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Biomedical subjects

K Stefansson

Publications and source records attributed to K Stefansson.

At least 19 recordsLinked to original sources
PubMed2003

Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes.

BACKGROUND: Psoriasis is strongly associated with certain human leucocyte-associated antigens, especially HLA-Cw*0602. Patients who are HLA-Cw*0602 positive have been reported to have more active disease and a younger age at disease onset than HLA-Cw6-negative patients. OBJECTIVES: To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients. METHODS: One thousand and six patients with chronic plaque psoriasis were evaluated clinically and HLA-C typed. In addition, 512 unrelated controls were typed for HLA-C. RESULTS: Of the patients 646 (64.2%) were HLA-Cw*0602 positive, and 68 (6.8%) were homozygous for this allele. Heterozygosity was associated with a relative risk of developing psoriasis of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset (mean 15.0 vs. 17.8 years, P = 0.04). However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes or any other clinical parameter recorded. CONCLUSIONS: Homozygosity for the gene in the major histocompatibility complex region has a major additive impact on the risk of developing psoriasis and predisposes to an earlier disease onset, but does not have any marked influence on the phenotype or the severity of the disease.

Adolescent↗
PubMed2002

Genetic factors contribute to the risk of developing endometriosis.

BACKGROUND: Endometriosis is known to cluster within nuclear families. The extent of familial clustering can be evaluated in Iceland with its large population-based genealogical database. METHODS AND RESULTS: Applying several measures of familiality we demonstrated that 750 women with endometriosis were significantly more interrelated than matched control groups. The risk ratio for sisters was 5.20 (P < 0.001) and for cousins 1.56 (P = 0.003). The average kinship coefficient for the patients was significantly higher than that calculated for 1000 sets of 750 matched controls (P < 0.001) and this remained significant when contribution from first-degree relatives was excluded (P < 0.05). The minimum number of ancestors required to account for the group of patients was compared with the minimum number of ancestors required to account for the control groups at different time points in the past. The minimum number of founders for the group of patients was significantly smaller than for the control groups. Affected cousin pairs were as likely to be paternally connected as maternally connected. CONCLUSIONS: This is the first population-based study using an extensive genealogy database to examine the genetic contribution to endometriosis. A genetic factor is present, with a raised risk in close and more distant relatives, and a definite kinship factor with maternal and paternal inheritance contributing.

Cluster Analysis↗
PubMed2001

Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland.

Numerous asthma and atopy loci have been reported in studies demonstrating associations of the asthma-related phenotypes atopy, elevated IgE levels, and bronchial hyperresponsiveness with alleles of microsatellite markers and single-nucleotide polymorphisms (SNPs) within specific cytokine/chemokine and IgE-regulating genes. Although the studies reporting these observations are compelling, most of them lack statistical power. We assessed the nature, pattern, and frequency of SNPs in 24 candidate genes in Iceland and looked for associations with asthma and atopy. We identified 42 SNPs with an average minor allele frequency of 20.3% (asthma) and 20.7% (control). Twenty SNPs (48%) were within coding sequences and 90% of those led to a predicted change in protein sequence. No differences were detected in the allelic frequencies of SNPs in any of these candidate genes between control subjects and the patients with atopic asthma. Moreover, linkage analysis that included 269 patients with atopic asthma uncovered no evidence of linkage to markers associated with these genes. We conclude that this study has failed to produce evidence in support of the notion that variations within these 24 candidate atopy and asthma genes significantly influence the expression of the atopic asthmatic phenotype or contribute to the susceptibility of atopic asthma.

Adolescent↗
PubMed2001

Endometriosis is not associated with or linked to the GALT gene.

OBJECTIVE: To investigate a possible association between the carrier frequency of the N314D mutation in the galactose-1-phosphate uridyl transferase (GALT) gene and endometriosis and linkage to the short arm of chromosome 9, where the GALT gene resides. DESIGN: Association and linkage study. SETTING: Population material collected for case and family studies in endometriosis. PATIENT(S): Women diagnosed with endometriosis by laparotomy or laparoscopy. INTERVENTION(S): Association with the GALT gene investigated by genotyping 85 affected women and 213 unrelated control women and a scan for linkage to chromosome 9 in 205 women from 64 families with endometriosis. MAIN OUTCOME MEASURE(S): Multipoint parametric lod scores and frequency of alleles. RESULT(S): There was no significant difference in allele frequency for the N314D polymorphism in patients compared with control subjects. No evidence for linkage was found to chromosome 9p, where the GALT gene resides. CONCLUSION(S): The experiments reported herein provide no evidence supporting involvement of the GALT locus in the development of endometriosis.

Chromosome Mapping↗
PubMed2001

The role of linkage studies for common diseases.

Linkage analysis when applied to common diseases has had limited success in mapping the genes contributing to them. We present a genealogic approach applied to the relatively isolated population of Iceland. We use an affecteds-only, allele-sharing method--which does not specify any particular inheritance model--implemented in the new statistical program, Allegro, which calculates lod scores based on multipoint calculations. We describe how this approach has helped us to map a gene contributing to the common late-onset form of Parkinson's disease to statistical significance.

Case-Control Studies↗
PubMed2001

Association between IL-1beta/TNF-alpha-induced glucocorticoid-sensitive changes in multiple gene expression and altered responsiveness in airway smooth muscle.

The pleiotropic cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha have been implicated in the pathophysiology of asthma. To elucidate the role of these cytokines in the pro-asthmatic state, the effects of IL-1beta and TNF-alpha on airway smooth muscle (ASM) responsiveness and ASM expression of multiple genes, assessed by high-density oligonucleotide array analysis, were examined in the absence and presence of the glucocorticoid dexamethasone (DEX). Administration of IL-1beta/TNF-alpha increased ASM contractility to acetylcholine and impaired ASM relaxation to isoproterenol. These pro-asthmatic- like changes in ASM responsiveness were associated with IL-1beta/ TNF-alpha-induced mRNA expression of a host of proinflammatory genes that regulate transcription, cytokines and chemokines, cellular adhesion molecules, and various signal transduction molecules that regulate ASM responsiveness. In the presence of DEX, the changes induced in ASM responsiveness were abrogated, and most of the IL-1beta/TNF-alpha-mediated changes in proinflammatory gene expression were repressed, although mRNA expression of a small number of genes was enhanced by DEX. Collectively, the observations support the concept that, together with its role as a regulator of airway tone, in response to IL-1beta/TNF-alpha, the ASM expresses a host of glucocorticoid-sensitive genes that contribute to the altered structure and function of the airways in the pro-asthmatic state. We speculate that glucocorticoid-sensitive, cytokine-induced pathways involved in ASM cell signaling represent important targets for new therapeutic interventions.

Acetylcholine↗
PubMed2000

Familial aggregation of Parkinson's disease in Iceland.

BACKGROUND: The role of genetics in early-onset Parkinson's disease has been established, but whether there is a genetic contribution to the more common, late-onset form remains uncertain. METHODS: We reviewed the medical records and confirmed the diagnosis of Parkinson's disease in 772 living and deceased patients in whom the disease had been diagnosed during the previous 50 years in Iceland. With the use of an extensive computerized data base containing genealogic information on 610,920 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than random members of the population (control subjects). RESULTS: Patients with Parkinson's disease, including a subgroup of 560 patients with late-onset disease (onset at >50 years of age), were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. The risk ratio for Parkinson's disease was 6.7 (95 percent confidence interval, 4.3 to 9.6) for siblings, 3.2 (95 percent confidence interval, 1.2 to 7.8) for offspring, and 2.7 (95 percent confidence interval, 1.6 to 3.9) for nephews and nieces of patients with late-onset Parkinson's disease. CONCLUSIONS: Late-onset Parkinson's disease has a genetic component as well as an environmental component.

Age of Onset↗
PubMed2000

Long PCR detection of the C4A null allele in B8-C4AQ0-C4B1-DR3.

The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.

Alleles↗
PubMed2000

The mutation rate in the human mtDNA control region.

The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

Base Sequence↗
PubMed1998

Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system.

The oligodendrocyte-myelin glycoprotein (OMgp) is a 110-kDa glycosylphosphatidylinositol-linked protein that was initially identified as a myelin-specific protein but whose precise function remains unknown. In this study, immunohistochemistry, western blots, in situ hybridization, and northern blots were used to determine the distribution of OMgp in the mouse brain. OMgp is present in a concentration detectable on western blots in the brains of newborn mice, and its concentration gradually increases until day 24 of life. OMgp mRNA is also present in amounts detectable on northern blots in the brains of newborn mice, and its concentration gradually increases until day 21 of life, after which the concentration diminishes a little. Most of the OMgp in the mouse brain appears to be expressed in diverse groups of neurons, but it is particularly prominent in large projection neurons such as the pyramidal cells of the hippocampus, the Purkinje cells of the cerebellum, motoneurons in the brainstem, and anterior horn cells of the spinal cord. However, OMgp is not confined to these cells and is expressed in cells in the white matter as well. The OMgp gene is placed within an intron of the neurofibromatosis type I gene and on the opposite strand. This organization raises the possibility that there may be a relationship between the functions of the products of the two genes. In support of this possibility, we show that within the mouse CNS OMgp and neurofibromin are expressed in the same cell types.

Aging↗
PubMed1998

Population genomics: laying the groundwork for genetic disease modeling and targeting.

The family has proven the most appropriate unit with which to study Mendelian diseases. There are, however, certain limitations on the use of the family as a fundamental unit in the study of common diseases, most of which are complex genetic diseases. The groups that are most likely to yield the genetics of complex diseases are isolated populations with strong founder effects. Therefore, access to such populations is proving to be a precious resource in the work on the genetics of common diseases. The Icelandic population is an excellent population for the study of the genetics of common diseases; it is genetically homogeneous, with founder effects for many traits, and the genealogy of the entire nation is well documented back to the founding days. Furthermore, the nature of the Icelandic national health care system facilitates the assignment of phenotypes in the search for disease genes. Decode Genetics has begun to study of the genetics of 20 of the most common diseases in the Western parts of the world. The company has placed the groundwork for the construction of an encrypted database with information on the health care of the entire nation, genealogy of the entire nation, genotyping information with high density of markers on a large part of the nation (including typing for known disease genes), and resource use in the Icelandic health care system. The plan is to build the database with approval of participating individuals as well as Icelandic government and health care officials. The database will be used to model health care as viewed in the context of genetic predisposition to the development of disease. The database will also be used in the search for drug targets in complex diseases and in the solution of pharmacogenomic problems. Basing the company in Iceland directly benefits the population in terms of employment and return on investment as well as providing the health care system with an information resource which may be used in preventive medicine and in the optimization of health care in Iceland.

Genealogy and Heraldry↗
PubMed1997

Beta-trace gene expression is regulated by a core promoter and a distal thyroid hormone response element.

We isolated and characterized the human beta-Trace protein (betaTP) gene promoter. betaTP, also known as prostaglandin D2 synthase, is a lipocalin secreted from the choroid plexus and meninges into cerebrospinal fluid. Basal transcription of the betaTP gene is directed from a core promoter found within the first 325 bases of the 5'-flanking sequence. The betaTP gene promoter is responsive to thyroid hormone (3,3',5-triiodothyronine, T3) and efficiently repressed by unliganded human thyroid hormone receptor beta (TRbeta). Functional analysis of the betaTP promoter in TE671 cells revealed that responsiveness to T3 occurs in sequences 2.5 kilobase pairs 5' of the start site. Within the hormone-responsive region we identified a thyroid hormone response element (TRE) located from -2576 to -2562 base pairs relative to the transcription start site. The betaTP TRE is composed of two directly repeated consensus half-sites separated by a 3-base pair space (DR3). The betaTP TRE forms specific complexes with TRbeta. We have shown that a gene active in the choroid plexus and meninges is responsive to T3. T3 may play a role in the regulated transport of substances into the cerebrospinal fluid and ultimately the brain.

Base Sequence↗
PubMed1996

Molecular evolution of tau protein: implications for Alzheimer's disease.

The brains of patients with Alzheimer's disease contain deposits of hyperphosphorylated tau proteins that have polymerized into insoluble fibrils. These deposits, in neurofibrillary tangles and dystrophic neurites, correlate with loss of cells and synapses, and consequently with dementia. Neurofibrillary pathology occurs in humans, as well as certain ungulates, including goats, sheep, and cows, but not in nonhuman primates. We hypothesize that the differences among species in the propensity to develop neurofibrillary pathology may be attributable to variations in the amino acid sequence of tau proteins. To investigate this hypothesis, we sequenced tau-encoding mRNA transcripts from the brains of rhesus monkey and domesticated goat and compared them with the known sequences of tau mRNAs from humans. The major difference we observed was that some tau mRNAs from rhesus monkey neocortex contain exon 8, whereas this exon has not been found in cortical tau from human or goat. Cows express very low levels of exon 8, and they tend to develop sparse neurofibrillary pathology with aging. We also found a transcribed tau-related pseudogene in rhesus monkey, which may be present in humans. We propose that differences in the expression of tau and tau-related protein sequences may underlie the predilection of human but not monkey brains to develop neurofibrillary degeneration.

Alzheimer Disease↗
PubMed1995

Focal brain injury and upregulation of a developmentally regulated extracellular matrix protein.

Tenascin is an extracellular matrix glycoprotein expressed during both normal development and neoplastic growth in both neural and nonneural tissues. During development of the central nervous system (CNS), tenascin is synthesized by glial cells, in particular by immature astrocytes, and is concentrated in transient boundaries around emerging groups of functionally distinct neurons. In the mature CNS, only low levels of the glycoprotein can be detected. The present study demonstrates that following trauma to the adult human cerebral cortex, discrete populations of reactive astrocytes upregulate their expression of tenascin and dramatically increase their transcription of the tenascin gene. The enhanced expression of tenascin may be involved in CNS wound healing, and may also affect neurite growth within and around a brain lesion.

Adult↗