The Well-Known Gene <i>HHIP</i> and Novel Gene <i>MECR</i> Are Implicated in Small Airway Obstruction

Plaat, Diana A van der; Jong, Kim de; Lahousse, Lies; Faiz, Alen; Vonk, Judith M.; Diemen, Cleo C. van; Nedeljković, Ivana; Obeidat, Ma’en; Duijn, Cornelia M. van; Boezen, H. Marike; Postma, Dirkje S.

doi:10.1164/rccm.201604-0843le

Cited by 11 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HHIP gene has now been found to affect both small and large airways [22]. The presence of allele A of the rs13118928 polymorphism of the HHIP gene may be associated with the emphysema-hyperinflation phenotype in patients with chronic obstructive pulmonary disease [23].…”

Section: Resultsmentioning

confidence: 99%

Association of Polymorphic Variants of HHIP, ADRB2 and IL-33 Genes with Clinical Manifestations of Bronchial Asthma in Children

Alieva,

Furman,

Kondratyeva

et al. 2023

Preprint

View full text Add to dashboard Cite

Studying the contribution of genetic mechanisms to the development of bronchial asthma (BA) is to look for associations of the disease and its phenotypes with polymorphic markers of candidate genes.ObjectiveTo investigate the association of polymorphic variants of HHIP, ADRB2 and IL-33 genes with the phenotypes of clinical course of BA in children and the effectiveness of therapy of the diseasePatients and methodsA cohort single-center study of 90 bronchial asthma patients aged 5 to 17 years with an established diagnosis of bronchial asthma of varying degree of severity and control was conducted. The allele and genotype frequencies of polymorphic loci of the following genes were studied: rs12551256-A and rs146597587-G of IL-33 gene; rs12504628 of HHIP gene and ARG16GLY rs1042713 of ADRB2 gene in 90 BA patients with regard to the severity and control of the disease. In children with severe BA, as well as in children with poorly controlled/uncontrolled asthma (n=26), sequencing of the entire coding sequence of the IL-33 gene located on the 9th chromosome in the 9p24.1 region was additionally performed (search for mutations in 9 exons).ResultsComparison of genetic markers in patients with severe BA (tBA) and non-severe BA (nBA) revealed a reduced risk of severe disease realization among those carrying the TT genotype (OR=0.221 (95% CI: 0.059-0.828; χ2=5.759; p=0.056)) and the T allele (OR=0.491 (95% CI: 0.190-1.269; χ2=4.270; p=0.039)) of the studied genetic variant rs12504628 (T>C) of the HHIP gene, the frequency of the CC genotype in severe BA was 64%, versus 28% in nonsevere BA, and the C allele 77% versus 52%.Comparison of genetic markers in patients with a combination of atopic dermatitis (AtD) and bronchial asthma (BA+AtD) and BA without AtD (BA without AtD) revealed an increased risk of combining asthma and dermatitis among individuals carrying the TT genotype (OR=2.875 (95% CI: 1.130-7.316; χ2=5.751; p=0.056)) of genetic variant rs12504628 (T>C) of the HHIP gene. Sequencing and exome analysis of the IL-33 gene showed a statistically significant positive association between the frequency of lesions in exons 4 (r=0.417; p=0.034) and 6 (r=0.593; p=0.001) on the one hand and the severity of BA on the other. Nucleotide substitutions in these exons were found to be more frequently associated with the severe course of bronchial asthma.ConclusionIt was shown that TT genotype of genetic variant rs12504628 (T>C) of HHIP gene reduces the risk of severe BA, but increases the risk of atopic dermatitis combined with BA by 2.8 times. The CC+ST genotype of the HHIP gene increases the risk of drug allergy against the background of BA by 2.9 times. Polymorphic variants in exons 4 and 6 of the IL-33 gene are more often combined with moderate and severe asthma, and nucleotide substitutions in exons 4 and 6 are associated with a severe course of BA.

show abstract

Section: Resultsmentioning

confidence: 99%

Association of Polymorphic Variants of HHIP, ADRB2 and IL-33 Genes with Clinical Manifestations of Bronchial Asthma in Children

Alieva,

Furman,

Kondratyeva

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…When leaving one of these three SNPs out, the effect of the overall MR-IVW was reduced by 17%, 13% and 9%, respectively. These loci have not only been linked to pulmonary function parameters such as FEV1/FVC [ 7 ], but also to COPD phenotypes including emphysema [ 30 ] and airway remodeling [ 31 ]. Rs995758 is located intergenic and the nearest gene, HHIP, encodes for the hedgehog interacting protein (HHIP).…”

Section: Discussionmentioning

confidence: 99%

Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

et al. 2021

View full text Add to dashboard Cite

Background Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. Methods We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. Results We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Conclusion Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

show abstract

“…В настоящее время установлено, что ген HHIP влияет на состояние как мелких, так и крупных дыхательных путей [22]. Наличие аллеля А полиморфизма rs13118928 гена HHIP может быть связано с фенотипом эмфизема-гиперинфляция у больных хронической обструктивной болезни легких [23].…”

Section: характеристика изучаемых генотиповunclassified

Ассоциация Полиморфных Вариантов Генов Hhip, Adrb2 И Ил-33 С Клиническими Проявлениями Бронхиальной Астмы У Детей

Алиева,

Фурман,

Кондратьева

et al. 2023

Preprint

View full text Add to dashboard Cite

Проведенное исследование полиморфизмов генов HHIP, ADRB2 и IL-33 у детей, страдающих БА, с разными фенотипами заболевания выявило ассоциацию между полиморфизмами генов и тяжестью заболевания, а также с сопутствующими заболеваниями. Показано, что генотип ТТ генетического варианта rs12504628 (T>C) гена HHIP снижает риск реализации тяжелой БА, однако увеличивает в 2,8 раза риск сочетанного с БА атопического дерматита. Генотип СС+СТ гена HHIP в 2,9 раза увеличивает риск реализации лекарственной аллергии на фоне БА. Генотипа АА гена ADRB2 ассоциирован со снижением риска реализации врожденных пороков развития трахеобронхиального дерева на фоне БА. Полиморфные варианты в 4 и 6 экзонах гена IL-33 чаще сочетаются со среднетяжелой и тяжелой астмой, а замены нуклеотидов в экзонах 4 и 6 ассоциированы с тяжелым течением БА. Таким образом, в данном исследовании установлены ассоциации полиморфных вариантов генов HHIP, ADRB2 и IL-33 с клиническими проявлениями бронхиальной астмы у детей, которые могут учитываться при персонализированном наблюдении за этими пациентами, и могут помочь в достижении полного контроля над заболеванием.

show abstract

The Well-Known Gene HHIP and Novel Gene MECR Are Implicated in Small Airway Obstruction

Cited by 11 publications

References 10 publications

Association of Polymorphic Variants of HHIP, ADRB2 and IL-33 Genes with Clinical Manifestations of Bronchial Asthma in Children

Association of Polymorphic Variants of HHIP, ADRB2 and IL-33 Genes with Clinical Manifestations of Bronchial Asthma in Children

Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

Ассоциация Полиморфных Вариантов Генов Hhip, Adrb2 И Ил-33 С Клиническими Проявлениями Бронхиальной Астмы У Детей

Contact Info

Product

Resources

About