and G types with reference to the A/G polymorphism at IVS14-19. On the basis of preliminary experimental data, we hypothesised that deviations from the expected frequency of these two haplotypes could exist in carriers of disease associated MLH1 germline mutations. METHODS: We assembled a series (n=119) of germline MLH1 mutation carriers in whom phase between the haplotype and the mutation had been conclusively established. Controls, without cancer, were obtained from each contributing centre. Cases and controls were genotyped for the polymorphism in IVS14. RESULTS: Overall, 66 of 119 MLH1 mutations occurred on a G haplotype (55.5%), compared with 315 G haplotypes on 804 control chromosomes (39.2%, p=0.001). The odds ratio (OR) of a mutation occurring on a G rather than an A haplotype was 1.93 (95% CI 1.29 to 2.91). When we compared the haplotype frequencies in mutation bearing chromosomes carried by people of different nationalities with those seen in pooled controls, all groups showed a ratio of A/G haplotypes that was skewed towards G, except the Dutch group. On further analysis of the type of each mutation, it was notable that, compared with control frequencies, deletion and substitution mutations were preferentially represented on the G haplotype (p=0.003 and 0.005, respectively). CONCLUSION: We have found that disease associated mutations in MLH1 appear to occur more often on one of only two known ancient haplotypes. The underlying reason for this observation is obscure, but it is tempting to suggest a possible role of either distant regulatory sequences or of chromatin structure influencing access to DNA sequence. Alternatively, differential behaviour of otherwise similar haplotypes should be considered as prime areas for further study.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Linkage disequilibrium between incompatibility locus region genes in the plant Arabidopsis lyrata.

We have studied diversity in Arabidopsis lyrata of sequences orthologous to the ARK3 gene of A. thaliana. Our main goal was to test for recombination in the S-locus region. In A. thaliana, the single-copy ARK3 gene is closely linked to the non-functional copies of the self-incompatibility loci, and the ortholog in A. lyrata (a self-incompatible species) is in the homologous genome region and is known as Aly8. It is thus of interest to test whether Aly8 sequence diversity is elevated due to close linkage to the highly polymorphic incompatibility locus, as is theoretically predicted. However, Aly8 is not a single-copy gene, and the presence of paralogs could also lead to the appearance of elevated diversity. We established a typing approach based on different lengths of Aly8 PCR products and show that most A. lyrata haplotypes have a single copy, but some have two gene copies, both closely linked to the incompatibility locus, one being a pseudogene. We determined the phase of multiple haplotypes in families of plants from Icelandic and other populations. Different Aly8 sequence types are associated with different SRK alleles, while haplotypes with the same SRK sequences tend to have the same Aly8 sequence. There is evidence of some exchange of sequences between different Aly8 sequences, making it difficult to determine which ones are allelic or to estimate the diversity. However, the homogeneity of the Aly8 sequences of each S-haplotype suggests that recombination between the loci has been very infrequent over the evolutionary history of these populations. Overall, the results suggest that recombination rarely occurs in the interval between the S-loci and Aly8 and that linkage to the S-loci can probably account for the observed high Aly8 diversity.

Arabidopsis↗
PubMed2003

Analysis and exploration of the use of rule-based algorithms and consensus methods for the inferral of haplotypes.

The difficulty of experimental determination of haplotypes from phase-unknown genotypes has stimulated the development of nonexperimental inferral methods. One well-known approach for a group of unrelated individuals involves using the trivially deducible haplotypes (those found in individuals with zero or one heterozygous sites) and a set of rules to infer the haplotypes underlying ambiguous genotypes (those with two or more heterozygous sites). Neither the manner in which this "rule-based" approach should be implemented nor the accuracy of this approach has been adequately assessed. We implemented eight variations of this approach that differed in how a reference list of haplotypes was derived and in the rules for the analysis of ambiguous genotypes. We assessed the accuracy of these variations by comparing predicted and experimentally determined haplotypes involving nine polymorphic sites in the human apolipoprotein E (APOE) locus. The eight variations resulted in substantial differences in the average number of correctly inferred haplotype pairs. More than one set of inferred haplotype pairs was found for each of the variations we analyzed, implying that the rule-based approach is not sufficient by itself for haplotype inferral, despite its appealing simplicity. Accordingly, we explored consensus methods in which multiple inferrals for a given ambiguous genotype are combined to generate a single inferral; we show that the set of these "consensus" inferrals for all ambiguous genotypes is more accurate than the typical single set of inferrals chosen at random. We also use a consensus prediction to divide ambiguous genotypes into those whose algorithmic inferral is certain or almost certain and those whose less certain inferral makes molecular inferral preferable.

Algorithms↗
PubMed2005

Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms.

BACKGROUND: Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA). METHODS: We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. RESULTS: Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth. CONCLUSIONS: Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.

Black or African American↗
PubMed2026

Haplotype-resolved 3D genome maps reveal RNAPII-mediated allelic regulation in hybrid rice.

To understand how the two parental genomes coordinate transcription in hybrids, chromatin architecture must be resolved at the haplotype level. Here, using phased Bridge-Linker Hi-C, we reconstructed a haplotype-resolved three-dimensional (3D) genome of the elite hybrid rice (Oryza sativa) line Shanyou 63 (SY63). We identified extensive allele-specific chromatin conformations. Furthermore, we generated allele-resolved RNAPII ChIA-PET maps and phased transcriptomes to explore how chromatin interactions contribute to allelic regulation. Although maternal and paternal homologs share broadly similar chromatin features, we detected widespread haplotype-biased RNAPII binding and chromatin looping at high resolution. These allele-specific RNAPII-mediated contacts were significantly associated with biased expression. Stronger RNAPII binding on one haplotype promoted the formation of long-range regulatory loops with distal genes, thereby contributing to allele-biased transcription at a subset of loci, even when promoter-proximal RNAPII occupancy was comparable between alleles. These results demonstrate that subtle differences in RNAPII engagement and 3D regulatory wiring between parental haplotypes can reshape transcriptional output in hybrids, providing new insights into the mechanisms underlying the allelic regulation of gene expression.

Allele-specific chromatin interactions↗
PubMed2006

Whole genome association mapping by incompatibilities and local perfect phylogenies.

BACKGROUND: With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed. RESULTS: We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set--the DeltaF508 mutation for cystic fibrosis--where the susceptibility variant is already known--and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene. CONCLUSION: Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.

Chromosome Mapping↗
PubMed2006

BMP-2 gene polymorphisms and osteoporosis: the Rotterdam Study.

UNLABELLED: After reported associations of variations in the BMP-2 gene with osteoporosis in small populations, we studied the association of the BMP-2 gene polymorphisms Ser37Ala and Arg190Ser with osteoporosis in 6353 men and women from the Rotterdam Study. We did not observe an association of these variants with BMD, bone loss, hip structural analysis parameters, and fracture risk. INTRODUCTION: Bone morphogenetic protein 2 (BMP-2) plays a role in osteoblast differentiation. BMP-2 gene variation has previously been associated with osteoporosis in various small populations, but current evidence remains inconclusive about the exact association with osteoporosis. Therefore, we studied the association of two polymorphisms located in the BMP-2 gene (Ser37Ala and Arg190Ser) and haplotypes defined by these polymorphisms with BMD, rates of bone loss, parameters of hip structural analysis (HSA), and fractures in the Rotterdam Study, a large prospective cohort study of diseases in the elderly. MATERIALS AND METHODS: Databases were searched for polymorphisms and haplotype blocks in the BMP-2 gene region. Allele frequencies for Ser37Ala and Arg190Ser were determined in 60 blacks and 110 Chinese from Coriell panels. Genotype data on Ser37Ala and Arg190Ser were available for 6353 individuals from the Rotterdam Study population. Haplotype alleles defined by Ser37Ala and Arg190Ser were inferred using PHASE software. Genotype and haplotype analyses for BMD (measured at the lumbar spine and femoral neck), bone loss per year (measured at the femoral neck), and HSA were performed using AN(C)OVA. Fractures were analyzed using a Cox proportional-hazards model and logistic regression. All outcomes were adjusted for age, height, and weight. RESULTS: Allele frequencies were 2.5% for Ala37 and 40.2% for Ser190, whereas haplotype allele frequencies were 57.28% (Ser37Arg190), 40.19% (Ser37Ser190), 2.50% (Ala37Arg190), and 0.02% (Ala37Ser190). For BMD, bone loss, HSA outcomes, and (incident) fractures, no differences could be seen between genotype and haplotype groups. CONCLUSIONS: In this large population-based cohort of Dutch whites, we conclude that the BMP-2 Ser37Ala and Arg190Ser polymorphisms or haplotypes thereof are not associated with parameters of osteoporosis.

Aged↗
PubMed1990

Haplotype of multiple polymorphisms resolved by enzymatic amplification of single DNA molecules.

We have developed a reliable method for the direct resolution of haplotypes or linkage phase from individuals who are multiply heterozygous in a given genomic region. The method is based on single-molecule dilution (SMD) of genomic template and amplification via biphasic polymerase chain reaction (booster PCR). We have verified the feasibility of the SMD method for a highly polymorphic region within the beta-globin cluster by analysis of triply heterozygous individuals of known haplotype. This approach should be useful in many studies in population or evolutionary genetics and in a variety of clinical settings.

Base Sequence↗
PubMed2006

Identification of polymorphisms and balancing selection in the male infertility candidate gene, ornithine decarboxylase antizyme 3.

BACKGROUND: The antizyme family is a group of small proteins that play a role in cell growth and division by regulating the biosynthesis of polyamines (putrescine, spermidine, spermine). Antizymes regulate polyamine levels primarily through binding ornithine decarboxylase (ODC), an enzyme key to polyamine production, and targeting ODC for destruction by the 26S proteosome. Ornithine decarboxylase antizyme 3 (OAZ3) is a testis-specific antizyme paralog and the only antizyme expressed in the mid to late stages of spermatogenesis. METHODS: To see if mutations in the OAZ3 gene are responsible for some cases of male infertility, we sequenced and evaluated the genomic DNA of 192 infertile men, 48 men of known paternity, and 34 African aborigines from the Mbuti tribe in the Democratic Republic of the Congo. The coding sequence of OAZ3 was further screened for polymorphisms by SSCP analysis in the infertile group and an additional 250 general population controls. Identified polymorphisms in the OAZ3 gene were further subjected to a haplotype analysis using PHASE 2.02 and Arlequin 2.0 software programs. RESULTS: A total of 23 polymorphisms were identified in the promoter, exons or intronic regions of OAZ3. The majority of these fell within a region of less than two kilobases. Two of the polymorphisms, -239 A/G in the promoter and 4280 C/T, a missense polymorphism in exon 5, may show evidence of association with male infertility. Haplotype analysis identified 15 different haplotypes, which can be separated into two divergent clusters. CONCLUSION: Mutations in the OAZ3 gene are not a common cause of male infertility. However, the presence of the two divergent haplotypes at high frequencies in all three of our subsamples (infertile, control, African) suggests that they have been maintained in the genome by balancing selection, which was supported by a test of Tajima's D statistic. Evidence for natural selection in this region implies that these haplotypes may be associated with a trait other than infertility. This trait may be related to another function of OAZ3 or a region in tight linkage disequilibrium to the gene.

Base Sequence↗
PubMed2005

Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians.

OBJECTIVES: To investigate the association of (i) seven SNPs and SNP haplotypes in the phase II conjugating enzyme N-acetyl transferase 2 gene; and (ii) slow acetylator phenotype, with the development of young onset (YO) and late onset (LO) Parkinson's disease (PD) among Indians. METHODS: A total of 267 cases (132 YOPD, age at onset < or =40 years; 135 LOPD, age at onset >40 years) and 324 age and sex matched controls (132 for YOPD and 192 for LOPD) were genotyped for NAT2 SNPs. Allelic, genotypic and haplotypic association was tested by chi2 using a case-control approach. Chi2 test of association of acetylation phenotype (by genotype) with PD was also carried out. RESULTS: Of the seven SNPs genotyped, SNP191 was monomorphic and therefore, not included for analysis. With SNPs 590 and 857 a significant allelic [OR (95% CI) 4.147 (2.28-7.54) for A allele and 2.565 (1.34-4.92) for A allele, respectively] and genotypic [OR (95% CI) 0.27 (0.14-0.52) for GG and 0.35 (0.174-0.712) for GG, respectively] association with YOPD was observed. There was a significant allelic and genotypic association of SNP 282 with LOPD [chi2 = 8.92, P = 0.003 and chi2 = 10.2, P = 0.006, respectively]. There was also a significant association of protective and predisposing haplotypes TCGG and TCAG [OR (95% CI) 0.446 (0.31-0.63) and 3.742 (2.0-6.99), respectively] with YOPD and predisposing haplotype TCGA [OR (95% CI) 3.214 (1.43-7.22)] with LOPD. Slow acetylator phenotype was significantly associated with YOPD [OR (95% CI) 2.32 (1.2-4.48)]. CONCLUSION: Specific SNPs and SNP haplotypes in NAT2 and slow acetylator phenotype are significantly associated with YOPD and to a lesser extent with LOPD among Indians.

Acetylation↗
PubMed1995

Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers.

In an affected-sib-pair study, the parents are often unavailable for typing, particularly for diseases of late onset. In many cases, however, it is possible to sample unaffected siblings. It is therefore desirable to assess the contribution of such siblings to the power of such a study. The likelihood ratio introduced by Risch and improved by Holmans was extended to incorporate data from unaffected siblings. Tests based on two likelihoods were considered: the full likelihood of the data, based on the identity-by-descent (IBD) sharing states of the entire sibship, and a pseudolikelihood based on the IBD sharing states of the affected pair only, using the unaffected siblings to infer parental genotypes. The latter approach was found to be more powerful, except when penetrance was high. Typing an unaffected sibling, or just one parent, was found to give only a small increase in power except when the PIC of the marker was low. Even then, typing an unaffected relative increased the overall number of individuals that had to be typed to achieve a given power. If there is no highly informative marker locus in the area under study, it may be possible to "build" one by combining the alleles from two or more neighboring tightly linked loci into haplotypes. Typing two loci gave a sizeable power increase over a single locus, but typing further loci gave much smaller gains. Building haplotypes will introduce phase uncertainties, with the result that such a system will yield less power than will a single locus with the same number of alleles. This power loss was small, however, and did not affect the conclusions regarding the worth of typing unaffected relatives.

Alleles↗