Filaggrin Gene Defects Are Independent Risk Factors for Atopic Asthma in a Polish Population: A Study in ECAP Cohort

BACKGROUND: FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population. METHODOLOGY: 2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination. PRINCIPAL FINDINGS: The FLG null variants were associated with AD (OR = 2.01, CI: 1.20-3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12-2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24-3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07-3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07-4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58-2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6). CONCLUSIONS/SIGNIFICANCE: In a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome

Background: Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis.Aims: The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients.Methods: The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death.Results: Thirty-four patients from 15 families were included, and five identified variants were novel. Probands’ mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06).Conclusions: LDS is associated with high burden of cardiovascular complications at a young age

Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed?

BACKGROUND: Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. METHODOLOGY: We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2). PRINCIPAL FINDINGS: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st) and the 2(nd) cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4) which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients). CONCLUSIONS/SIGNIFICANCE: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms

Distribution of the <i>FLG</i> variants in subjects with persistent allergic rhinitis (pAR) stratified by diagnosis of atopic dermatitis.

<p>All comparisons vs. healthy controls (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016933#pone-0016933-t001" target="_blank">Table 1</a>), NA: not available.</p

Distribution of the <i>FLG</i> variants in subjects with atopic asthma (AA) stratified by diagnosis of atopic dermatitis.

<p>All comparisons vs. healthy controls (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016933#pone-0016933-t001" target="_blank">Table 1</a>), NA: not available.</p

Prevalence of <i>FLG</i> variants according to clinical diagnosis.

1<p>In 24 subjects allergic rhinitis could not be classified as intermittent or persistent; NA not applicable; All comparisons vs. healthy controls.</p

Prevalence of the <i>FLG</i> variants vs. concordance between diagnosis of asthma (all kinds or atopic asthma) by a physician (i.e. diagnosed during the present study) and individual awareness of having asthma (all kinds) according to questionnaire data.

<p>* Calculated for the comparison of the frequency of the combined genotype (2282del4 or R501X) vs. healthy controls. Cells with P values <0.05 are <b>boldfaced</b>; Questionnaire data were not available in 18 subjects with asthma including 9 with AA.</p

Haplotype dependent association of rs7927894 (11q13.5) with atopic dermatitis and chronic allergic rhinitis: A study in ECAP cohort

<div><p>The T allele of rs7927894 (at 11q13.5) was associated with atopic dermatitis and other allergic diseases. Our purpose was to replicate the association with allergic phenotypes and explore the role of rs7927894 in predisposing to persistent allergic rhinitis and atopic asthma. We also wanted to explore if other SNPs at 11q13.5 contributed to effect of rs7927894. We studied patients with atopic dermatitis (N = 270), atopic asthma (N = 486), persistent allergic rhinitis (N = 589) and controls matched for age, sex and region (N = 540, N = 372 and N = 1178, respectively). We found that rs7927894 T was associated with atopic dermatitis (OR = 1.39, CI: 1.12–1.73, P = 0.003) and independently with persistent allergic rhinitis (OR = 1.24, CI:1.07–1.43, P = 0.0043, P_corrected = 0.013) but not atopic asthma. Analysis of additional tagging SNPs (rs7930763, rs2513517, rs7125552) showed that effect of rs7927894 T was limited to haplotypes encoding G at rs7125552. In conclusion, rs7927894 T is associated not only with atopic dermatitis but also persistent allergic rhinitis. Since these effects are haplotype dependent rs7927894 alone does not account for the association between 11q13.5 and atopic dermatitis/persistent allergic rhinitis.</p></div

Distribution of genotypes of 11q13.5 SNPs among subjects with AD and controls.

<p>Distribution of genotypes of 11q13.5 SNPs among subjects with AD and controls.</p