bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene
Authors: Hamon S. C. , Stengard J. H. , Clark A. G. , Salomaa V. , Boerwinkle E. , Sing C. F. 
Published: December 2004

SummaryWe analyzed 13 single nucleotide polymorphisms (SNPs) within the apolipoprotein E (APOE) gene, to identify pairs of SNPs that interact in a non‐additive manner to influence genotypic mean levels of the ApoE protein in blood. An overparameterized general linear model of two‐SNP genotype means was applied to data from 456 female and 398 male unrelated European Americans from Rochester, MN, USA. We found statistically significant evidence for non‐additivity between SNPs within the male sample, but not within the female sample. We observed nine pairs of SNPs with evidence of non‐additivity at the α= 0.05 level of statistical significance within the male sample, when approximately three were expected by chance. Five of the nine pairs involved three SNPs (560, 624 and 1163) that did not have a statistically significant influence when considered separately in a single‐site analysis. Three of the nine pairs involving four SNPs (832, 1998, 3937 and 4951) showed significant evidence for non‐additivity in at least one of two other male samples from Jackson, MS, USA and North Karelia, Finland. Although all four of these SNPs had a statistically significant influence in Rochester when considered separately, only SNP 3937 gave a significant result in the other male samples. The four SNPs are located in the promoter, intronic and exonic regions, and 3' to the polyadenylation signal in the APOE gene. Our study suggests that analyses that only consider SNPs located in exons and ignore contexts such as those indexed by gender and population, and disregard non‐additivity of SNP effects, may inappropriately model the contribution of a gene to the genetic architecture of a trait that has a complex multifactorial etiology.
Novel HMBS founder mutation and significant intronic polymorphism in Spanish patients with acute intermittent porphyria
Authors: Guillén‐Navarro E. , Carbonell P. , Glover G. , Sánchez‐Solís M. , Fernández‐Barreiro A. 
Published: December 2004

SummaryAcute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis, caused by a partial deficiency of hydroxymethylbilane synthase (HMBS). Knowledge of the nature of the HMBS mutations causing AIP in Spanish families is very limited. Here we report a novel 669_698del of the HMBS gene in twenty‐two individuals from five independent Spanish AIP families, settled in Murcia (southeastern region of Spain). All mutation carriers shared a common disease associated haplotype indicating an ancestral founder effect. Identification of the 669_698del founder mutation allowed rapid and simple molecular diagnosis of AIP in families from this region in Spain. In addition, 771 + 58C>T in intron 12 on the non‐669_698del allele was identified in six AIP patients, which promoted homozygous AIP misdiagnosis.
Compound haplotypes at Xp11.23 and human population growth in Eurasia
Authors: Alonso S. , Armour J. A. L. 
Published: December 2004

SummaryTo investigate patterns of diversity and the evolutionary history of Eurasians, we have sequenced a 2.8 kb region at Xp11.23 in a sample of African and Eurasian chromosomes. This region is in a long intron of CLCN5 and is immediately flanked by a highly variable minisatellite, DXS255, and a human‐specific Ta0 LINE. Compared to Africans, Eurasians showed a marked reduction in sequence diversity. The main Euro‐Asiatic haplotype seems to be the ancestral haplotype for the whole sample. Coalescent simulations, including recombination and exponential growth, indicate a median length of strong linkage disequilibrium, up to ∼9kb for this area. The Ka/Ks ratio between the coding sequence of human CLCN5 and its mouse orthologue is much less than 1. This implies that the region sequenced is unlikely to be under the strong influence of positive selective processes on CLCN5, mutations in which have been associated with disorders such as Dent's disease. In contrast, a scenario based on a population bottleneck and exponential growth seems a more likely explanation for the reduced diversity observed in Eurasians. Coalescent analysis and linked minisatellite diversity (which reaches a gene diversity value greater than 98% in Eurasians) suggest an estimated age of origin of the Euro‐Asiatic diversity compatible with a recent out‐of‐Africa model for colonization of Eurasia by modern Homo sapiens.
Contribution of Chromosome 1q21‐q23 to Familial Combined Hyperlipidemia in Mexican Families
Authors: Huertas‐Vázquez A. , del Rincón J. P. , Canizales‐Quinteros S. , Riba L. , Vega‐Hernández G. , Ramírez‐Jiménez S. , Aurón‐Gómez M. , Gómez–Pérez F. J. , Aguilar‐Salinas C. A. , Tusié‐Luna M. T. 
Published: December 2004

SummaryFamilial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, with a prevalence of 1‐2% in the general population. A major locus for FCHL has been mapped to chromosome 1q21‐q23 in Finnish, Chinese, German and US families. We studied seven extended Mexican families with 153 members, including 64 affected subjects. A total of 11 markers were genotyped, including D1S104 which has been linked to FCHL in other studies. Two point linkage analysis for the FCHL phenotype, and for the elevated triglyceride (TG) trait, allowing for heterogeneity, gave a maximum HLOD of 1.67 (α= 0.49) and 1.93 (α= 0.43) at D1S2768 (2.69 cM proximal to D1S104) respectively. Heterogeneity and non‐parametric (NPL) multipoint analyses for the FCHL phenotype and the TG trait showed maximum HLODs of 1.27 (α= 0.46) and 1.64 (α= 0.38), and NPLs of 4.00 (P = 0.0001) and 3.68 (P = 0.0003) near D1S2768, respectively. In addition, analysis of four candidate genes putatively involved in the expression of FCHL showed no evidence of linkage for the LCAT gene or the APOA1/C3/A4/A5 gene cluster. However, we cannot exclude the participation of these genes, or the LIPC and LPL genes, as minor susceptibility loci in the expression of FCHL, or the TG or elevated total cholesterol (TC) traits in our families. In conclusion, our data confirm the involvement of a major susceptibility locus on chromosome 1q21‐q23 in FCHL Mexican families, consistent with findings in other populations.
Genetic Dissection of Human Stature in a Large Sample of Multiplex Pedigrees
Authors: Liu Yao‐Zhong , Xu Fu‐Hua , Shen Hui , Liu Yong‐Jun , Zhao Lan‐Juan , Long Ji‐Rong , Zhang Yuan‐Yuan , Xiao Peng , Xiong Dong‐Hai , Dvornyk Volodymyr , Li Jin‐Long , Conway Theresa , Davies K. Michael , Recker Robert R. , Deng Hong‐Wen 
Published: December 2004

SummaryRecently, we reported a whole genome scan on a sample of 630 Caucasian subjects from 53 human pedigrees. Several genomic regions were suggested to be linked to height. In an attempt to confirm the identified genomic regions, as well as to identify new genomic regions linked to height, we conducted a whole genome linkage study on an extended sample of 1,816 subjects from 79 pedigrees, which includes the 53 pedigrees containing the original 630 subjects from our previous whole genome study and an additional 128 new subjects, and 26 further pedigrees containing 1,058 subjects. Several regions achieved suggestive linkage signals, such as 9q22.32 [MLS (multipoint LOD score) = 2.74], 9q34.3 [MLS = 2.66], Xq24 [two‐point LOD score = 2.64 at the marker DXS8067], and 7p14.2 [MLS = 2.05]. The importance of the above regions is supported either by other whole genome studies or by candidate genes within these regions relevant to linear growth or pathogenesis of short stature. In addition, this study has tentatively confirmed the Xq24 region's linkage to height, as this region was also detected in the previous whole genome study. To date, our study has achieved the largest sample size in the field of genetic linkage studies of human height. Together with the findings of other studies, the current study has further delineated the genetic basis of human stature.
Y Chromosome and Mitochondrial DNA Variation in Lithuanians
Authors: Kasperavičiūtė D. , Kučinskas V. , Stoneking M. 
Published: December 2004

SummaryThe genetic composition of the Lithuanian population was investigated by analysing mitochondrial DNA hypervariable region 1, RFLP polymorphisms and Y chromosomal biallelic and STR markers in six ethnolinguistic groups of Lithuanians, to address questions about the origin and genetic structure of the present day population. There were no significant genetic differences among ethnolinguistic groups, and an analysis of molecular variance confirmed the homogeneity of the Lithuanian population. MtDNA diversity revealed that Lithuanians are close to both Slavic (Indo‐European) and Finno‐Ugric speaking populations of Northern and Eastern Europe. Y‐chromosome SNP haplogroup analysis showed Lithuanians to be closest to Latvians and Estonians. Significant differences between Lithuanian and Estonian Y chromosome STR haplotypes suggested that these populations have had different demographic histories. We suggest that the observed pattern of Y chromosome diversity in Lithuanians may be explained by a population bottleneck associated with Indo‐European contact. Different Y chromosome STR distributions in Lithuanians and Estonians might be explained by different origins or, alternatively, be the result of some period of isolation and genetic drift after the population split.
Gene Expression Profile Analysis in Human T Lymphocytes from Patients with Down Syndrome
Authors: Giannone S. , Strippoli P. , Vitale L. , Casadei R. , Canaider S. , Lenzi L. , D'Addabbo P. , Frabetti F. , Facchin F. , Farina A. , Carinci P. , Zannotti M. 
Published: December 2004

SummaryDown Syndrome (DS) is caused by the presence of three copies of the whole human chromosome 21 (HC21) or of a HC21 restricted region; the phenotype is likely to have originated from the altered expression of genes in the HC21. We apply the cDNA microarray method to the study of gene expression in human T lymphocytes with trisomy 21 in comparison to normal cells.Two patients with DS were investigated, along with two normal subjects as a control, all being tested in independent, duplicated cell culture experiments. The most consistent finding was the overexpression of the superoxide dismutase gene (SOD1), located on 21q, and of MHC DR beta 3 (HLA‐DRB3), GABA receptor A gamma 2 (GABRG2), acetyltransferase Coenzyme, A 2 (ACAT2) and ras suppressor protein 1 (RSU1) genes. When the data were clustered according to chromosome localization, the HC21 gene set showed, on average, the highest expression in DS cells in all the experiments. Moreover, separate clustering of patients and controls was obtained when analysis was restricted to HC21 gene expression values.These findings reinforce the specific gene dosage theory for the pathogenesis of the DS phenotype, and show a consistent overexpression of the SOD1 gene on 21q.
Linkage Disequilibrium and Haplotype Architecture for two ABC Transporter Genes (ABCC1 and ABCG2) in Chinese Population: Implications for Pharmacogenomic Association Studies
Authors: Wang Haijian , Hao Bingtao , Zhou Kaixin , Chen Xiaoping , Wu Songfeng , Zhou Gangqiao , Zhu Yunping , He Fuchu 
Published: December 2004

SummaryInformation about linkage disequilibrium (LD) patterns and haplotype structures for candidate genes is instructive for the design and analysis of genetic association studies for complex diseases and drug response. ABCC1 and ABCG2 are genes coding for two multidrug resistance (MDR) associated transporters; they are also related to some pathophysiological traits. To pinpoint the LD profiles of these MDR genes in Chinese, we systemically screened 27 unrelated individuals for single nucleotide polymorphisms (SNPs) in the coding and regulatory regions of these genes, and thereby characterized their haplotype structures. Despite marked variations in haplotype diversity, LD pattern and intragenic recombination intensity between the two genes, both loci could be partitioned into several LD blocks, in which a modest number of haplotypes accounted for a high fraction of the sampled chromosomes. We concluded that each locus has its own genomic LD profile, but that they still share a common segmental LD architecture with low haplotype diversity. Our data will benefit genetic association studies of complex traits and drug response possibly related to these genes.
A Tale of Aborigines, Conquerors and Slaves: Alu Insertion Polymorphisms and the Peopling of Canary Islands
Authors: Maca‐Meyer N. , Villar J. , Pérez‐Méndez L. , De León A. Cabrera , Flores C. 
Published: December 2004

SummaryClassical, mitochondrial DNA (mtDNA) and Y chromosome markers have been used to examine the genetic admixture in present day inhabitants of the Canary Islands. In this study, we report the analysis of ten autosomal Alu insertion polymorphisms in 364 samples from the seven main islands of the Archipelago, and their comparison to continental samples. The detection of population‐specific alleles from the Iberian Peninsula and Northwest Africa, as well as their affinities on the basis of genetic distances and principal component analysis, support a clear link between these populations. Coincident with previous results, the Canarian gene pool can be distinguished as being halfway between those of its putative parents, although with a major Iberian contribution (62‐78%). Both the substantial Northwest African contribution (23‐38%), and the minor sub‐Saharan African input (3%), suggest that the genetic legacy from the aborigines and slaves still persists in the Canary Islanders.
DNA Sequence Variation and Haplotype Structure of the ICAM1 and TNF Genes in 12 Ethnic Groups of India Reveal Patterns of Importance in Designing Association Studies
Authors: Sengupta Sanghamitra , Farheen Shabana , Mukherjee Neelanjana , Dey Badal , Mukhopadhyay Barun , Sil Samir K. , Prabhakaran N. , Ramesh A. , Edwin Deepa , Rani M.V. Usha , Mitra Mitashree , Mahadik Chitra Thakur , Singh Sunita , Sehgal Subhash C. , Majumder Partha P. 
Published: December 2004

SummaryWe have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non‐synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF‐376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between‐population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case‐control association studies.
Estimated Frequency of Genetic and Nongenetic Causes of Congenital Idiopathic Cerebral Palsy in West Sweden
Authors: Costeff H. 
Published: December 2004

SummaryMathematical analysis of prenatal and perinatal risk factors was performed on the first 681 published cases of idiopathic congenital cerebral palsy (born 1959–1970) in the west Swedish population‐based cerebral palsy (CP) study. Analysis indicates that an estimated 40% of etiologically undiagnosed cases of CP in the community (48% of those born at term and 24% of those born prematurely) are genetically caused. These proportions of genetic causation are no less in CP than in idiopathic mental retardation. Genetic causes account for 60% of maturely born hemiplegics, 45% of maturely born spastic diplegics, 32% of premature spastic diplegics and virtually all cases of pure ataxia. About 23% of CP cases in the community have suffered nongenetic brain damage in accordance with the two‐stage model. The residue of 37% is characterized by a single risk factor, usually perinatal.
Commingling Analysis of Intraocular Pressure and Glaucoma in an Older Australian Population
Authors: Viswanathan Ananth C. , Hitchings Roger A. , Indar Andrea , Mitchell Paul , Healey Paul R. , McGuffin Peter , Sham Pak C. 
Published: December 2004

Summary Purpose: To test the hypothesis of a major genetic determinant of intraocular pressure (IOP) under the mixed genetic model in a defined population, and to elucidate the relationship between IOP and glaucoma. Methods: IOP was measured in 3654 persons attending the Blue Mountains Eye Study. A commingling analysis on IOP was performed using a new program, SKUDRIVER. The goodness of fit of 1‐, 2‐ and 3‐distribution models was measured. This was repeated after the glaucoma cases had been removed from the dataset, and further repeated on the glaucoma cases in the dataset. Results: The best model was 3‐distribution with no evidence for Hardy‐Weinberg disequilibrium. The proportion of variance explained by this major effect was 0.18. When glaucoma cases were removed, the best model had 2 distributions. There was no evidence of admixture in glaucoma patients. Conclusions: The findings of this study are consistent with the presence of a major gene accounting for 18% of the variance of IOP, which could therefore influence the risk of glaucoma, in this population. These findings suggest methods of optimizing strategies for family and association studies to identify quantitative trait loci for IOP. No evidence for distinct IOP‐dependent and IOP‐independent subgroups of glaucoma was found.
Exploration of Multilocus Effects in a Highly Polymorphic Gene, the Apolipoprotein (APOB) Gene, in Relation to Plasma apoB Levels
Authors: Tahri‐Daizadeh N. , Tregouet D. A. , Nicaud V. , Poirier O. , Cambien F. , Tiret L. 
Published: December 2004

SummaryA detailed exploration of all the polymorphisms in candidate genes is required to better characterize the relationship between gene variability and complex traits. We propose a novel strategy for investigating the association between a highly polymorphic gene and a phenotype, by combining a multilocus genotype analysis and an haplotype analysis. For the multilocus genotype analysis, a data mining tool ‐ termed DICE (Detection of Informative Combined Effects) – was developed to identify the best subset of polymorphisms that are associated ‐ individually or in combination – with the phenotype. For the haplotype analysis, we used our recently developed method of haplotype‐phenotype association to determine the most informative and parsimonious haplotype model fitting the data. We illustrate this strategy by investigating the association between twelve polymorphisms of the APOB gene and plasma apoB levels in 1442 European subjects. After exploring all main effects and interactions between polymorphisms, DICE identified the N4311S polymorphism as the most informative polymorphism in relation to apoB levels. Haplotype analysis led to the same conclusion. Additionally, DICE identified the E4154K (EcoRI) and the T2488T (XbaI) polymorphisms as potentially interesting. This selection was not modified by inclusion of the common APOE polymorphism in the analysis.
Mitochondrial DNA Diversity in Tribal and Caste Groups of Maharashtra (India) and its Implication on Their Genetic Origins
Authors: Baig M. M. , Khan A. A. , Kulkarni K. M. 
Published: December 2004

SummaryGenetic relationships among caste‐groups are not uniform across the geographical regions of India. Many anthropologists have speculated on the tribal origin of some caste groups in Maharashtra and other states of India. To test this hypothesis, we used neutral mtDNA markers to study genetic relatedness among tribal and caste groups from Maharashtra. Descriptive statistics such as nucleotide diversity, gene diversity and average mismatches were found to be of the same magnitude. Phylogenetic network analysis exhibited a star‐like expansion that may date back to the peopling of Eurasia, ∼50,000 year ago. The reconstruction of mtDNA haplogroups showed that both the caste and tribal populations share similar branches of the tree. Also, the coalescence age estimation of caste and tribal populations suggests the persistence of maternal lineages with their root in early late Pleistocene. Our mtDNA analyses show some preliminary and significant evidence for the origin of prehistoric tribal and hierarchical caste societies of Maharashtra.
Inferring the Most Likely Geographical Origin of mtDNA Sequence Profiles
Authors: Egeland T. , Bøvelstad H.M. , Storvik G.O. , Salas A. 
Published: December 2004

SummaryIn a number of practical cases it is important to determine the likely geographical origin of an individual or a biological sample. A dead body, old bones or a sample of semen may be available. Information on where the sample might come from can assist investigation or research. The first part of this paper is independent of specific data structure. We formulate the problem as a classification problem. Bayes' theorem allows different sources of information or data to be reconciled conveniently. The main part of the paper involves high dimensional data for which simple, standard methods are not likely to work properly. Mitochondrial DNA (mtDNA) data is a typical example of such data. We propose a procedure involving essentially two steps. First, principal component analysis is used to reduce the dimension of the data. Next, quadratic discriminant analysis performs the actual classification. A cross validation procedure is implemented to select the optimal number of principal components. The importance of using separate data sets for model fitting and testing is emphasized. This method distinguishes well between individuals with a self reported European (Icelandic or German) origin and SE Africans. In this case the error rate is 2.0%.
The FBN1 (R2726W) mutation is not fully penetrant
Authors: Buoni S. , Zannolli R. , Macucci F. , Ansaldi S. , Grasso M. , Arbustini E. , Fois A. 
Published: December 2004

SummaryThe R2726W mutation in the fibrillin 1 (FBN1, Marfan syndrome) gene segregates with isolated skeletal features of Marfan syndrome and/or high stature. Here we report a family in which two out of four individuals, an 18‐year‐old son and his mother, a 41‐year‐old woman, had the R2726W mutation of FBN1. Both family members carrying the mutation were of average height. The son had a Marfan‐like phenotype, but his mother did not. The FBN1 R2776W mutation, which is associated with skeletal features of Marfan syndrome, appears incompletely penetrant. Consequently, genetic counselling in the presence of this mutation is difficult.
Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus
Authors: Giardina E. , Capon F. , De Rosa MC. , Mango R. , Zambruno G. , Orecchia A. , Chimenti S. , Giardina B. , Novelli G. 
Published: December 2004

SummaryPsoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Non‐parametric linkage analyses have mapped many susceptibility loci on different chromosomes. We mapped one of these loci, PSORS4, on human chromosome 1q21. Using the linkage disequilibrium approach, we refined the critical region to a specific genomic interval of about 100 Kb which contains only the loricrin (LOR) gene. Here we report a genetic and functional study of this gene to verify its involvement in psoriasis pathogenesis. We document low expression of LOR in psoriatic skin of patients selected from families in which the disease was segregrating with the PSORS4 locus. Re‐sequencing of the entire gene in a subset of patients revealed the existence of novel polymorphisms able to influence the protein structure, as shown by molecular modelling studies. However, no evidence for genetic association was detected in a large cohort of Italian nuclear families. This rules out the LOR gene as a candidate for the PSORS4 locus.