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PubMed2005

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition.

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

Chromosomes, Human, Pair 17↗

PubMed2006

Computation of haplotypes on SNPs subsets: advantage of the "global method".

BACKGROUND: Genetic association studies aim at finding correlations between a disease state and genetic variations such as SNPs or combinations of SNPs, termed haplotypes. Some haplotypes have a particular biological meaning such as the ones derived from SNPs located in the promoters, or the ones derived from non synonymous SNPs. All these haplotypes are "subhaplotypes" because they refer only to a part of the SNPs found in the gene. Until now, subhaplotypes were directly computed from the very SNPs chosen to constitute them, without taking into account the rest of the information corresponding to the other SNPs located in the gene. In the present work, we describe an alternative approach, called the "global method", which takes into account all the SNPs known in the region and compare the efficacy of the two "direct" and "global" methods. RESULTS: We used empirical haplotypes data sets from the GH1 promoter and the APOE gene, and 10 simulated datasets, and randomly introduced in them missing information (from 0% up to 20%) to compare the 2 methods. For each method, we used the PHASE haplotyping software since it was described to be the best. We showed that the use of the "global method" for subhaplotyping leads always to a better error rate than the classical direct haplotyping. The advantage provided by this alternative method increases with the percentage of missing genotyping data (diminution of the average error rate from 25% to less than 10%). We applied the global method software on the GRIV cohort for AIDS genetic associations and some associations previously identified through direct subhaplotyping were found to be erroneous. CONCLUSION: The global method for subhaplotyping can reduce, sometimes dramatically, the error rate on patient resolutions and haplotypes frequencies. One should thus use this method in order to minimise the risk of a false interpretation in genetic studies involving subhaplotypes. In practice the global method is always more efficient than the direct method, but a combination method taking into account the level of missing information in each subject appears to be even more interesting when the level of missing information becomes larger (>10%).

Apolipoproteins E↗

PubMed2004

Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk: a case control study.

INTRODUCTION: Oestrogen receptor alpha, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor alpha gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C --> T, 1557 cases and 1512 controls; c.454-351A --> G, 1556 cases and 1512 controls; c.729C --> T, 1562 cases and 1513 controls; c.975C --> G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A --> G or c.454-397C --> T and c.975C --> G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A --> G and c.975C --> G haplotype entailed an OR of 1.19 (95% CI 1.06-1.33) and two copies with an OR of 1.42 (95% CI 1.15-1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C --> T and c.975C --> G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women.

Aged↗

PubMed2025

UAV-based multispectral image analysis revealed stay-green haplotypes in wheat specific for different soil nitrogen levels.

BACKGROUND: The so-called stay-green trait, a delay in onset and progression of leaf senescence, is associated with slower chlorophyll degradation and higher photosynthesis rates during maturation resulting in higher crop yields. Understanding the genetic and physiological basis of the stay-green trait and breeding cultivars with stable stay-green behaviour across a range of different nitrogen (N) conditions and specifically under low N availability can contribute to ensuring wheat yields and reducing N fertilizer application. The goal of this study was therefore to identify haplotypes associated with high stay-green capacity under different N availability conditions in wheat. A diverse set of 221 wheat cultivars was grown under three different N levels and phenotyped by uncrewed aerial vehicle (UAV)-based multispectral imaging to characterise genetic and environmental variation in stay-green. Haplotypes associated with stay-green were identified across N levels and specifically under low N availability. RESULTS: The plant senescence reflectance index (PSRI) calculated from multispectral images was identified as the most specific stay-green indicator allowing for differentiation of genotypic effects due to its greater sensitivity to senescence-related changes in pigment composition and its higher reliability. We found genetic variance for stay-green and a consistent genetic correlation between stay-green and grain yield at all imaging dates and N levels within the utilised diversity panel confirming its potential as a future breeding target. Haplotype analyses revealed two favourable major allele haplotypes present in 95% of the stay-green cultivars, i.e. the top 25% of the diversity set based on PSRI values, which significantly enhance stay-green performance and grain yield. In addition, we identified a favourable minor allele haplotype specifically associated with stay-green under low N availability and capable of further increasing stay-green and grain yield when stacked onto the two favourable major allele haplotypes. CONCLUSIONS: The newly identified stay-green haplotypes can be further used for fine-mapping and identifying the underlying genes as well as for selecting for higher stay-green and grain yield. Thereby our results can contribute to improving our understanding of the complex genetic regulation underlying stay-green in different environments and to breeding new cultivars with stable performance across N levels or specifically under low N availability.

Triticum↗

PubMed2000

Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes.

The incidence of type 1 diabetes in Korea is less than 1/10th of that in the United States, and it has been suggested that human leukocyte antigen (HLA) alleles of Asian patients associated with diabetes differ from those of Caucasians. In this study we analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. We performed HLA DR and DQ typing of 158 type 1 diabetic patients in a case control study, 140 nondiabetic subjects from the same geographical area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the two populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families (r = 0.8; P: < 10(-)(4)). Allowing for ethnic differences in allelic associations due to different frequencies of DRB1 and DQB1 haplotypes (linkage disequilibrium), these data show, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of type 1 diabetes.

Adolescent↗

PubMed1993

Multiple sclerosis is associated with genes within or close to the HLA-DR-DQ subregion on a normal DR15,DQ6,Dw2 haplotype.

The HLA class II haplotype DR15,DQ6,Dw2 is associated with an increased risk for multiple sclerosis (MS). It has previously been shown that this haplotype extends to the HLA-DQA2 locus but not to the HLA-DP subregion. We report the distribution in 148 MS patients and 158 healthy controls of Taq I restriction fragments of the C4, cytochrome P-21 (CYP21), and HLA-B genes. Approximately 90% of the DR15,DQ6,Dw2 haplotypes extend to the C4/CYP21 loci and 50% to the HLA-B locus, indicated by a significant association of the haplotype with restriction fragments of these loci. However, there was no independent association in MS patients with these genes. This indicates that the susceptibility to MS is coded for by genes within or close to the HLA-DR-DQ subregion. Furthermore, the delineation of the DR15,DQ6,Dw2 haplotype is very similar in MS patients and control subjects. This observation supports the hypothesis that "normal" genes, common to all carriers of the DR15,DQ6,Dw2 haplotype, confer the increased genetic susceptibility to MS associated with this haplotype.

Blotting, Southern↗

PubMed2000

An extended 5'-tau susceptibility haplotype in progressive supranuclear palsy.

OBJECTIVE: To confirm the association of an extended 5'-tau haplotype on chromosome 17q with the disease phenotype in clinically ascertained individuals with sporadic progressive supranuclear palsy (PSP). BACKGROUND: PSP is a neurodegenerative disease with parkinsonian signs accompanied by vertical supranuclear palsy and tau pathologic features. Previously, we documented the complete segregation of an extended 5'-tau haplotype consisting of four single nucleotide polymorphisms (SNP) with the disease phenotype in sporadic PSP. This study was conducted in an independent cohort to confirm these results and to improve the statistical power of the data. DESIGN AND METHODS: Direct sequencing and restriction enzyme digests were used to analyze four SNP in tau Exons 1, 4A, and 8. These contiguous SNP were used to reconstruct an extended 5'-tau haplotype in 52 affected and 54 age-matched control individuals. RESULTS: The four SNP formed two homozygous 5'-tau haplotypes (HapA and HapC) or a heterozygous genotype. Fifty-one (98%) patients with PSP had HapA; one (2%) with a later onset was heterozygous; and none had HapC. These PSP haplotype frequencies were different (p < 0.00001) from those of the age-matched control group, in which 18 (33%) people had HapA; 26 (48%) were heterozygous; and 10 (19%) had HapC. The extended 5'-tau haplotype, HapA, had a high sensitivity (98%) and a moderate specificity (67%) as a marker for PSP. CONCLUSIONS: A 5'-tau susceptibility haplotype may be a sensitive marker for sporadic PSP and a genetic defect in, or closely linked to, tau may contribute to the cause of PSP.

Chromosomes, Human, Pair 17↗

PubMed2006

Haplotype block structure is conserved across mammals.

Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.

Animals↗

PubMed2025

Knockdown-resistance (kdr) mutations in Indian Aedes aegypti populations: Lack of recombination among haplotypes bearing V1016G, F1534C, and F1534L kdr alleles.

BACKGROUND: Knockdown resistance (kdr) mutations in the voltage-gated sodium channel (VGSC) gene are a key mechanism of insecticide resistance in mosquitoes. In Asian Aedes aegypti populations two main VGSC haplogroups with kdr mutations have been identified: one carrying the F1534C mutation and another with V1016G and/or S989P mutations. Previous functional studies have demonstrated that these three mutations on a single haplotype confer up to a 1100-fold increase in pyrethroid resistance, underscoring the importance of monitoring these triple mutations in distinct populations. This study investigates the prevalence of kdr mutations in Indian populations and explores the linkage association between these mutations and two distinct conserved types of introns located between exons 20 and 21. METHODS: Ae. aegypti specimens collected from eight different locations were genotyped for kdr alleles and intron (between exons 20 and 21) haplotypes using PCR-based assays. Representative samples underwent DNA sequencing of VGSC regions. RESULTS: Five kdr mutations namely S989P, V1016G, T1520I, F1534C, and F1534L were identified, each exhibiting varying distribution and frequencies across different geographical regions. Two distinct and stably-diverged intron haplotypes, designated as intron-A and intron-B, were identified between exons 20 and 21. Seven haplotypes, including two wild-type variants, were observed among Indian populations. The kdr-bearing haplotypes can be classified into three distinct haplogroups: haplogroup G (V1016G with/or without S989P and with intron-A), haplogroup L (F1534L and intron-A), and haplogroup C (F1534C with/or without T1520I and with intron-B). Importantly, no evidence of recombination within Indian populations was detected among these three haplogroups. CONCLUSIONS: Five kdr mutations were identified in the VGSC of Indian Ae. aegypti populations, each showing a definitive linkage with one of the two types of intron haplotypes. The lack of recombination among haplogroups bearing 1016G with 989P, 1534C and 1534L mutations suggests that the most potent insecticide resistance haplotype, bearing the triple kdr mutation, is currently absent. This finding has significant operational implications, as it may indicate that current vector control measures remain effective against these populations, potentially delaying the emergence of highly resistant phenotypes.

Animals↗

PubMed2025

A Swedish genome-wide haplotype association analysis identifies novel candidate loci associated with endometrial cancer risk.

Genome-wide association studies [GWAS] have identified a limited number of endometrial cancer risk loci by analyzing single nucleotide polymorphisms [SNPs]. We hypothesized that analyzing haplotypes rather than SNPs could provide novel and more detailed information on genetic cancer susceptibility loci. To examine the association of a SNP or haplotype with endometrial cancer risk we performed a two-stage haplotype GWAS. The discovery GWAS included a sub-cohort of 1,116 Swedish endometrial cancer cases and 5,021 controls from previously published GWAS data. A sliding window analysis was employed with window sizes of 1-25 SNPs using a logistic regression model. The Swedish haplotype analysis identified 15 novel candidate risk loci (2q31.1, 4p16.1, 4p15.31, 6q13, 7p21.1, 9p13.3, 10q26.3, 11q21, 12q13.11, 13q12.11, 15q13.3, 16q24.3, 19q13.32, 20p12.3 and 22q13.2) with OR ranging from 1.6 to 3.3 and p-values from 4.25 × 10-8 to 9.86 × 10-15. A second replication haplotype analysis of the Swedish novel loci was performed using two cohorts from Belgium and Germany. In spite of small sample sizes in the replication cohorts, there was still support for most loci with positive ORs. In addition, the findings in the two European cohorts motivates further studies to search for founder haplotypes. These novel findings suggested that endometrial cancer loci, identified through haplotype analysis, conferred a higher risk compared to previous single-variant GWAS.

Humans↗

PubMed2004

Beta 2-adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.

STUDY OBJECTIVE: To investigate the relationship of common single nucleotide polymorphisms (SNPs) of the beta(2)-adrenergic receptor (AR) gene at codons 16 and 27, and the intermediate phenotype of airways hyperresponsiveness. DESIGN: A case-control study in 543 white men (152 case patients and 391 control subjects), who were nested in an ongoing longitudinal cohort. SETTING: Subjects were selected from the Normative Aging Study, an ongoing longitudinal cohort of healthy aging. PARTICIPANTS: Case patients were defined as those having a positive response to methacholine challenge testing. Control subjects were selected among those who did not have a diagnosis of asthma and who had no response to methacholine. RESULTS: There was a trend for an association of the Arg16 SNP genotype with airways hyperresponsiveness (odds ratio, 1.25; 95% confidence interval, 0.96 to 1.64 [in an additive model]). In stratified analyses, the effect of the Arg16 variant was seen mainly among nonsmokers. Smokers had increased risks for airway hyperresponsiveness regardless of genotype at either SNP. Using a program to estimate haplotype frequencies, three common haplotypes were identified. Adjusting for age, baseline FEV(1), serum IgE level, and smoking status, the Gly16/Gln27 haplotype was negatively associated with airways hyperresponsiveness in the full complement of case patients and control subjects (score statistic, - 2.43; p = 0.02). The effect of the beta(2)-AR haplotypes was much stronger among lifelong nonsmokers, among whom the Gly16/Gln27 haplotype remained negatively associated with airways hyperresponsiveness (score statistic, - 3.114; p = 0.002), whereas the Arg16/Gln27 haplotype was positively associated with airways hyperresponsiveness (score statistic, 3.142; p = 0.002). No effects were seen among ever-smokers. CONCLUSIONS: In this cohort of middle-aged to older white men, beta(2)-AR polymorphisms were associated with airways hyperresponsiveness, particularly among lifelong nonsmokers. Our results illustrate an instance in which greater power is obtained by performing haplotype analyses as opposed to single SNP analysis.

Adult↗

PubMed2001

The relative power of SNPs and haplotype as genetic markers for association tests.

Identifying the polymorphisms that contribute to disease predisposition and drug response is a major goal of the post-genome era. Single nucleotide polymorphisms (SNPs) in disease-related genes are often used as candidates in the search for causative variations. Association tests based on haplotypes have also been suggested and, at times, have provided greater statistical power than tests based on the underlying SNPs. Here we review the statistical model traditionally used to describe association studies for complex traits and derive novel results for the relative power of SNP-based and haplotype-based tests of association. In the model, a set of independent SNP-based variations, some of which contribute to a measured phenotype, may be used as markers directly or may be organised into haplotype markers. Provided that the marker set includes all the causative SNPs, we find a simple rule for the relative power of SNP and haplotype markers: SNP-based tests have greater power when the number of causative SNPs (a subset of the total set of SNPs) is smaller than the total number of haplotypes. Furthermore, we find that regression tests for the simple main effect of each haplotype are generally more powerful than ANOVA tests applied to haplotype pairs. A review of recent literature supports our findings.

Analysis of Variance↗

PubMed2005

Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response.

OBJECTIVES: The aim of this study was to investigate the association of the complex haplotype system of the adenosine triphosphate-binding cassette B1 (ABCB1) gene with the epilepsy treatment response. METHODS AND RESULTS: Ten polymorphisms were genotyped in 108 drug-resistant epileptic patients, 223 seizure-free patients and 287 normal controls. Highly significant linkage disequilibrium was shown among exon 12 C1236T, exon 21 G2677T and exon 26 C3435T. Haplotypic analysis demonstrated that patients with the CGC, TGC, and TTT haplotypes were more likely to be drug resistant. Further analysis of haplotype combinations demonstrated that drug-resistant patients tended to have the CGC/CGC, CGC/TGC, CGC/TTT, and TGC/TTT haplotype combinations over the seizure-free patients and controls (all p-values < 0.0001). In contrast, patients with the TTC/TTC, TTC/CGT, TTC/TGT, CGT/CGT and TGT/CGT haplotype combinations were more likely to be seizure-free (all p-values<0.0001 except CGT/CGT [p=0.0063]). CONCLUSION: Our results showed that the three loci, C1236T, G2677T and C3435T, jointly influenced the treatment response for epileptic patients. They should be regarded together as a complex polymorphic drug-response system. These findings suggest that examination of the haplotypes of the three loci could be useful in predicting drug resistance in epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

The impact of using related individuals for haplotype reconstruction in population studies.

Recent studies have highlighted the dangers of using haplotypes reconstructed directly from population data for a fine-scale mapping analysis. Family data may help resolve ambiguity, yet can be costly to obtain. This study is concerned with the following question: How much family data (if any) should be used to facilitate haplotype reconstruction in a population study? We conduct a simulation study to evaluate how changes in family information can affect the accuracy of haplotype frequency estimates and phase reconstruction. To reconstruct haplotypes, we introduce an EM-based algorithm that can efficiently accommodate unrelated individuals, parent-child trios, and arbitrarily large half-sib pedigrees. Simulations are conducted for a diverse set of haplotype frequency distributions, all of which have been previously published in empirical studies. A wide variety of important results regarding the effectiveness of using pedigree data in a population study are presented in a coherent, unified framework. Insight into the different properties of the haplotype frequency distribution that can influence experimental design is provided. We show that a preliminary estimate of the haplotype frequency distribution can be valuable in large population studies with fixed resources.

Algorithms↗

PubMed2005

Optimal haplotype structure for linkage disequilibrium-based fine mapping of quantitative trait loci using identity by descent.

A linkage disequilibrium-based method for fine mapping quantitative trait loci (QTL) has been described that uses similarity between individuals' marker haplotypes to determine if QTL alleles are identical by descent (IBD) to model covariances among individuals' QTL alleles for a mixed linear model. Mapping accuracy with this method was found to be sensitive to the number of linked markers that was included in the haplotype when fitting the model at a putative position of the QTL. The objective of this study was to determine the optimal haplotype structure for this IBD-based method for fine mapping a QTL in a previously identified QTL region. Haplotypes consisting of 1, 2, 4, 6, or all 10 available markers were fit as a "sliding window" across the QTL region under ideal and nonideal simulated population conditions. It was found that using haplotypes of 4 or 6 markers as a sliding "window" resulted in the greatest mapping accuracy under nearly all conditions, although the true IBD state at a putative QTL position was most accurately predicted by IBD probabilities obtained using all markers. Using 4 or 6 markers resulted in greater discrimination of IBD probabilities between positions while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Fitting IBD probabilities on the basis of a single marker resulted in the worst mapping accuracy under all conditions because it resulted in poor accuracy of IBD probabilities. In conclusion, for fine mapping using IBD methods, marker information must be used in a manner that results in sensitivity of IBD probabilities to the putative position of the QTL while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Contrary to expectation, use of haplotypes of 4-6 markers to derive IBD probabilities, rather than all available markers, best fits these criteria. Thus for populations similar to those simulated here, optimal mapping accuracy for this IBD-based fine-mapping method is obtained with a haplotype structure including a subset of all available markers.

Crosses, Genetic↗

PubMed2006

Test of association between haplotypes and phenotypes in case-control studies: examination of validity of the application of an algorithm for samples from cohort or clinical trials to case-control samples using simulated and real data.

The use of haplotype information in case-control studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. We examined the validity of the application of the likelihood-based algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from case-control studies. This algorithm was implemented in a computer program called PENHAPLO. In this program, haplotype frequencies and penetrances are estimated using the expectation-maximization algorithm, and the haplotype-phenotype association is tested using the generalized likelihood ratio. We show that this algorithm was useful not only for cohort studies but also for case-control studies. Simulations under the null hypothesis (no association between haplotypes and phenotypes) have shown that the type I error rates were accurately estimated. The simulations under alternative hypotheses showed that PENHAPLO is a robust method for the analysis of the data from case-control studies even when the haplotypes were not in HWE, although real penetrances cannot be estimated. The power of PENHAPLO was higher than that of other methods using the likelihood-ratio test for the comparison of haplotype frequencies. Results of the analysis of real data indicated that a significant association between haplotypes in the SAA1 gene and AA-amyloidosis phenotype was observed in patients with rheumatoid arthritis, thereby suggesting the validity of the application of PENHAPLO for case-control data.

Algorithms↗

PubMed2006

Interleukin-10 haplotype frequencies in children with gingivitis.

BACKGROUND: Polymorphisms in the promoter region of the interleukin (IL)-10 gene have been identified at positions -1082 (G-->A), -819 (C-->T), and -592 (C-->A). Linkage disequilibrium between alleles -819*C, and -592*C was observed. A previous study addressed the association between the -1082*A allele and gingivitis in white Caucasian children. The aim of this case-control study was to test whether differences could exist between children with and without gingivitis in the distribution of IL-10 alleles and haplotypes at positions -1082, -819, and -592. METHODS: A total of 248 subjects aged 8 to 12 years from the University Dental Hospital of Manchester were enrolled in this study. According to gingival and bleeding on probing indices, 84 children were classified as controls and 164 as children with gingivitis. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used for genotyping IL-10 polymorphisms. Allele and haplotype frequencies were calculated by direct counting and by a haplotype frequency estimation (EH) program. Differences between subjects with gingivitis and controls in the frequency of haplotypes were determined by a chi2 test of homogeneity. RESULTS: The GCC/GCC genotype, which has been associated with increased production of IL-10, was significantly more frequent in controls than in children with gingivitis (36% versus 23%) (P=0.036). In addition, there was a marginally significant difference between controls and cases in the frequency of haplotypes (P=0.06). The GCC haplotype was more frequent in controls than in children with gingivitis (60% versus 50%). In contrast, the ACC and ATA haplotypes were more frequent in children with gingivitis (27% and 23% versus 19% and 21% in controls). CONCLUSION: These findings suggest that IL-10 gene promoter polymorphisms could have an active role in the pathogenesis of gingivitis in Caucasian children.

Alleles↗

PubMed2005

Genetic variations and haplotypes of UGT1A4 in a Japanese population.

Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.

Arrhythmias, Cardiac↗