Biomedical subjects
P Kauppi
Publications and source records attributed to P Kauppi.
A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma.
We have analyzed a dense set of single-nucleotide polymorphisms (SNPs) and microsatellites spanning the T-helper cytokine gene cluster (interleukins 3, 4, 5, 9, and 13, interferon regulatory factor-1, colony-stimulating factor-2, and T-cell transcription factor-7) on 5q31 and the gene encoding the interleukin-4 receptor (IL4R) on 16p12 among Finnish families with asthma. As shown by haplotype pattern mining analysis, the number of disease-associated haplotype patterns differed from that expected for the 129Q allele polymorphism in IL13 for high serum total immunoglobulin (Ig) E levels, but not for asthma. The same SNP also yielded the best haplotype associations. For IL4R, asthma-associated haplotype patterns, most spanning the S411L polymorphism, showed suggestive association. However, these haplotypes consisted of the major alleles for the intracellular part of the receptor and were very common among both patients and controls. The minor alleles 503P and 576R have been reported to be associated with decreased serum IgE levels and changes in the biological activity of the protein, especially when inherited together. In the Finnish population, these two polymorphisms segregated in strong linkage disequilibrium. Our data support previous findings regarding L4R, indicating that 503P and 576R may act as minor protecting alleles for IgE-mediated disorders.
A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population.
The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment. The pedigrees in our study (n=86) originate in eastern central Finland (Kainuu province). According to census records, this region had only 200 households (2,000 inhabitants) in the mid sixteenth to mid seventeenth centuries. The current population of 100,000 represents the expansion of these founders within the past 400 years. Because this population is relatively homogeneous, we hypothesized that the molecular genetic mechanisms underlying asthma might also have reduced heterogeneity and therefore be easier to dissect than in mixed populations. A recent twin family study supported a strong genetic component for asthma in Finland. We carried out a genome-wide scan for susceptibility loci in asthma in the Kainuu subpopulation. We identified two regions of suggestive linkage and studied them further with higher-density mapping. We obtained evidence for linkage in a 20-cM region of chromosome 7p14-p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes. The strongest linkage was seen for high serum IgE (non-parametric linkage (NPL) score 3.9, P=0.0001), exceeding the threshold for genome-wide significance based on simulations. We also observed linkage between this locus and asthma or atopy in two independent data sets.
Cystic fibrosis gene mutations deltaF508 and 394delTT in patients with chronic sinusitis in Finland.
Previous studies have shown that cystic fibrosis (CF) gene mutations are linked to several severe chronic infections. Chronic sinusitis is one condition that may well be influenced by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We studied two prevalent CF mutations (AF508 and 394delTT) in a population with a low incidence of CF. The carrier frequency of the CF mutations in the Finnish population is approximately 1 in 80. We examined DNA specimens from 127 chronic sinusitis patients and found one patient who was heterozygous for 394delTT gene mutation. None of the DNA specimens had any AF508 mutation. This study shows that in a population with a low incidence of CF there was no abnormal carrier distribution of the two most common CF gene mutations in a group of chronic sinusitis patients. Routine screening of sinusitis patients for CF mutations provides no additional information on the etiology of chronic sinusitis.
The IL9R region contribution in asthma is supported by genetic association in an isolated population.
Interleukin 9 (IL9) is involved in mast cell maturation and the enhancement of IgE production by B cells. Furthermore, linkage data in human and mice have suggested that IL9 may contribute to asthma. Since our genetic analysis of the 5q cytokine cluster did not support a genetic role for the IL9 gene, we became interested in the IL9 receptor gene (IL9R) in the pseudoautosomal region. We genotyped markers sDF2 and sDF1 close to the IL9R gene among 289 affected and 368 family-based controls. The results were studied by using linkage, transmission disequilibrium, association and homozygosity analyses. Linkage analyses remained negative, presumably because of our low power for linkage study. However, all the other analyses yielded evidence that the IL9R gene region may have a role in the development of asthma. The sDF2*10 allele was more frequently transmitted than untransmitted to asthmatic offspring (34 vs 16, pchi2 < or = 0.01), and it was found homozygotic among asthma patients more often than expected (Psimul2 = 0.009). Also, a specific X chromosomal haplotype, sDF2*10-sDF1*6 associated with asthma (40 vs 7, Pchi2 < 0.005, Psimul1 = 0.04).
Association study of the chromosomal region containing the FCER2 gene suggests it has a regulatory role in atopic disorders.
On the basis of studies with animal models, the gene for the low-affinity receptor for immunoglobulin E (IgE) (FCER2, CD23) has been implicated as a candidate for IgE-mediated allergic diseases and bronchial hyperreactivity, or related traits. Given evidence for genetic complexity in atopic disorders, we sought to study two European subpopulations, Finnish and Catalonian. We studied three phenotypic markers: (1) total serum IgE level; (2) asthma; and (3) specific IgE level for a mixture of the most common aeroallergens in Finland. Altogether, eight polymorphic markers spanning a region of 10 cM around the FCER2 gene on chromosome 19p13 were analyzed in 124 families. The physical order of the markers and the location of the FCER2 gene were confirmed by using radiation hybrids. The allele and haplotype association study showed a suggestive haplotype association (significance of p </= 0.03 based on a permutation test) for a high serum IgE response. In a subset of chromosomes segregating with asthma in families with two or more affected members, a single haplotype was found to be highly enriched (p = 8.3 x 10(-6)). However, sequence polymorphisms, which would verify structural differences in the FCER2 gene, were not detected in the coding region of the receptor. Our results suggest that chromosome 19p13 might harbor a genetic determinant of IgE-related traits. Studies in other population samples are needed to verify this finding.
Verification of self-reported asthma and allergy in subjects and their family members volunteering for gene mapping studies.
Studies which aim at mapping genes contributing to the development of asthma and atopy demand that hundreds of patients and their family members be assessed. In Finland, the Social Insurance Institution (SII) grants substantial reimbursement for medication to all patients who meet diagnostic criteria of asthma, which include a history of asthmatic symptoms and a measured reversibility of bronchial obstruction. To recruit a large number of asthma patients efficiently in a short period of time, we took advantage of the national reimbursement procedure and retrospectively collective data on patients' medical history and lung function test results at the time of diagnosis. First, we wanted to investigate if the reimbursements could be regarded as objective verification for self-reported asthma. Altogether 335 adult self-reported asthma patients were evaluated, 87% of them were verified as having chronic asthma. Reimbursement for medication showed a sensitivity of 95% and a specificity of 76% for verified asthma. Second, we were interested to see if self-reported nasal allergic symptoms or self-reported physician diagnosed allergic rhinitis were sensitive and specific measures of allergy. The self-reported allergic nasal symptoms had a poor specificity (31% in the proband group and 59% in the family members group) when compared to the allergy screening test (Phadiatop). The best verification for self-reported asthma was achieved by combining the information on self-reported disease, granted reimbursement by the SII and the medical records. For allergies, the specificity of self-reporting was far too low to be used alone, and a positive allergy screening test together with relevant symptoms was chosen as a marker of allergy.
Phenotyping asthma patients for a gene mapping study in Finland.
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Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population.
Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and to delimit the critical region, we took advantage of an isolated founder subpopulation in Finland to study genetic linkage and haplotype associations. Sixteen polymorphic markers, including the Interleukin-4 and -9 genes (IL4, IL9), were physically ordered and genotyped in 157 nuclear families. Genetic linkage studies involving sib- and cousin-pair analyses found no evidence of genetic linkage between markers in 5q and either serum IgE levels or asthma. Haplotype association studies were also performed. Although initial inspection suggested the possibility of linkage disequilibrium in the region of IL9, we developed a rigorous permutation test for assessing association and determined that the association was no greater than would be expected by chance. Sequence analysis of the IL9 gene in three patients sharing a possibly conserved haplotype revealed a T113M coding polymorphism, but this variant showed no association with either serum IgE levels or asthma. We conclude that allelic variation at chromosome 5q31 is not likely to contribute to inheritance of serum IgE levels or the development of asthma in this Finnish subpopulation.
Ocular characteristics in nephropathia epidemica or Puumala virus infection.
PURPOSE: We documented the largest series so far concerning the ocular characteristics of nephropathia epidemica. METHODS: A total of 37 consecutive nephropathia epidemica patients underwent a comprehensive ophthalmic examination during hospitalization for systemic infection, and a control examination after recovery. RESULTS: The most common ocular symptoms were: frontal headache or periocular pain (75.6%), blurred vision (54.1%) and photophobia (10.8%). The best corrected visual acuity of 7 patients (18.9%) was reduced during the acute phase as compared to the later control examination. Myopic shift was found in 15 patients (40.5%), three of whom (8.1%) developed real transient myopia. There were no attacks of angle closure glaucoma in this series. On the contrary, the intraocular pressure was decreased in 49 eyes (66.2%) during the acute stage of the disease. Lid edema was present in 28 eyes (37.8%), conjunctival injection in 20 eyes (27.0%), chemosis in 8 eyes (10.8%) and subconjuctival bleeding in 3 eyes (4.1%). Signs of acute anterior uveitis were found in 10 eyes (13.5%), however, this resolved without treatment. In one eye retinal edema with hemorrhages was detected. Ultrasonography revealed narrowing of the anterior chamber during the acute phase in 69 eyes (93.2%) and thickening of the crystalline lens in 64 eyes (86.5%). CONCLUSION: Ophthalmic findings in nephropathia epidemica are not uncommon. The symmetry of the clinical manifestations reflects the systemic nature of the underlying infection.