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T Laitinen

Publications and source records attributed to T Laitinen.

At least 19 recordsLinked to original sources
PubMed2007

Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma.

BACKGROUND: Several genome scans have reported linkage of markers on chromosome 7p with asthma and related phenotypes in different populations. A fine mapping in Finnish and French-Canadian populations has associated the GPR154 gene (also known as G-protein-coupled receptor for asthma susceptibility, GPRA) with elevated IgE or asthma. OBJECTIVE: To confirm chromosome 7p linkage and candidate gene association in Italian families with atopic asthma. METHODS: In a two-phase approach, we first performed a linkage analysis of chromosome 7, and then a family-based association study on the GPR154 gene for allergic asthma phenotypes in the Italian population. RESULTS: The screening of 117 families with 19 microsatellite markers showed potential linkage for elevated IgE (P<0.002 at 22 cM from p-ter), asthma (P<0.005 at 44 cM), or atopy (P<0.005 at 54 cM). In the second phase of the present study, candidate gene GPR154, which is located in the phase one-linked region, was investigated in 211 families with seven single nucleotide polymorphisms (SNPs) that tag most haplotype variability, by the pedigree disequilibrium test. Elevated IgE levels were associated with two GPR154 gene SNPs (SNP 546333, P=0.0046; rs740 347, P=0.006), and with haplotypes in the global test (P=0.013). Haplotype analysis performed in nuclear families having at least 1 asthmatic parent showed a significant association with asthma (P=0.0173), atopy (P=0.0058), SPT (P=0.0025), and bronchial hyper reactivity (P=0.0163). CONCLUSION: These results support a susceptibility locus for asthma and related phenotypes on chromosome 7, and are in agreement with recent reports suggesting that a common susceptibility factor for atopic manifestations in asthma is likely conferred by the locus containing the GPR154 gene.

Asthma↗
PubMed2004

Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

We investigated inducibility of life-threatening arrhythmias with programmed ventricular stimulation (PVS) in relation to clinical markers of sudden cardiac death (SCD) in subjects with hypertrophic cardiomyopathy (HCM) attributable to the Asp175Asn mutation in the alpha-tropomyosin gene (TPM1-Asp175Asn). PVS was performed with up to three extrastimuli and distribution of markers of SCD was evaluated in 21 adult subjects with the TPM1-Asp175Asn. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in seven of 21 subjects (33%). Inducible subjects had more severe left ventricular hypertrophy (LVH) and an increased number of markers of SCD (family history of SCD, syncope or presyncope, fall in systolic blood pressure (BP) during exercise, documented non-sustained VT (NSVT), and marked LVH) compared to non-inducible subjects (IVS 2.4 +/- 0.3 cm vs. 1.6 +/- 0.5 cm, P < 0.001; and two to three vs. one to two markers of SCD, P = 0.007, respectively). In conclusion, in HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, life-threatening arrhythmias were induced in one third of the patients. Inducibility was associated with the maximum left ventricular (LV) thickness and the number of markers of SCD, suggesting that in HCM patients with an identical causative mutation, susceptibility to ventricular arrhythmias is related to the cardiomyopathic phenotype.

Adult↗
PubMed2004

Association study of 15 novel single-nucleotide polymorphisms of the T-bet locus among Finnish asthma families.

OBJECTIVE: T-box expressed in T cells (T-bet) is a transcription factor regulating the commitment of T helper (Th) cells by driving the cells into the Th1 direction. Abnormal Th1/Th2 balance may lead to complex disorders like asthma or autoimmune diseases. Recent studies have suggested that T-bet might be a candidate gene for asthma. This led us to screen 23 Finnish individuals for single-nucleotide polymorphisms (SNPs) in the T-bet locus and study the association between the SNPs and high serum IgE level and asthma. METHODS: We screened all six exons, adjacent intronic areas and 2 kb of the 5'-flanking region from 23 individuals utilizing WAVE trade mark technology. To explore whether T-bet is associated in serum IgE regulation or asthma we genotyped the SNPs in a Finnish asthmatic founder population. The association analyses were made using haplotype pattern mining. RESULTS: Fifteen novel SNPs were found in the T-bet gene. Within the Finnish asthmatic founder population, there was no association between T-bet SNPs and high serum IgE level or asthma. CONCLUSIONS: The genetic variability in the T-bet gene does not play a role in the pathogenesis of human asthma. Our results provide a novel panel of SNPs in T-bet and will help determine whether the SNPs have a functional role in other T cell-mediated diseases.

Asthma↗
PubMed2004

Two functional variants of the superoxide dismutase genes in Finnish families with asthma.

BACKGROUND: Functional polymorphisms in the genes encoding superoxide dismutases (SOD)-that is, superoxide scavenging antioxidant enzymes-may play an important role in the development of inflammatory airway diseases such as asthma. METHODS: The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon-intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis. RESULTS: None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded. CONCLUSIONS: It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.

Adolescent↗
PubMed2003

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Activin Receptors, Type I↗
PubMed2002

Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.

BACKGROUND: The prevalence of sporadic and familial idiopathic pulmonary fibrosis (IPF) cases in Finland was evaluated according to the revised recommendations of the American Thoracic Society. METHODS: All Finnish pulmonary clinics (n=29) were included in the primary screening. Hospital data bases were used to identify patients with the diagnosis "alveolitis fibroticans idiopathica" (J84.1 in ICD-10 classification). The total number of patients with IPF was extrapolated based on the evaluation of random samples of case records in different centres. Families with more than one potentially affected member were identified from a questionnaire study and the diagnosis was verified from the medical records. RESULTS: Using this approach, the nationwide prevalence of IPF in Finland was estimated to be 16-18/100 000. In 90% of the patients lung involvement was assessed by high resolution computed tomographic (HRCT) scanning and in 31% a surgical biopsy specimen was available, further confirming the diagnosis. Seventeen multiplex families with 2-5 affected family members were identified, giving a prevalence of 5.9/million for familial IPF in Finland. Both multiplex and sporadic families were clustered in Eastern Finland. This clustering reflects the demographic history of Finland in the 16th century and suggests that multiplex families may share a common ancestor in the last 20-25 generations. CONCLUSION: The familial form explained 3.3-3.7% of all Finnish cases of IPF diagnosed according to the revised international guidelines. Geographical clustering of multiplex families suggests a recent founder effect in patients with familial IPF.

Aged↗
PubMed2001

Role of major histocompatibility complex class III genes in recurrent spontaneous abortions.

Increased parental Human Leukocyte Antigen (HLA) sharing has been repeatedly reported in recurrent spontaneous abortions (RSA). Parental HLA sharing increases the chance of feto-maternal histocompatibility and potentially affects maternal allo-recognition of the fetus. However, strong linkage disequilibrium across the whole Major Histocompatibility Complex (MHC) region makes it difficult to interpret parental HLA sharing conclusively. It is not known whether the shared HLA gene as such or an unknown gene(s) in linkage disequilibrium or a combination of several loci are causing the disease. Interestingly, in mouse and rat MHC-linked, recessive genes are known to control the reproduction, development and growth of the fetus. Human analogs have not been identified. Compared to HLA genes, MHC Class III has been studied much less in RSA. However, there are some observations of an increased number of unexpressed complement C4 alleles in RSA spouses. Complement C4 genes are located in a chromosomal region characterized by extremely high gene density and frequent gene rearrangements. C4 "null" alleles can act as markers of gene rearrangements in Class III unfavorable for pregnancy outcome. Many of the novel genes located in this region by sequencing serve as new candidates for RSA, since they have housekeeping functions and some of them are highly expressed in human reproductive organs.

Abortion, Habitual↗
PubMed2001

Single region linkage analyses of asthma: description of data sets.

Linkage (genotypic) data from the 5q31-33 candidate region for asthma were contributed to Genetic Analysis Workshop 12 by members of the International Consortium on Asthma Genetics (COAG). Data came from five independent studies sampled from five countries. Genotypic data for a total of 26 markers were available, although the number of markers typed in each data set varied. Phenotypic and genotypic data was available from a total of 569 families and 3,175 subjects. The phenotypic data available varied among the studies; however information regarding physician-diagnosed asthma and total serum IgE levels was available in all five studies. This paper describes the ascertainment, data collection methods, phenotypic data, and genotypic data available for the single linkage region analyses undertaken for Genetic Analysis Workshop 12.

Adolescent↗
PubMed2001

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.

Alleles↗
PubMed2001

Normal values for the Pelli-Robson contrast sensitivity test.

PURPOSE: To define normal values for the Pelli-Robson contrast sensitivity test in different age groups. SETTING: University Eye Clinic of Kuopio, Kuopio, Finland. METHODS: Contrast sensitivity was measured with the Pelli-Robson contrast sensitivity test in 87 persons (60 women and 27 men) with a mean age of 34.5 years +/- 20.8 (SD) (range 6 to 75 years). Results were studied by age group (years): 6 to 9, 10 to 19, 20 to 29, 30 to 39, 40 to 49, 50 to 59, and 60 and older. Of 163 eyes, both were healthy in 76 persons and 1 was healthy in 11. Study participants consisted of members of the staff of the Kuopio University Hospital Eye Clinic, medical students at the Kuopio University, and patients of the Strabismus and General Ophthalmology Units of the Eye Clinic and their accompanying persons. Two test distances were used: 1 m and 3 m. Eyes were tested individually; thereafter, the test was done binocularly. RESULTS: There were significant differences in logarithmic contrast sensitivity values among the age groups except on the test of the left eye at 1 m. The P values for the right eye at 1 m and 3 m, left eye at 1 m and 3 m, and both eyes at 1 m and 3 m were 0.003, 0.002, 0.19, 0.043, 0.037, and 0.003, respectively. The mean test results in 1 eye varied from 1.68 in the 60 year and older group to 1.84 in the 20 to 29 and 30 to 39 year groups. Binocularly, the variation was from 1.73 in the 40 year group to 1.99 in the 30 year group. CONCLUSIONS: The Pelli-Robson contrast sensitivity test is a quick and reliable method in a clinical setting. Normal values of the test can be of help in evaluating cataract patients or patients having refractive surgery.

Adolescent↗
PubMed2001

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.

Asthma↗
PubMed2001

Heart rate variability and its determinants in patients with severe or mild essential hypertension.

How cardiac autonomic nervous control is related to the severity of essential hypertension in patients receiving long-term antihypertensive therapy is not well known. The aim of this study was to examine heart rate variability (HRV), a non-invasive measure of cardiac autonomic function, in patients with long-term and medically treated mild and severe essential hypertension and healthy control subjects, and to assess the clinical determinants of HRV in these patients. Thirty-four patients with severe essential hypertension (SEHT) and 29 with mild essential hypertension (MEHT) as well as healthy age- and sex-matched control subjects were studied. HRV was assessed from 10 min ECG-recordings during paced (0.2 Hz) breathing at rest and expressed as time and frequency domain measures. In the SEHT group time (SDNN, RMSSD) and frequency domain measures (total power, low-frequency (LF) power and high-frequency (HF) power of HRV in absolute units, and LF and HF power of HRV in normalized units) of HRV were significantly lower when compared with those of the control group. The MEHT and control groups did not differ from each other with respect to time or frequency domain measures of HRV. Comparison between the hypertensive groups showed that SDNN, total power, LF power and HF power were lower in the SEHT group compared with the MEHT group (P<0.05 for all). Among hypertensive patients RR-interval, age, gender, systolic finger blood pressure and diastolic office blood pressure as well as 24-h blood pressure were significant determinants of HRV. In conclusion, we found that the severity of chronic essential hypertension seems to be related to the severity of impairment of cardiac autonomic control.

Adult↗
PubMed2001

Mitral valve prolapse and mitral regurgitation are common in patients with polycystic kidney disease type 1.

Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased occurrence of cardiac valve abnormalities. However, the prevalence of cardiac abnormalities in patients with a uniform genotype of ADPKD has not been previously reported. We performed M-mode and color Doppler echocardiography on 109 patients from 16 families with polycystic kidney disease type 1 (PKD1). Findings were compared with those of 73 unaffected family members and 73 healthy controls. Mitral valve prolapse was found in 26% of patients with PKD1, 14% of unaffected relatives, and 10% of control subjects. The prevalence of hemodynamically significant mitral regurgitation (grade 2 or 3) was 13%, 4%, and 3%, respectively. Prevalences of grade 2 or 3 aortic regurgitation (8%, 4%, and 3%, respectively) and tricuspid regurgitation (4%, 6%, and 7%, respectively) were not significantly different among the three groups. Left ventricular hypertrophy (LVH) was found in 19% of subjects with PKD1, 6% of unaffected relatives, and 4% of control subjects. Systolic blood pressure and severity of renal insufficiency were related to mitral regurgitation and LVH in subjects with PKD1. The prevalence of cardiac valve abnormalities did not differ between unaffected relatives and control subjects. Mitral valve prolapse is a characteristic finding in patients with PKD1. Conversely, mitral regurgitation and LVH are likely to be secondary to elevated blood pressure in these patients.

Adolescent↗
PubMed2001

The functionally important IL-10 promoter polymorphism (-1082G-->A) is not a major genetic regulator in recurrent spontaneous abortions.

Enhanced secretion of anti-inflammatory Th2 cytokines is a characteristic feature in normal physiological pregnancy. In recurrent spontaneous abortions (RSA), however, defective production of interleukin-10 (IL-10) and other Th2 cytokines has been shown in humans. Association studies have shown that a base exchange polymorphism (guanine-->adenine) at position -1082 of the IL-10 promoter is associated with differential IL-10 production. Since factors contributing to IL-10 production appear to be important in RSA, we studied the IL-10 genotypes of 38 Finnish women with a history of three or more consecutive abortions and 131 ethnically matched healthy controls. No significant differences in the -1082 allele or genotype frequencies were found between the controls and the RSA women. The present study suggests that the IL-10 -1082 (G-->A) polymorphism is not a major genetic regulator in RSA.

Abortion, Habitual↗
PubMed2001

Perinatal risk factors for hay fever--a study among 2550 Finnish twin families.

Previous studies have suggested that perinatal factors influence the risk for asthma but population studies on perinatal factors and risk for hay fever are few. We studied the effect of perinatal factors on the risk for hay fever among adolescent twins by a questionnaire study involving five consecutive nation-wide birth cohorts of 16-year-old twins and their parents. The risk for parent-reported, doctor-diagnosed hay fever in the adolescents associated with several perinatal characteristics was assessed with logistic regression analysis among individuals and by a discordant pair analysis. In the univariate analysis of the birth factors, the risk for hay fever increased with increasing birth weight (p for trend = 0.048, OR for those > or = 3000 g 1.35, 95% CI 0.91-2.02 compared to those < 2000 g) and gestational age (p for trend = 0.04, OR for those born after 40 weeks of gestation 2.24, 95% CI 1.03-4.86, compared to those born before 33 weeks of gestation) and was lower in those subjects hospitalised in the neonatal period (OR 0.74, 95% CI 0.58-0.93). Because of significant interactions between parental hay fever status and birth factors (ponderal index, p = 0.03 and maternal age p = 0.04), stratified analysis were performed. The positive association between birth weight and hay fever was most obvious among adolescents with no parental history of hay fever (p for trend = 0.03). Similar, though not significant, trends were found with other birth factors among these families, whereas no such trend was found among adolescents with parental hay fever, suggesting that gestational maturity increases the risk for hay fever in the absence of genetic predisposition. However, of the perinatal factors only neonatal hospitalisation (OR 0.75, 95% CI 0.59-0.96) remained a significant risk factor for the development of hay fever, when adjusted for non-perinatal factors.

Adolescent↗
PubMed2000

A first trial of retrospective collaboration for positional cloning in complex inheritance: assay of the cytokine region on chromosome 5 by the consortium on asthma genetics (COAG).

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that differ in several ways. Combination of evidence over multiple samples with 1,037 families supports loci contributing to asthma susceptibility in the cytokine region on 5q [maximum logarithm of odds (lod) = 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboration on linkage appear to have been solved, providing far more information than a single study. A multipoint lod table evaluated at commonly agreed reference loci is required for both collaboration and metaanalysis, but variations in ascertainment, pedigree structure, phenotype definition, and marker selection are tolerated. These methods are invariant with statistical methods that increase the power of lods and are applicable to all diseases, motivating collaboration rather than competition. In contrast to linkage, positional cloning by allelic association has yet to be extended to multiple samples, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology.

Asthma↗
PubMed2000

A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele.

A susceptibility gene for psoriasis, a chronic skin disorder, resides in chromosome 6p near the HLA-C locus. Sequencing of the region has allowed the identification of a new gene, HCR. We found that HCR is highly polymorphic with at least 12 coding variants. An association study of the new HCR polymorphisms and the previously suggested susceptibility alleles HLA-Cw*0602 and corneodesmosin allele 5 (CD*5) with psoriasis revealed a specific HCR variant associated with psoriasis susceptibility. However, the HLA-Cw*0602 allele was rarer in controls and associated with a stronger relative risk. Association analysis did not support CD*5 as a psoriasis susceptibility allele in our sample of patients (n = 100) and population-matched controls (n = 93) from an isolated population. We found HCR to be overexpressed in keratinocytes of psoriatic lesions compared with paired samples of healthy skin. Our results suggest a potential role for HCR in the pathogenesis of psoriasis.

Adolescent↗