A Long Non-coding RNA, LOC157273, Is an Effector Transcript at the Chromosome 8p23.1-PPP1R3B Metabolic Traits and Type 2 Diabetes Risk Locus

Manning, Alisa K.; Goustin, Anton Scott; Kleinbrink, Erica L.; Thepsuwan, Pattaraporn; Cai, Juan; Ju, Donghong; Leong, Aaron; Udler, Miriam S.; Brown, James; Goodarzi, Mark O.; Rotter, Jerome I.; Sladek, Robert; Meigs, James B.; Lipovich, Leonard

doi:10.3389/fgene.2020.00615

Cited by 17 publications

(15 citation statements)

References 63 publications

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“…These SNPs were confirmed (except for those otherwise mentioned below) for residing in non-coding regions. It is widely known that genetic variants are prone to mis-annotation and there is a substantial bias toward protein-coding genes in SNP annotations and in the related literature [ 23 , 24 ]; therefore, an unbiased reannotation was essential, and we used the UCSC Genome Browser to implement such a reannotation. In this regard, out of the 64 selected SNPs, 13 were classified as “corrections” because of discrepancies between the previous annotation and our interpretation of the UCSC Browser results.…”

Section: Resultsmentioning

confidence: 99%

LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

Giordo

Gulsha

Kalla

et al. 2022

Cancers

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Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the identification of genetic variants predisposing individuals to both T2D and cancer may help explain the increased risk of cancer in T2D patients. We aim to investigate whether lncRNA genetic variants with significant diabetes and cancer associations overlap in the UAE population. We first performed an annotation-based analysis of UAE T2D GWAS, confirming the high prevalence of variants at or near non-coding RNA genes. We then explored whether these T2D SNPs in lncRNAs were relevant to cancer. We highlighted six non-coding genetic variants, jointly reaching statistical significance in T2D and cancer, implicating a shared genetic architecture between the two diseases in the UAE population.

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Section: Resultsmentioning

confidence: 99%

LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

Giordo

Gulsha

Kalla

et al. 2022

Cancers

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“…Interestingly, LOC157273 , one of the transcript variants of the AC022784.1 gene ( AC022784.1‐248 ), is a long noncoding RNA that has been reported to down‐regulate PPP1R3B expression. ( 37 ) While we could not link AC022784.1 with PPP1R3B expression or with bile acid levels, we cannot exclude it because our analysis did not focus on the splice variant composition. On the other hand, we observed a correlation between expression of PPP1R3B and another long noncoding RNA, AC022784.6 (Fig.…”

Section: Discussionmentioning

confidence: 96%

Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition

Männistö

Kaminska

Käkelä

et al. 2021

Hepatology Communications

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The protein phosphatase 1 regulatory subunit 3B (PPP1R3B) gene is a target of farnesoid X receptor (FXR), which is a major regulator of bile acid metabolism. Both PPP1R3B and FXR have been suggested to take part in glycogen metabolism, which may explain the association of PPP1R3B gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of PPP1R3B rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6 ± 9.0 years, body mass index 43.2 ± 5.4 kg/m 2) with PPP1R3B genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the PPP1R3B rs4240624 genotype. However, the concentration of total bile acids (109 ± 55 vs. 35 ± 19 mM; P = 1.0 × 10 −5) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol (P = 0.011) and phospholipid (P = 0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of PPP1R3B, tankyrase (TNKS), Homo sapiens chromosome 8 clone RP11-10A14.5 (AC022784.1 [LOC157273]), Homo sapiens chromosome 8 clone RP11-375N15.1 (AC021242.1), and Homo sapiens chromosome 8, clone RP11-10A14 (AC022784.6) associated with the PPP1R3B genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. Conclusion: The rs4240624 variant in PPP1R3B has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect. (Hepatology Communications 2020;0:1-14).

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“…KLF12 is a significant quantitative trait locus from multiple GWAS (Genome-Wide Association Studies) for a host of non-pregnancy associated outcomes such as cancers ( Petersen et al, 2010 ), lipids ( Kathiresan et al, 2007 ), eye disorders ( Macgregor et al, 2010 ), sudden cardiac arrest ( Aouizerat et al, 2011 ), and heart function abnormalities ( Sotoodehnia et al, 2010 ). GWAS is a highly reliable, robust, and well-established method that utilizes population genetics and genomic epidemiology to identify new contributing candidate genes, in an unbiased manner, for common diseases that have a genetic component; these genes can be functionally validated in the laboratory for development into biomarkers or drug targets ( Manning et al, 2020 ). The antisense intronic lncRNA of the KLF12 gene, RP11_552M6.1 , is a promising functional target, because KLF12— despite its promiscuous expression — is known to repress AP-2 , the alpha -a developmental specific transcription factor.…”

Section: Discussionmentioning

confidence: 99%

Gestational Age Dependence of the Maternal Circulating Long Non-Coding RNA Transcriptome During Normal Pregnancy Highlights Antisense and Pseudogene Transcripts

Kleinbrink

Gomez‐Lopez

et al. 2021

Front. Genet.

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In the post-genomic era, our understanding of the molecular regulators of physiologic and pathologic processes in pregnancy is expanding at the whole-genome level. Longitudinal changes in the known protein-coding transcriptome during normal pregnancy, which we recently reported (Gomez-Lopez et al., 2019), have improved our definition of the major operant networks, yet pregnancy-related functions of the non-coding RNA transcriptome remain poorly understood. A key finding of the ENCODE (Encyclopedia of DNA Elements) Consortium, the successor of the Human Genome Project, was that the human genome contains approximately 60,000 genes, the majority of which do not encode proteins. The total transcriptional output of non-protein-coding RNA genes, collectively referred to as the non-coding transcriptome, is comprised mainly of long non-coding RNA (lncRNA) transcripts (Derrien et al., 2012). Although the ncRNA transcriptome eclipses its protein-coding counterpart in abundance, it has until recently lacked a comprehensive, unbiased, genome-scale characterization over the timecourse of normal human pregnancy. Here, we annotated, characterized, and selectively validated the longitudinal changes in the non-coding transcriptome of maternal whole blood during normal pregnancy to term. We identified nine long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs) as well as lncRNAs antisense to or otherwise in the immediate vicinity of protein-coding genes, that were differentially expressed with advancing gestation in normal pregnancy: AL355711, BC039551 (expressed mainly in the placenta), JHDM1D-AS1, A2M-AS1, MANEA-AS1, NR_034004, LINC00649, LINC00861, and LINC01094. By cross-referencing our dataset against major public pseudogene catalogs, we also identified six transcribed pseudogenes that were differentially expressed over time during normal pregnancy in maternal blood: UBBP4, FOXO3B, two Makorin (MKRN) pseudogenes (MKRN9P and LOC441455), PSME2P2, and YBX3P1. We also identified three non-coding RNAs belonging to other classes that were modulated during gestation: the microRNA MIR4439, the small nucleolar RNA (snoRNA) SNORD41, and the small Cajal-body specific ncRNA SCARNA2. The expression profiles of most hits were broadly suggestive of functions in pregnancy. These time-dependent changes of the non-coding transcriptome during normal pregnancy, which may confer specific regulatory impacts on their protein-coding gene targets, will facilitate a deeper molecular understanding of pregnancy and lncRNA-mediated molecular pathways at the maternal-fetal interface and of how these pathways impact maternal and fetal health.

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A Long Non-coding RNA, LOC157273, Is an Effector Transcript at the Chromosome 8p23.1-PPP1R3B Metabolic Traits and Type 2 Diabetes Risk Locus

Cited by 17 publications

References 63 publications

LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition

Gestational Age Dependence of the Maternal Circulating Long Non-Coding RNA Transcriptome During Normal Pregnancy Highlights Antisense and Pseudogene Transcripts

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