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Results for “Haplotype structures”

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PubMed2006

Origin of the prevalent SFTPB indel g.1549C > GAA (121ins2) mutation causing surfactant protein B (SP-B) deficiency.

The SFTPB gene indel g.1549C > GAA (121ins2) accounts for about 2/3 of the mutant alleles underlying complete surfactant protein B deficiency. It is unclear, however, whether its prevalence is due to recurrent mutation or a founder effect. The underlying mutational mechanism was therefore sought through the analysis of local DNA sequence complexity. A relatively complex two-step process was proposed: the first step involving slipped mispairing mediated by a direct repeat and generating an AGAA micro-insertion, the second step involving hairpin loop resolution resulting in a CA micro-deletion. The possibility of a founder effect was then assessed by typing 8 intragenic SNPs in 17 independent 121ins2 chromosomes from 10 probands, with parental non-121ins2 chromosomes serving as controls. The 121ins2 chromosomes were assigned to three discrete haplotypes, whilst control chromosomes were distributed between 10 of the 11 observed parental haplotypes. The 121ins2 mutation was in strong and significant linkage disequilibrium (LD) with the tightly linked marker g.1580T/C (|D'| = 1; P approximately 0.024), although only moderate LD was found with the rest of the locus (|D'| approximately 0.54; P approximately 0.136). Data on haplotype structure and the locus LD pattern, obtained from 81 independent Western-European chromosomes, were consistent with the three mutation-bearing haplotypes having originated from a common ancestor by recombination. Interestingly, all families harboring the 121ins2 indel had ancestors from a region of Northwestern Europe populated by Frankish/Saxon migration. Taken together, these data are consistent with the view that an indel mutation occurred on a relatively common SFTPB haplotype and now accounts for the majority of (and possibly all) extant 121ins2 chromosomes.

Base Sequence↗

PubMed2006

Identification of cis- and trans-acting factors possibly modifying the risk of epimutations on chromosome 15.

In the majority of patients with a chromosome 15 imprinting defect (ID) causing Prader-Willi syndrome (PWS) or Angelman syndrome (AS), the defect is a primary epimutation that occurred spontaneously in the absence of a DNA mutation. We have investigated whether common DNA sequence variants in the bipartite imprinting centre (IC) are associated with an increased susceptibility to imprinting defects. We have determined the haplotype structure of the IC and found that the two IC elements called 'PWS-SRO' and 'AS-SRO' lie on separate haplotype blocks. To identify susceptible IC sequence variants, we have used the transmission disequilibrium test. While we did not observe preferential transmission of a paternal allele or haplotype in 41 PWS-ID trios, we found a trend for preferential maternal transmission of one AS-SRO haplotype (H-AS3) in 48 AS-ID trios (P=0.058) and could identify two sequence variants in H-AS3 that are responsible for this effect. We also obtained tentative evidence that homozygosity for the 677C>T variant of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on chromosome 1 might increase the risk of a maternal imprinting defect: the frequency of the TT genotype was significantly higher in the mothers of the AS patients with an imprinting defect than in the patients' fathers or the general population (P=0.028). Our findings suggest that women with the IC haplotype H-AS3 or homozygosity for the MTHFR 677C>T variant may have an increased risk of conceiving a child with an imprinting defect, although the absolute risk is low.

Alleles↗

PubMed2003

Genomewide distribution of high-frequency, completely mismatching SNP haplotype pairs observed to be common across human populations.

Knowledge of human haplotype structure has important implications for strategies of disease-gene mapping and for understanding human evolutionary history. Many attributes of SNPs and haplotypes appear to exhibit highly nonrandom behavior, suggesting past operation of selection or other nonneutral forces. We report the exceptional abundance of a particular haplotype pattern in which two high-frequency haplotypes have different alleles at every SNP site (hence the name "yin yang haplotypes"). Analysis of common haplotypes in 62 random genomic loci and 85 gene coding regions in humans shows that the proportion of the genome spanned by yin yang haplotypes is 75%-85%. Population data of 28 genomic loci in Drosophila melanogaster reveal a similar pattern. The high recurrence (>/=85%) of these haplotype patterns in four distinct human populations suggests that the yin yang haplotypes are likely to predate the African diaspora. The pattern initially appeared to suggest deep population splitting or maintenance of ancient lineages by selection; however, coalescent simulation reveals that the yin yang phenomenon can be explained by strictly neutral evolution in a well-mixed population.

Algorithms↗

PubMed2001

Evidence for selection at the fused1 locus of Drosophila americana.

We analyze genetic variation at fused1, a locus that is close to the centromere of the X chromosome-autosome (X/4) fusion in Drosophila americana. In contrast to other X-linked and autosomal genes, for which a lack of population subdivision in D. americana has been observed at the DNA level, we find strong haplotype structure associated with the alternative chromosomal arrangements. There are several derived fixed differences at fused1 (including one amino acid replacement) between two haplotype classes of this locus. From these results, we obtain an estimate of an age of approximately 0.61 million years for the origin of the two haplotypes of the fused1 gene. Haplotypes associated with the X/4 fusion have less DNA sequence variation at fused1 than haplotypes associated with the ancestral chromosome arrangement. The X/4 haplotypes also exhibit clinal variation for the allele frequencies of the three most common amino acid replacement polymorphisms, but not for adjacent silent polymorphisms. These patterns of variation are best explained as a result of selection acting on amino acid substitutions, with geographic variation in selection pressures.

Animals↗

PubMed2005

Evidence of balancing selection at the HLA-G promoter region.

HLA-G is a class Ib HLA gene with unique tissue expression pattern and immunomodulatory properties. Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation. Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing. In all three populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and a genealogy with two common haplotypes separated by deep branches, features that are suggestive of balancing selection acting in this region. Comparisons to HLA-A and a pseudogene, HLA-J, suggested that the observed pattern of sequence variation in the HLA-G promoter region is not likely due to other selected HLA genes. We suggest that the mechanism for this selection is related to the highly regulated expression pattern of HLA-G and that high- and low-expressing promoters may be favored under temporally and/or spatially varying selective pressures.

Black or African American↗

PubMed2006

A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans.

BACKGROUND: Sitosterolemia is an autosomal recessive disorder that maps to the sitosterolemia locus, STSL, on human chromosome 2p21. Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ABCG5 and ABCG8 are thought to have evolved by gene duplication event and are arranged in a head-to-head configuration. We report here a detailed characterization of the STSL in Caucasian and African-American cohorts. METHODS: Caucasian and African-American DNA samples were genotypes for polymorphisms at the STSL locus and haplotype structures determined for this locus RESULTS: In the Caucasian population, 13 variant single nucleotide polymorphisms (SNPs) were identified and resulting in 24 different haplotypes, compared to 11 SNPs in African-Americans resulting in 40 haplotypes. Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Allele frequencies of SNPs varied also between these populations. CONCLUSION: We confirmed that despite their close proximity to each other, significantly more variations are present in ABCG8 compared to ABCG5. Pairwise D' values showed wide ranges of variation, indicating some of the SNPs were in strong linkage disequilibrium (LD) and some were not. LD was more prevalent in Caucasians than in African-Americans, as would be expected. These data will be useful in analyzing the proposed role of STSL in processes ranging from responsiveness to cholesterol-lowering drugs to selective sterol absorption.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2003

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations.

The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.

Gambia↗

PubMed2005

Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis.

BACKGROUND: The PROGINS allele of the progesterone receptor (PGR) gene has been associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. We set out to refine the association between common variation at the PGR gene locus and these two diseases. METHODS: We characterized the haplotype structure of the PGR gene by genotyping 54 single-nucleotide polymorphisms (SNPs) in 349 women. We then selected a subset of 17 haplotype-tagging SNPs that captured variation across the locus and typed them in 267 ovarian cancer case patients and 397 control subjects from two case-control studies and in 1715 breast cancer case patients and 2505 control subjects from a cohort study. RESULTS: The PGR locus was characterized by four blocks of strong linkage disequilibrium. Two SNPs in block 4 were associated with an increased risk of ovarian cancer among homozygous carriers as compared with noncarriers: rs1042838 (PROGINS allele; odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.19 to 8.75, P = .022) and rs608995 (minor allele; OR = 3.10, 95% CI = 1.63 to 5.89, P<.001). The PROGINS allele was observed on a subset of chromosomes carrying the minor allele at rs608995, and its association with ovarian cancer was fully explained by its association with rs608995. In addition, rs608995 fell on two common haplotypes (4-D and 4-E), whose association with ovarian cancer was the same as that of rs608995. These same two haplotypes were associated with a non-statistically significantly reduced risk of breast cancer. CONCLUSIONS: Variation in PGR was associated with ovarian cancer risk, although the strongest result was not with the PROGINS allele. Instead, any causal allele(s) are likely in or downstream of block 4 and carried on haplotypes 4-D and 4-E. There was some evidence that the same variation was associated with a reduced risk of breast cancer, but the association was not statistically significant.

Adult↗

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↗

PubMed2003

Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position - 107, implicating the Sp1 transcription factor.

Accumulating data suggest that paraoxonase-1 (PON1) is a primary determinant of the antioxidant and anti-inflammatory capacities of high-density lipoproteins (HDLs). Variations in HDLs and PON1 have been shown to influence the functions of both. There is a wide spectrum of serum PON1 mass in humans, to which promoter polymorphisms make an important contribution. The present studies attempted to define: (i) the relevance in vivo of promoter polymorphisms by analysing haplotype structure; and (ii) molecular mechanisms implicated in promoter activity. Highly significant differences (P <0.0001) in serum mass and activity were observed as a function of haplotype sequence. Of three promoter polymorphisms (-107, -824 and -907), the -107 site was shown to be of predominant importance to serum PON1. Significant increases in serum PON1 mass and activities between haplotype subgroups could be explained by unit increases in the number of high-expresser variants of the -107 site (-107C) alone. No significant contribution was observed for the -824 and -907 sites. The coding-region Leu(55)-->Met (L55M) polymorphism made an independent contribution to serum PON1 mass, which may account for variations in serum PON1 mass and activity within haplotype subgroups defined by the -107 site. A molecular basis for the effect of the -107 polymorphism on serum PON1 was indicated by the greater affinity of the high-expresser variant (-107C) for hepatocyte nuclear extracts, indicating higher affinity for transcription factors. Competition studies with oligonucleotides representing the consensus (and mutated) sequence for Sp1, and the use of Sp1 antibodies, confirmed formation of complexes between the transcription factor and the PON1 promoter during incubation with nuclear extracts. The data underline the importance of the region containing the C(-107)T polymorphism for gene expression in vivo. Differences in the affinity of the -107C and -107T polymorphic fragments for nuclear extracts have been demonstrated, and coincide with their impact on gene expression. A potential role for the transcription factor Sp1 has been demonstrated, which is consistent with the disruption of an Sp1 recognition sequence by the -107 polymorphism.

Aryldialkylphosphatase↗

PubMed2004

CYP3A variation and the evolution of salt-sensitivity variants.

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.

Black or African American↗

PubMed2006

Focusing on the goat casein complex.

The analysis of casein polymorphisms in goat species is rather difficult, because of a large number of mutations at each locus, and the tight linkage involving the 4 casein genes. Three goat breeds from Northern Italy, Orobica, Verzasca, and Frisa, were analyzed at the casein complex by milk isoelectrofocusing and analyses at the DNA level to identify the majority of all known polymorphisms. The casein gene structure of the 3 local breeds at alpha(S1)-casein (CSN1S1), beta-casein (CSN2), alpha(S2)-casein (CSN1S2), and kappa-casein (CSN3) was compared with that of Camosciata, a more widely distributed breed. A new allele was identified and characterized at CSN2 gene, which seemed to be specific to the Frisa breed. It was named CSN2*E, and was characterized by a transversion TCT --> TAT responsible for the amino acid exchange Ser(166) --> Tyr(166) in the mature protein. The casein haplotype structure is highly different among breeds. A total of 26 haplotypes showed a frequency higher than 0.01 in at least 1 of the 4 breeds considered, with 12, 3, 5, and 19 haplotypes in Frisa, Orobica, Verzasca, and Camosciata breeds, respectively. Only 13 haplotypes occurred at a frequency higher than 0.05 in at least 1 breed. With the molecular knowledge of each locus, the ancestral haplotype coding for CSN1S1*B, CSN2*A, CSN1S2*A, and CSN3*B protein variants can be postulated. A protein evolutionary model considering the whole casein haplotype is proposed.

Alleles↗

PubMed2005

Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease.

The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.

Adult↗

PubMed2005

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). OBJECTIVE: To investigate the pathogenic basis of this association. METHODS: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. RESULTS: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case-control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least approximately 56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. CONCLUSIONS: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson's disease and other tauopathies, including Alzheimer's disease.

Aged↗

PubMed2004

[Haplotypes extending across AGT are associated essential hypertension].

Present studies examined the DNA polymorphisms in the AGT genes in a Chinese population in Henan province of central China. By using PCR-RFLP and maximum likelihood estimation (MLE), we estimated the pattern of intragenic linkage disequilibrium and the haplotype structure and explored the possible association between the polymorphisms of AGT gene and essential hypertension in a case-control study. Seven polymorphic sites (SNPs) and seven major haplotypes of AGT gene were analyzed. Among the individual SNP pairs examined, the A-6G, C+31T and M235T are nearly completely disequilibrium. All those single polymorphism loci were individually not associated with hypertension. But we found the frequency of haplotype H2 (-217: G, -152: G, -20: A, -6: G, +31: T, 174: T, 235: M) was significantly higher in controls than patients (P=0.010). Our study suggested that few haplotypes derived seven polymorphism loci could account for the most of the variation in AGT gene in Chinese Hans. The haplotype H2 of AGT gene might represent or be in disequilibrium with a genetic protective factor against EH.

Adult↗

PubMed2004

Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population.

Both UDP-glucuronosyltransferase 2B4 (UGT2B4) and UGT2B7 are expressed mainly in the human liver and have several overlapping substrates; e.g., catechol estrogens, bile acids, codeine, and carvedilol. To identify novel single nucleotide polymorphisms (SNPs) and haplotypes in a Japanese population, the enhancer/promoter regions, all the exons, and the surrounding intronic regions of UGT2B4 and UGT2B7 were sequenced from 136 Japanese individuals. We found 16 and 21 polymorphisms, including 10 and 4 novel ones in UGT2B4 and UGT2B7, respectively. The novel nonsynonymous SNPs were 1364A>G (K455R) and 1531T>C (C511R) in UGT2B4 and 1192G> A (D398N) in UGT2B7. From linkage disequilibrium analysis, several SNPs in UGT2B7 were found to be highly linked with each other. No close linkage between the SNPs in UGT2B4 and UGT2B7 was observed, indicating that each gene is located within an independent haplotype block. Thus, haplotype analysis was separately performed for the two genes. In UGT2B4, we unambiguously determined 8 haplotypes and inferred an additional 12 haplotypes using an expectation-maximization-based program. In UGT2B7, five haplotypes were unambiguously assigned and an additional eight haplotypes were inferred. The haplotype structure of UGT2B7 was more diverse than that of UGT2B4 in terms of the number of frequent SNPs. In addition, ethnic differences in the UGT2B4(*)2 and UGT2B7(*)2 haplotypes between the Japanese and the Caucasian and/or African populations were found. Our findings provide fundamental and useful information for genotyping UGT2B4 and UGT2B7 in the Japanese, and probably other populations.

Asian People↗

PubMedDate not supplied

Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.

PURPOSE: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder resulting from a deficiency of the lysosomal glycosidase, alpha-L-iduronidase (IDUA). Patients with MPS I present with variable clinical manifestations ranging from severe to mild. To facilitate studies of phenotype-genotype correlation, the authors performed molecular studies to detect mutations in MPS I patients and characterize single nucleotide polymorphism (SNP) in the gene. METHODS: Twenty-two unrelated MPS I patients were subjects for mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine intragenic single nucleotide polymorphic alleles. RESULTS: Eleven different mutations including two common mutations (Q70X, W402X), five recurrent mutations (D315Y, P533R, R621X, R628X, S633L), and four novel mutations (R162I, G208D, 1352delG, 1952del25bp) were identified from MPS I patients. Multiple SNP alleles coexisting with the disease-causing mutations were detected. Allelic frequencies for nine SNP alleles including A8, A20, Q33H, L118, N181, A314, A361T, T388, and T410 were determined. CONCLUSIONS: The results provide further evidence for the mutational heterogeneity among MPS I patients and point out possible common haplotype structures in the gene.

Black People↗

PubMed2006

Polymorphisms of estrogen-biosynthesis genes CYP17 and CYP19 may influence age at menarche: a genetic association study in Caucasian females.

Variation in age at menarche (AAM) is known to be substantially influenced by genetic factors, but the true causal genes remain largely unidentified. Because the increased amplitude of estrogen exposure of tissues initiates the onset of menarche, the genes involved in estrogen biosynthesis are natural candidate genes underlying AAM. Our study aimed to identify whether the CYP17 and CYP19, the two key genes involved in the biosynthesis of estrogen, are associated with AAM variation in 1048 females from 354 Caucasian nuclear families. We genotyped 38 SNPs and established the linkage disequilibrium blocks and haplotype structures that covered the full transcript length of those two genes. Family-based and population-based statistical analyses were used to test for associations with all of the single SNPs and haplotypes. Both methods consistently detected significant associations for five SNPs of CYP19 with AAM. Haplotype analyses corroborated our single-SNP results by showing that the haplotypes in block 1 were highly significant to AAM in population-based analyses. However, we could not find any association of CYP17 with AAM. Our study is the first to suggest the important effect of CYP19 on AAM variation in Caucasian females. It will be valuable to replicate and confirm these findings in other independent studies, aiming at eventually finding the hidden genetic mechanisms underlying the variation in AAM.

Adolescent↗