Tarja Laitinen

Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P Stage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P Stage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.

Cardiovascular autonomic dysfunction is associated with central obesity in persons with impaired glucose tolerance

Diabet. Med. 28, 699–704 (2011)

Genetic Variants of TSLP and Asthma in an Admixed Urban Population

Background Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. Objectives To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. Methodology and Main Results Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09–2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04–3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93–1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10–2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07–1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08–1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94–1.17, p = 0.33). Conclusions Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction.

HLA‐G polymorphism in Finnish couples with recurrent spontaneous miscarriage

HLA‐G is a class 1 major histocompatibility complex gene that is expressed in cytotrophoblasts at the materno‐fetal interface. It has been suggested that HLA‐G could play a key role in materno‐fetal immunological interactions during pregnancy. To investigate whether there is an association between HLA‐G locus and recurrent spontaneous miscarriage, HLA‐G alleles were determined by a PCR‐RFLP method in 38 couples with recurrent spontaneous miscarriage and in 26 random control couples. In this series parental HLA‐G sharing, extended HLA‐G/A haplotypes and the frequencies of the HLA‐G alleles were similar in the two groups. Thus, our data suggest that there is no detectable relation between susceptibility to recurrent spontaneous miscarriage and HLA‐G locus.

IL-1 receptor antagonist gene polymorphism in recurrent spontaneous abortion

Genetic factors may contribute to the development of an aberrant pro-inflammatory immune response during pregnancy, thereby increasing the risk of some pregnancy-related pathologies such as recurrent spontaneous abortion (RSA). Interleukin 1 receptor antagonist is an important anti-inflammatory molecule encoded by the IL1RN gene, in which an intronic polymorphism has been described. Even though the molecular genetic mechanisms are not understood, this non-coding polymorphism, and especially IL1RN*2, has been associated with several chronic inflammatory and autoimmune diseases. IL1RN*2 is also associated with increased activity of IL-1beta, which is an important pro-inflammatory cytokine. We investigated the genetic variants of IL1RN in 37 Finnish women with RSA and 800 randomly selected Finnish blood donors. The women with RSA showed a significantly increased frequency of genotypes bearing the rare allele IL1RN*3 compared to the blood donors (10.8 vs 2.1%, odds ratio 5.6, 95% CI: 1.5-19.0, P=0.006). Our results suggest that IL1RN polymorphisms may predispose to RSA in a small subgroup of patients.

Real-world clinical data identifies gender-related profiles in chronic obstructive pulmonary disease.

This study aims to compare diagnostic and clinical outcomes of Chronic Obstructive Pulmonary Disease (COPD) from the gender perspective using retrospective health care data and patient reported outcomes in a real-world setting. An electronic database was constructed from complete medical records of 844 COPD patients who were recruited in Helsinki and Turku University Central Hospitals during the years 2005—07. The patients were identified from the hospital discharge registries by ICD10 code J44.8 in the age group of 18–75 years of age. The medical history was obtained from all healthcare providers who had treated these patients during the previous 5-10 years; the study intends to continue their follow-up annually for the next 10 years. Thirty-six percent (N = 266) of the participants were women. The COPD diagnosis had been made at the same age for both genders. Women, however, reported significantly less pack-years than men. Compared to the men, the women displayed less advanced airway obstruction, but more severe gas transfer impairment. Parenchymal damage when evaluated by diffusion capacity correlated significantly stronger with FEV1 (% of predicted) in women than men. The BMI index of the women was lower than that of the men. Cardiovascular diseases, diabetes and alcoholism were significantly more common in men, but women suffered more psychiatric conditions, especially depression. This cohort showed several significant gender dependent differences in the clinical presentation that need to taken under consideration in the assessment of COPD progression and the disease management.

Comparison between the disease-specific Airways Questionnaire 20 and the generic 15D instruments in COPD

BackgroundGiven that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population.MethodsThe AQ20 and 15D were administered to 739 COPD patients representing an unselected hospital-based COPD population. The completion rates and validity of, and correlations among the questions and dimension scores were examined. A factor analysis with varimax rotation was performed in order to find subsets of highly correlating items of the questionnaires.ResultsThe summary scores of AQ20 and 15D were highly correlated (r = - 0.71, p < 0.01). In AQ20 over 50% of patients reported frequent cough, breathlessness during domestic work, and chest problem limiting their full enjoyment of life. 15D results showed a noteworthy decrease of HRQoL in breathing, mobility, sleeping, usual activities, discomfort and symptoms, vitality, and sexual activity (scores ≤ 0.75). Compared to the age- and gender-standardized Finnish general population, the COPD patients were statistically significantly worse off on 13 of 15 dimensions.ConclusionsThe AQ20 and 15D summary scores are comparable in terms of measuring HRQoL in COPD patients. The data support the validity of 15D to measure the quality of life in COPD. COPD compromises the HRQoL broadly, as reflected by the generic instrument. Both questionnaires are simple and short, and could easily be used in clinical practice with high completion rates.

FOETO-MATERNAL COMPATIBILITY IN HLA-DR, -DQ, AND -DP LOCI IN FINNISH COUPLES SUFFERING FROM RECURRENT SPONTANEOUS ABORTIONS

The polymorphism of Major Histocompatibility Complex (MHC) class II genes DRB, DQA, DQB, and DPA was studied by Taq I Restriction Fragment Length Polymorphism (RFLP) in recurrent spontaneous abortions (RSA). The study group consisted of 35 primary abortion (PA) couples (no children) and 15 secondary abortion (SA) couples (1‐2 children before abortions). We found no increase in DR‐DQ compatibility between the mother and the foetus in the Finnish RSA group. In contrast to findings in some other populations, foeto‐maternal incompatibility was increased in the PA group. Thus, our results do not support the theory that increased MHC class II compatibility is a cause of abortions as such. The Finns are a small and relatively isolated population with a unique gene inheritance. Thus, one can speculate that, if the human MHC class II is in the linkage with disadvantageous ‘fertility genes’, and these genes might nonetheless still be clustered in only a few MHC haplotypes among the Finns. This would be the reason, that DR‐DQ sharing is not seen. The presence of rare HLA alleles, such as DR2 and DR6, among the aborters also supports this. In addition, this study extends our previous findings on MHC class III in regards to PA and SA couples differing immunogenetically from each other. In MHC class II, this was most obvious in the DPA1 locus. The vast majority of SA women were heterozygous for the two most common DPA1 alleles (14.0kb and 13.5kb), resulting in significantly smaller chances for a DPA1 mismatched foetus to occur in the SA group than in the controls or in the PA women.

A Set of MHC Haplotypes Found Among Finnish Couples Suffering From Recurrent Spontaneous Abortions

PROBLEM AND METHOD: The role of major histocompatibility complex (MHC) genes in the etiology of recurrent spontaneous abortion (RSA) was studied by analyzing the polymorphism of several, at least 14, immunogenetically important MHC genes either by serological or molecular methods in 56 Finnish RSA couples, and in 29 infants born to these families during the follow‐up period of two years after the abortions.

Tumour Necrosis Factor B Gene Polymorphism in Relation to Complotype in Couples with Spontaneous Abortions and in Control Families

Nco I restriction fragment length polymorphism (RFLP) of the tumour necrosis factor B (TNFB) gene gives two allelic fragments of 5.5 and 10.5 kb, corresponding to the TNFB*1 and TNFB*2 alleles, respectively.