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PubMed2000

The Human Genome Project--an overview.

The human genome sequence will underpin human biology and medicine in the next century, providing a single, essential reference to all genetic information. The international program to determine the complete DNA sequence (3,000 million bases) is well underway. As of January 2000, 50% of the sequence is available in the public domain. A comprehensive working draft is expected this year, and the entire sequence is projected to be finished in 2003. DNA sequencing is carried out on mapped, overlapping bacterial clones of 150-200 kb. The working draft comprises assembled unfinished sequence and is released immediately in the public domain. The draft sequence of each clone is then completed, by closing any remaining gaps and resolving any ambiguities, before the entire sequence is checked, annotated, and submitted to the public databases. The sequence of each clone is finished to an accuracy of >99.99%. The availability of a reference sequence of the genome provides the basis for studying the nature of sequence variation, particularly single nucleotide polymorphisms (SNPs), in human populations. SNP typing is a powerful tool for genetic analysis, and will enable us to uncover the association of loci at specific sites in the genome with many disease traits. SNPs occur at a frequency of approximately 1 SNP/kb throughout the genome when the sequence of any two individuals is compared. Programs to detect and map SNPs in the human genome are underway with the aim of establishing a SNP map of the genome during the next two years. The human genome sequence will provide a complete description of all the genes. Annotation of the sequence with the gene structures is achieved by a combination of computational analysis (predictive and homology-based) and experimental confirmation by cDNA sequencing. Detecting homologies between newly defined gene products and proteins of known function helps to postulate biochemical functions for them, which can then be tested. Establishing the association of specific genes with disease phenotypes by mutation screening, particularly for monogenic disorders, provides further assistance in defining the functions of some gene products, as well as helping to establish the cause of the disease. As our knowledge of gene sequences and sequence variation in populations increases, we will pinpoint more and more of the genes and proteins that are important in common, complex diseases. A more detailed understanding of the function of the human genome will be achieved as we identify sequences that control gene expression. Given the availability of gene sequences, the expression status of genes in particular tissues can be monitored in parallel. By comparing corresponding genomic sequences in different species (for example: man, mouse, chicken, and zebrafish), regions that have been highly conserved during evolution can be identified, many of which reflect conserved functions such as gene regulation. These approaches promise to greatly accelerate our interpretation of the human genome sequence.

Human Genome Project↗
PubMed2003

Variation in the HLA-G promoter region influences miscarriage rates.

The HLA-G gene is primarily expressed in placental cells that invade the maternal decidua during pregnancy. This gene encodes multiple isoforms that fulfill a variety of functions at the maternal-fetal interface throughout gestation. Recently, a null allele for the most abundant HLA-G isoform was associated with recurrent miscarriage in two independent studies, suggesting that reduced levels of the HLA-G1 protein may compromise successful pregnancy. We initiated the present study to determine whether other polymorphisms that could affect expression levels of HLA-G were associated with fetal loss in women participating in a 15-year prospective study of pregnancy outcome. We genotyped these subjects for 18 single-nucleotide polymorphisms in the 1,300 bp upstream of exon 1, 13 of which were identified as part of this study, as well as for an insertion/deletion (in/del) polymorphism in the 3' untranslated region. The 18 SNPs defined eight unique haplotypes. One polymorphism, -725C/G, was associated with fetal loss, with an increased risk for miscarriage in couples in which both partners carried the -725G allele, compared with couples not carrying this allele (odds ratio 2.76, 95% confidence interval 1.08-7.09; P=.035). Further, the G at nucleotide -725 creates a CpG dinucleotide, and we demonstrate that this CpG site is methylated on -725G alleles. Overall, this study identified extraordinary levels of variation in the 5'-upstream regulatory region of HLA-G and provides evidence for an association between a promoter-region SNP and fetal loss rates, further attesting to the novel features and critical role of this gene in pregnancy.

Abortion, Spontaneous↗
PubMed2005

Global analysis of uniparental disomy using high density genotyping arrays.

BACKGROUND: Uniparental disomy (UPD), the inheritance of both copies of a chromosome from a single parent, has been identified as the cause for congenital disorders such as Silver-Russell, Prader-Willi, and Angelman syndromes. Detection of UPD has largely been performed through labour intensive screening of DNA from patients and their parents, using microsatellite markers. METHODS: We applied high density single nucleotide polymorphism (SNP) microarrays to diagnose whole chromosome and segmental UPD and to study the occurrence of continuous or interspersed heterodisomic and isodisomic regions in six patients with Silver-Russell syndrome patients who had maternal UPD for chromosome 7 (matUPD7). RESULTS: We have devised a new high precision and high-throughput computational method to confirm UPD and to localise segments where transitions of UPD status occur. Our method reliably confirmed and mapped the matUPD7 regions in all patients in our study. CONCLUSION: Our results suggest that high density SNP arrays can be reliably used for rapid and efficient diagnosis of both segmental and whole chromosome UPD across the entire genome.

Chromosome Mapping↗
PubMed2006

CARAT: a novel method for allelic detection of DNA copy number changes using high density oligonucleotide arrays.

BACKGROUND: DNA copy number alterations are one of the main characteristics of the cancer cell karyotype and can contribute to the complex phenotype of these cells. These alterations can lead to gains in cellular oncogenes as well as losses in tumor suppressor genes and can span small intervals as well as involve entire chromosomes. The ability to accurately detect these changes is central to understanding how they impact the biology of the cell. RESULTS: We describe a novel algorithm called CARAT (Copy Number Analysis with Regression And Tree) that uses probe intensity information to infer copy number in an allele-specific manner from high density DNA oligonuceotide arrays designed to genotype over 100,000 SNPs. Total and allele-specific copy number estimations using CARAT are independently evaluated for a subset of SNPs using quantitative PCR and allelic TaqMan reactions with several human breast cancer cell lines. The sensitivity and specificity of the algorithm are characterized using DNA samples containing differing numbers of X chromosomes as well as a test set of normal individuals. Results from the algorithm show a high degree of agreement with results from independent verification methods. CONCLUSION: Overall, CARAT automatically detects regions with copy number variations and assigns a significance score to each alteration as well as generating allele-specific output. When coupled with SNP genotype calls from the same array, CARAT provides additional detail into the structure of genome wide alterations that can contribute to allelic imbalance.

Algorithms↗
PubMed2006

Possible gender-dependent association of vascular endothelial growth factor (VEGF) gene and ALS.

Individuals homozygous for haplotypes -2578-A/-1154-A/-634-G or -2578-A/-1154-G/-634-G in the promoter/5'UTR of the VEGF gene have a 1.8-fold increased risk of ALS in several European populations. We did not observe any significant association with single markers, or haplotype pairs, in a German sample of 580 sporadic ALS patients and 628 controls. However, the promoter SNP-1154 (rs1570360) was associated with affection status in women (p = 0.036), suggesting that the VEGF effect may be dependent on the sex ratio of the sample.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Nucleotide alteration of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukemia.

The retinoblastoma protein-interacting zinc finger gene (RIZ) is a zinc-finger type DNA binding protein and is postulated as a member of the nuclear protein-methyltransferase superfamily. RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the N-terminal PR (PRDI-BF1 and RIZ homologous)-domain, RIZ2 lacks it. RIZ1 is now considered as a tumor suppressor. We analyzed nucleotide alteration of RIZ gene in human leukemia. The results revealed a single nucleotide polymorphism (SNP), T1704 to A, near the conserved Rb-binding domain, leading to an amino acid change, Asp283 to Glu. Interestingly, 17 of 21 leukemia cell lines are homozygous for the T1704 allele whereas only 2 of 20 normal subjects are homozygous for the allele. In addition, one base pair deletion in the poly (A)9 tract in the coding region near the C-terminal zinc-fingers was identified, resulting in frameshift, in 1 out of 17 leukemia cell lines, but no mutation in samples from 15 patients with acute lymphoblastic leukemia (ALL) and 6 patients with adult T cell leukemia (ATL). In the PR or SH3 (src homology 3) domain of the RIZ gene, no mutation was found. These findings suggest that RIZ may be a possible target of structural alteration leading to leukemia.

Alleles↗
PubMed2005

Nitric oxide modulation of ET(B) receptor-induced vasopressin release by rat and mouse hypothalamo-neurohypophyseal explants.

Endothelin (ET) peptides stimulate vasopressin (AVP) secretion via ET(B) receptors at hypothalamic loci. Nitric oxide modulates the actions of ET in the cardiovascular system and also influences neurotransmission and specifically suppresses firing of magnocellular neurons. The purpose of these studies was to ascertain whether nitric oxide, generated in response to ET(B) receptor stimulation, buffers the stimulatory effect of ET and suppresses AVP release. Studies were performed using a pharmacological approach in hypothalamo-neurohypophyseal explants from rats, and an alternative strategy using explants from mice with an inactivating mutation of neuronal NOS (nNOS-/-) and their wild-type parent strain. Whole explants in standard culture or only the hypothalamus of compartmentalized explants was exposed to the ET(B) selective agonist, IRL 1620 (10(-13) to 10(-8) M). Rat and wild-type mouse explants displayed similar responses, although absolute basal release rates were higher from murine explants. Maximal AVP release at 0.1 nM IRL 1620 was 311 +/- 63 (rat) and 422 +/- 112% basal x explant(-1) x h(-1) (mouse). Sodium nitroprusside (SNP; 0.1 mM) suppressed maximal AVP release to basal values. N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 microM), which did not itself stimulate AVP secretion, more than doubled the response to 1 pM IRL 1620, from 136 +/- 28 to 295 +/- 49% basal x explant(-1) x h(-1) (P < 0.05) by rat explants. Explants from wild-type mice responded similarly. Explants from nNOS-/- mice had higher basal AVP secretory rate in response to 1 pM IRL 1620: 271 +/- 48 compared with 150 +/- 24% basal x explant(-1) x h(-1) (P < 0.05) from wild-type murine explants. In the nNOS-/-, SNP suppressed stimulated release, and L-NAME exerted no additional stimulatory effect: 243 +/- 38% basal x explant(-1) x h(-1). Thus nitric oxide inhibits the AVP secretory response induced by ET(B) receptor activation within the hypothalamo-neurohypophyseal system and is generated primarily by the nNOS isoform. The modulation of AVP secretion by ET and also nitric oxide can take place independently from their effects on cerebral blood flow, systemic hemodynamics, or the arterial baroreflex.

Animals↗
PubMed2005

Polymorphisms of the CLCN7 gene are associated with BMD in women.

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

Adult↗
PubMed2005

Molecular mechanisms of myocardial infarction.

Despite an increased knowledge of risk factors for atherosclerotic heart disease, it remains nearly endemic in Western society. Despite the high penetrance, only a fraction of those with the disease progress to develop a frank myocardial infarction (MI). Over the past decade, it has become clear that inflammation plays an important role in the pathogenesis of MI. Inflammatory arterial disease therefore may be a better term for the subset of patients that develop the serious adverse consequences related to the rupture of the intracoronary plaque. Using newer molecular techniques such as high-throughput SNP analysis, genome-wide scanning, and enriched pedigree analysis, many of the specific mechanisms underlying the inflammatory milieu involved in this transition have been elucidated and may help identify those at risk for the adverse events associated with atherosclerotic disease.

Arteriosclerosis↗
PubMed2006

The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder.

The brain-derived neurotrophic factor (BDNF) is involved not only in promoting neuronal outgrowth and differentiation, synaptic connectivity and neuronal repair, but also in modulating eating behavior. Since genetic factors likely contribute to the biological vulnerability to bulimia nervosa (BN) and binge eating disorder (BED), we investigated whether the functional 196G/A single nucleotide polymorphism (SNP) of the BDNF gene was associated to BN and/or BED or to some phenotypic aspects of the disordered eating. Two hundred and ten Caucasian women (126 with BN, 84 with BED and 121 healthy controls) participated into the study. No significant differences were found in the frequencies of the 196G/A variants of the BDNF gene among patients with BN or BED and healthy controls. In both BN and BED groups, subjects carrying the 196A/A genotype exhibited a weekly frequency of bingeing and a severity of binge eating (as assessed by the Bulimia Investigation Test Edinburgh) significantly higher than those with the 196A/G and 196G/G genotypes. These results suggest that the 196G/A SNP of the human BDNF gene does not contribute to the genetic susceptibility to BN and BED, but may predispose those patients to a more severe binge eating behavior.

Amino Acid Substitution↗
PubMed2000

Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.

Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.

Algorithms↗
PubMed2006

High incidence of single nucleotide polymorphisms in the prion protein gene of native Brazilian Caracu cattle.

Different alleles of the human and ovine prion protein gene correlate with a varying susceptibility to transmissible spongiform encephalopathies. However, the pathogenic implications of specific polymorphisms in the bovine prion protein gene (PRNP) are only poorly understood. Previous studies on the bovine PRNP gene investigated common European and North American cattle breeds. As a consequence of decades of intensive breeding for specific traits, these modern breeds represent only a small fraction of the bovine gene pool. In this study, we analysed PRNP polymorphisms in the native Brazilian Caracu breed, which developed in geographical isolation since the 16th century. A total of 10 single nucleotide polymorphisms (SNPs) were discovered in the coding region of the Caracu PRNP gene. Eight of the SNPs occurred at high frequencies in Caracu cattle (variant allele frequencies = 0.10-0.76), but were absent or only rarely observed in European and North American breeds. One of the Caracu SNPs was associated with an amino acid exchange from serine to asparagine (f = 0.17). This SNP was not detected in Holstein-Friesian, Simmental and German Gelbvieh and was only rarely detected in beef cattle (f = 0.01). We found 17 haplotypes for PRNP in the Caracu breed.

Animals↗
PubMed2006

Analysis and visualization of chromosomal abnormalities in SNP data with SNPscan.

BACKGROUND: A variety of diseases are caused by chromosomal abnormalities such as aneuploidies (having an abnormal number of chromosomes), microdeletions, microduplications, and uniparental disomy. High density single nucleotide polymorphism (SNP) microarrays provide information on chromosomal copy number changes, as well as genotype (heterozygosity and homozygosity). SNP array studies generate multiple types of data for each SNP site, some with more than 100,000 SNPs represented on each array. The identification of different classes of anomalies within SNP data has been challenging. RESULTS: We have developed SNPscan, a web-accessible tool to analyze and visualize high density SNP data. It enables researchers (1) to visually and quantitatively assess the quality of user-generated SNP data relative to a benchmark data set derived from a control population, (2) to display SNP intensity and allelic call data in order to detect chromosomal copy number anomalies (duplications and deletions), (3) to display uniparental isodisomy based on loss of heterozygosity (LOH) across genomic regions, (4) to compare paired samples (e.g. tumor and normal), and (5) to generate a file type for viewing SNP data in the University of California, Santa Cruz (UCSC) Human Genome Browser. SNPscan accepts data exported from Affymetrix Copy Number Analysis Tool as its input. We validated SNPscan using data generated from patients with known deletions, duplications, and uniparental disomy. We also inspected previously generated SNP data from 90 apparently normal individuals from the Centre d'Etude du Polymorphisme Humain (CEPH) collection, and identified three cases of uniparental isodisomy, four females having an apparently mosaic X chromosome, two mislabelled SNP data sets, and one microdeletion on chromosome 2 with mosaicism from an apparently normal female. These previously unrecognized abnormalities were all detected using SNPscan. The microdeletion was independently confirmed by fluorescence in situ hybridization, and a region of homozygosity in a UPD case was confirmed by sequencing of genomic DNA. CONCLUSION: SNPscan is useful to identify chromosomal abnormalities based on SNP intensity (such as chromosomal copy number changes) and heterozygosity data (including regions of LOH and some cases of UPD). The program and source code are available at the SNPscan website http://pevsnerlab.kennedykrieger.org/snpscan.htm.

Base Sequence↗
PubMed2006

Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer.

Lung cancer is the leading cause of cancer mortality in the world. Although exposure to carcinogens is considered to be the main cause, genetic variation may contribute to lung cancer risk. Murine double minute 2, MDM2, is a key regulator of p53 activity and recently a polymorphism in the promoter region of the MDM2 gene was characterized. This single nucleotide polymorphism, SNP309, was shown to influence MDM2 transcription, MDM2 protein levels and p53 activity. The aim of this study was to investigate whether this functionally important SNP is associated with risk of nonsmall cell lung cancer. The study consisted of 341 nonsmall cell lung cancer cases and 412 healthy controls of Norwegian origin. Our results indicate that the G/G genotype of SNP309 is associated with lung cancer risk with an odds ratio of 1.62 (95% CI: 1.06-2.50). Interestingly, the strongest effect of the polymorphism was seen among women. Females homozygous for SNP309 G/G had associated odds ratio 4.06 (1.29-12.8). We also explored the MDM2 SNP309 in relation to TP53 gene mutations and age at nonsmall cell lung cancer diagnosis. Our results indicate that the G/G genotype of SNP309 is associated with higher age at diagnosis in individuals with TP53 mutations (p=0.037).

Aged↗
PubMed2004

Polymorphism analysis within the HLA-A locus by universal oligonucleotide array.

Human leukocyte antigen (HLA) class I genes present some of the most complex single nucleotide polymorphism (SNP) patterns in the human genome. HLA typing is therefore extremely challenging. In this article, we use the ligation detection reaction (LDR) combined with a universal array (UA) as a robust and efficient method to analyze SNPs within the HLA-A region that includes HLA-A alleles of interest for immunotherapy in tumor diseases. The LDR, combined with a UA platform, has been optimized for the detection of 27 alleles distributed within exons 2 and 3 of HLA-A. The assay involves the amplification by PCR of the HLA-A genomic region (1,900 bp), the cycled ligation reaction, followed by the capture of ligated products through hybridization onto a UA. Each slide was designed to allow the detection of up to eight samples in parallel. The PCR/LDR/UA HLA-A assay was evaluated by analyzing 62 individuals (31 homozygous and 31 heterozygous) previously typed by direct sequencing. We demonstrate that the microarray genotyping procedure described here is a robust and efficient method for unambiguous detection of HLA alleles. HLA genotyping by PCR/LDR/UA is in perfect agreement with typing obtained by direct sequencing. Our results clearly demonstrate that the combination of enzymatic processing (LDR) and a demultiplexing hybridization onto a UA is a robust tool for SNP discrimination within the highly polymorphic HLA region. We demonstrate the specificity and efficiency of such an approach, suggesting the feasibility of a PCR/LDR/UA low resolution HLA typing procedure.

Alleles↗
PubMed2001

Genomic characterization of human SEC14L1 splice variants within a 17q25 candidate tumor suppressor gene region and identification of an unrelated embedded expressed sequence tag.

Human SEC14L1 shows partial sequence homology to the budding yeast SEC14 protein and the Japanese flying squid retinal-binding protein and was previously generally localized to 17q25. We more precisely mapped SEC14L1 within a discrete region of 17q25 that likely harbors at least one putative breast and ovarian tumor suppressor gene. We determined that this gene consists of 18 exons ranging in size from 70 bp (exon 11) to 3088 bp (exon 17) and spanning at least 58 kb of DNA. Exon 17 contained a highly polymorphic variable number of tandem repeats (VNTR) and was present only in the larger ubiquitously expressed 5.5-kb transcript. The 3.0-kb ubiquitously expressed transcript included sequences at the beginning of exon 17 (designated exon 17a) and the end of exon 17 (designated exon 18), but lacked the internal 2439 bp of exon 17, including the VNTR. This alternative splicing resulted in a predicted protein of 719 residues from the smaller transcript with four more terminal amino acids than the 715 residue protein predicted from the larger transcript. EST H49244 spanned exon 11 of SEC14L1 and was specifically expressed in human peripheral blood leukocytes. One intragenic single nucleotide polymorphism (SNP) was confirmed. SEC14L1 contained the CRAL/TRIO domain also found in alpha-tocopherol transfer protein (TTPA) and cellular retinaldehyde-binding protein (CRALBP). As retinoids have been shown to inhibit the growth of breast cancer cells, loss of the proposed SEC14L1 retinal-binding function may contribute to breast tumorigenesis. As TTPA and CRALBP have been implicated in retinitis pigmentosa (RP), altered SEC14L1 expression may contribute to RP in previously unlinked families. Coding exon-specific PCR primers were designed to aid in future expression and mutational analyses.

Adult↗
PubMed2000

Use of single nucleotide polymorphisms for gene discovery in hypertension.

Genetic susceptibility to common diseases is likely influenced by common DNA variants with small-to-moderate effects, rather than by rare mutations with large effects. The majority of such common variation occurs in the form of single nucleotide polymorphisms (SNPs). DNA sequence variation, including SNPs, is created and maintained by the action of evolutionary forces such as mutation, recombination, and selection. Over time and space, these forces have shaped the relationships between the contemporary organization of the human genome and disease susceptibility in the population at large. Single nucleotide polymorphisms have emerged as valuable new tools to uncover these relationships. In particular, their use in both genome-wide and gene-based association studies holds great promise for the identification of genes and gene variations involved in predisposition to essential hypertension. New advances in biotechnology are making possible large-scale discovery of SNP variation and rapid application of this information to disease gene discovery.

Base Sequence↗
PubMed2002

Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene.

Primary open-angle glaucoma (POAG) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin (MYOC) gene is the only one that has thus far been shown to have mutations in patients with POAG. Apolipoprotein E (APOE) plays an essential role in lipid metabolism, and the APOE gene has been involved in neuronal degeneration that occurs in Alzheimer disease (AD). Here, we report that two APOE-promoter single-nucleotide polymorphisms (SNPs) previously associated with AD also modify the POAG phenotype. APOE(-219G) is associated with increased optic nerve damage, as reflected by increased cup:disk ratio and visual field alteration. In addition, APOE(-491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition and an increased frequency of glaucoma in patients with AD. The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG.

Adult↗