Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan

Lin, Ying; Chang, Jen‐Ping; Liu, Xiang; Tsang, Hsinyi; Chien, Wen Kuei; Chen, Jin Hua; Hsieh, Hsin Yang; Hsueh, Kai Chung; Shiao, Yi Tzone; Li, Ju Pi; Lin, Cheng Wen; Lai, Chih Ho; Wu, Jer Yuarn; Chen, Chien Hsiun; Lin, Jaung Geng; Lin, Ting Hsu; Liao, Chien-Chang; Huang, Shao Mei; Lan, Yu Ching; Ho, Tsung Jung; Liang, Wen Miin; Yeh, Yi Chun; Lin, Ji-Ping; Tsai, Fuu Jen

doi:10.1038/srep14762

Cited by 35 publications

(26 citation statements)

References 55 publications

(105 reference statements)

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“…In addition to these studies, PLCL1 has been implicated in coronary artery aneurysm in Kawasaki disease and PLCL1 might play a role in the regulation of vascular endothelial cell inflammation via interference with proinflammatory cytokine expression. (36)…”

Section: Discussionmentioning

confidence: 99%

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Hahn

Brown

et al. 2020

Preprint

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64Background 65 Genome-wide association studies have identified multiple genomic loci associated with coronary artery 66 disease, but most are common variants in non-coding regions that provide limited information on causal 67 genes and etiology of the disease. To better understand etiological pathways that might lead to discovery 131 Houston (21); SHIP was called in Illumina GenomeStudio using the CHARGE Consortium joint calling 132 cluster file; GeneSTAR used the Illumina GenomeStudio and zCall software (22); and WGHS data was 133 called using the Illumina BeadStudio v.3.3. Variant quality control (QC) was performed centrally (21) 134 and by the individual studies, including checking concordance with previous GWAS data, and excluding 135 participants with missing >5% genotypes, population clustering outliers, individuals with high inbreeding 136 coefficients or heterozygote rates, gender mismatches, duplicated pairs, and unexpectedly high proportion 137 of identity-by-descent sharing for family studies.

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Section: Discussionmentioning

confidence: 99%

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Hahn

Brown

et al. 2020

Preprint

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“…PLCB1 is highly relevant, as this gene has been reported to be differentially expressed in therapy-resistant childhood asthma compared to controlled persistent asthma or age-matched healthy control subjects in a Swedish cohort [68]. Functional studies also reported that silencing PLCB1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation through inhibiting expression of proinflammatory cytokines [69]. Further functional studies are necessary to establish the role of NFKB1 and PLCB1 on BDR.…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing of pharmacogenetic drug response in racially and ethnically diverse children with asthma

Mak

White

Szpiech

et al. 2017

Preprint

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Asthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene, SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of the NFKB1 variants demonstrated by our functional assays. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.AUTHOR SUMMARYAsthma is the most common chronic disease among children. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. In the U.S., asthma prevalence is the highest among Puerto Ricans, intermediate among African Americans and lowest in Whites and Mexicans. Asthma disparities extend to mortality, which is four- to five-fold higher in Puerto Ricans and African Americans compared to Mexicans [1]. Puerto Ricans and African Americans, the populations with the highest asthma prevalence and death rate, also have the lowest albuterol bronchodilator drug response (BDR). We conducted the largest pharmacogenetic study using whole genome sequencing data from 1,441 minority children with asthma who had extremely high or low albuterol bronchodilator drug response. We identified population-specific and shared pharmacogenetic variants associated with BDR. Our findings help inform the direction of future development of asthma medications and our study advances the foundation of precision medicine for at-risk, yet understudied, racially/ethnically diverse populations.

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“…PLCB1 has been identified as a pro-inflammatory regulator involved in several cardiovascular diseases as acute, inflammatory, and self-limited vasculitis, Kawasaki Syndrome, endothelial cell inflammation with varying degrees of pro-inflammatory cytokine expression, and coronary artery aneurysm. [60] 4.1.2. Senescence Regulation PLEC.…”

Section: Eif4a2mentioning

confidence: 99%

In-silico cardiac aging regulatory model including microRNA post-transcriptional regulation

Politano

Logrand

Brancaccio

et al. 2017

Methods

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In most developed countries, cardiovascular diseases are among the top causes of death and their development has been shown closely related to aging. In this context, because of their ability to pervasively influence gene networks, miRs have been found as possible key players in the development of cardiac pathologies, suggesting their potential role as therapeutic targets or diagnostic markers. Based on these assumptions, we hereby present a computational study that applies data fusion techniques coupled with network analysis theory to identify a regulatory model able to represent the relationship between key genes and miRs involved in cardiac senescence processes. The proposed model has been validated through an extensive literature analysis, which confirmed that 94% of the identified genes and miRs are related with cardiac senescence. Furthermore, two relevant genes of the model have been also validated by Western blot experiments on heart samples from young and old mice, confirming in vitro their ectopic expression in aged hearts. The pure computationally inferred model presented in the paper is therefore a good candidate to represent the relationship between key genes and miRs involved in cardiac senescence processes, and represents a reliable selection of genes and miRs for further studies, in order to elucidate and better detail their involvement in cardiac aging.

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Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan

Cited by 35 publications

References 55 publications

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Whole genome sequencing of pharmacogenetic drug response in racially and ethnically diverse children with asthma

In-silico cardiac aging regulatory model including microRNA post-transcriptional regulation

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