Identification of <i>STOML2</i> as a putative novel asthma risk gene associated with <i>IL6R</i>

Revez, Joana A.; Matheson, Melanie C.; Hui, Jennie; Baltic, Svetlana; Upham, John W.; Dharmage, Shyamali C.; Thompson, Philip J.; Martin, Nicholas G.; Hopper, John L.; Ferreira, Manuel

doi:10.1111/all.12869

Cited by 8 publications

(5 citation statements)

References 67 publications

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“…(Figure 4b). BCL6 modulates the response of interleukin 4, known to be involved in asthma 63 , and has been linked to asthma in mice 64 and humans 65 , but to our knowledge BCL6 has not previously been implicated as an asthma gene using GWAS data. BCL6 was implicated by 3 of the functionally informed S2G strategies used by cS2G, including EpiMap enhancer-gene linking in common myeloid progenitor CD34+ cells (for rs509399 only), identified by LDSC-SEG 50 as a critical cell-type for asthma (P = 1.2 x 10 -4 ; see Methods; also see ref.…”

Section: Leveraging the Combined S2g Strategy To Pinpoint Disease Genesmentioning

confidence: 84%

Combining SNP-to-gene linking strategies to pinpoint disease genes and assess disease omnigenicity

Gazal

Weissbrod

Hormozdiari

et al. 2021

Preprint

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Although genome-wide association studies (GWAS) have identified thousands of disease-associated common SNPs, these SNPs generally do not implicate the underlying target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis, but it is unclear how these strategies should be applied in the context of interpreting common disease risk variants. We developed a framework for evaluating and combining different S2G strategies to optimize their informativeness for common disease risk, leveraging polygenic analyses of disease heritability to define and estimate their precision and recall. We applied our framework to GWAS summary statistics for 63 diseases and complex traits (average N=314K), evaluating 50 S2G strategies. Our optimal combined S2G strategy (cS2G) included 7 constituent S2G strategies (Exon, Promoter, 2 fine-mapped cis-eQTL strategies, EpiMap enhancer-gene linking, Activity-By-Contact (ABC), and Cicero), and achieved a precision of 0.75 and a recall of 0.33, more than doubling the precision and/or recall of any individual strategy; this implies that 33% of SNP-heritability can be linked to causal genes with 75% confidence. We applied cS2G to fine-mapping results for 49 UK Biobank diseases/traits to predict 7,111 causal SNP-gene-disease triplets (with S2G-derived functional interpretation) with high confidence. Finally, we applied cS2G to genome-wide fine-mapping results for these traits (not restricted to GWAS loci) to rank genes by the heritability linked to each gene, providing an empirical assessment of disease omnigenicity; averaging across traits, we determined that the top 200 (1%) of ranked genes explained roughly half of the heritability linked to all genes. Our results highlight the benefits of our cS2G strategy in providing functional interpretation of GWAS findings; we anticipate that precision and recall will increase further under our framework as improved functional assays lead to improved S2G strategies.

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Section: Leveraging the Combined S2g Strategy To Pinpoint Disease Genesmentioning

confidence: 84%

Combining SNP-to-gene linking strategies to pinpoint disease genes and assess disease omnigenicity

Gazal

Weissbrod

Hormozdiari

et al. 2021

Preprint

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“…STOML2 is a gene that plays a key role in mitochondrial function and T-cell activation. Recently, the expression of STOML2 was negatively correlated with that of the IL6R, which has been implicated in asthma pathophysiology, and the increased expression of STOML2 was associated with an increased asthma risk by RNA-seq analysis 32. The exact roles and mechanisms of HDAC10, STOML2, and other genes in COPD, especially in early stages of the disease, need to be clarified in future studies.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, the expression of STOML2 was negatively correlated with that of the IL6R, which has been implicated in asthma pathophysiology, and the increased expression of STOML2 was associated with an increased asthma risk by RNA-seq analysis. 32 The exact roles and mechanisms of HDAC10, STOML2, and other genes in COPD, especially in early stages of the disease, need to be clarified in future studies. BAX, an apoptosis regulator, is a marker of upregulated apoptosis in COPD, and it was found to downregulated in the COPD without emphysema group compared with that in healthy smokers in the present study, contrary to a previous report that patients with emphysema showed a significant increase in the Bax index.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile of human lung in a relatively early stage of COPD with emphysema

Jeong

Lim

et al. 2018

COPD

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PurposeAs only some smokers develop COPD with emphysema, we explored the molecular pathogenesis of early-stage COPD with emphysema using gene expression profiling of human lung tissues.Patients and methodsFirst, 110 subjects who had smoked more than ten pack-years were classified into three groups: COPD with emphysema, COPD without emphysema, and healthy smokers. COPD and emphysema were confirmed by post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 and by chest computed tomography. Lung tissues obtained surgically from the 110 subjects were processed and used for RNA-Seq analysis.ResultsAmong the 110 subjects, 29 had COPD with emphysema, 21 had COPD without emphysema, and 60 were healthy smokers; their mean post-bronchodilator forced expiratory volume in 1 second values were 78%, 80%, and 94%, respectively. Using RNA-Seq, we evaluated 16,676 genes expressed in lung tissues. Among them, 1,226 genes in the COPD with emphysema group and 434 genes in the COPD without emphysema group were differentially expressed genes compared to the expression in healthy smokers. In the COPD with emphysema group, ACER2 and LMAN2L were markedly increased and decreased, respectively. In the COPD without emphysema group, the CHRM3 gene, previously reported to be associated with COPD, and HDAC10 were markedly increased and decreased, respectively.ConclusionOur study identified differences in gene expression in subjects with COPD according to emphysema status using RNA-Seq transcriptome analysis. These findings may have mechanistic implications in COPD.

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“…Also, Hirschfield et al observed the association between primary biliary cirrhosis and variants of immune regulatory gene CLEC16A (Hirschfield et al, 2012). Besides, CLEC16A polymorphisms may involve in pathogenesis of allergic diseases (Revez et al, 2016;Ashley et al, 2017), which can increase or decrease susceptibility to AR through interleukin, and other genes (Black et al, 2009). In an article reported by Ferreira et al, they observed CLEC16A rs62026376 associated with increased asthma with hay fever risk (Ferreira et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

CLEC16A variants conferred a decreased risk to allergic rhinitis in the Chinese population

Niu

Wang

et al. 2022

Front. Genet.

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Background: Allergic rhinitis (AR) is a chronic respiratory disease. Hereditary factors played a key role in the pathogenesis of the AR. This study investigated the association between CLEC16A variants and AR risk in the Chinese population.Methods: We applied Agena MassARRAY technology platform to genotype five single nucleotide polymorphisms (SNPs) located in CLEC16A in 1004 controls and 995 cases. The association between CLEC16A SNPs (rs2286973, rs887864, rs12935657, rs11645657 and rs36045143) and AR risk were calculated by logistic regression analysis, with odds ratio (OR) and 95% confidence interval (CI). False-positive report probability (FPRP) was also used to assess the significant results to reduce false positives. Multifactor dimensionality reduction (MDR) was completed to assess the interaction between CLEC16A variants to predict AR risk.Results: Totally, CLEC16A (rs887864, rs12935657, rs2286973, rs11645657 and rs36045143) were significantly associated with AR risk. Therein, rs2286973, rs11645657 and rs36045143 were related to a decreased risk of AR in the people ≤ 43 years old, females and the people with BMI≤24, respectively. And rs887864 and rs12935657 were also associated with a decreased susceptibility of AR in the people >43 years old. Meanwhile, in the results of region stratification, rs887864 conferred a reduced risk to AR in the people from loess hilly area.Conclusion:CLEC16A variants conferred a decreased risk to AR in the Chinese population.

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Identification of STOML2 as a putative novel asthma risk gene associated with IL6R

Cited by 8 publications

References 67 publications

Combining SNP-to-gene linking strategies to pinpoint disease genes and assess disease omnigenicity

Combining SNP-to-gene linking strategies to pinpoint disease genes and assess disease omnigenicity

Gene expression profile of human lung in a relatively early stage of COPD with emphysema

CLEC16A variants conferred a decreased risk to allergic rhinitis in the Chinese population

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