Genetic association analysis of LARS2 with type 2 diabetes

Reiling, Erwin; Jafar-Mohammadi, Bahram; Riet, Esther van't; Weedon, Michael N.; Vliet-Ostaptchouk, Jana V. Van; Hansen, Torben; Saxena, Richa; Haeften, Timon W. van; Arp, Pascal; Das, Sreena; Nijpels, Giel; Groenewoud, Marlous J.; Hove, Els C. van; Uitterlinden, André G.; Smit, Johannes W. A.; Morris, Andrew D.; Doney, Alex S.F.; Palmer, Colin N.A.; Guiducci, Candace; Hattersley, Andrew T.; Frayling, Timothy M.; Pedersen, Oluf; Slagboom, P. Eline; Altshuler, David; Groop, Leif; Romijn, Johannes A.; Maassen, J. A.; Hofker, Marten H.; Dekker, Joost; McCarthy, Mark I.; Hart, Leen M ’t

doi:10.1007/s00125-009-1557-7

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…Interestingly, one CpG site mediating (cg15733049, Chromosome 1:2334974) FAM214A is found in low-DNase activity sites in placenta samples taken at various timepoints; additionally, cg15733049 is local to EPS15 , the RP predicted to mediate genetic regulation of FAM214A . Furthermore, expression of LARS2 , a TWAS gene for adult BMI, is mediated by cg04097236 (found within ELOVL2 ), a CpG site found in low DNase or high H3K27 activity regions; LARS2 houses multiple GWAS risk SNPs for type 2 diabetes 54 and has shown adult BMI TWAS associations in other tissues 17 , 28 . Results from these external datasets add more evidence that these mediators play a role in gene regulation of these TWAS-identified genes and should be investigated experimentally in future studies.…”

Section: Resultsmentioning

confidence: 99%

Placental genomics mediates genetic associations with complex health traits and disease

et al. 2022

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As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At $$P \; < \; 2.5\times {10}^{-6}$$ P < 2.5 × 10 − 6 , we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.

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Section: Resultsmentioning

confidence: 99%

Placental genomics mediates genetic associations with complex health traits and disease

et al. 2022

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“…Using purified islets from multiple GIT2KO or WT ( n ≥ 3) mice, a differentially regulated transcriptomic profile was generated (Table S14 in Supplementary Material). At the basic transcriptomic level multiple transcripts closely linked to diabetic pathology and islet dysfunction were differentially regulated in GIT2KO compared to WT islets, e.g., Slc2a2 [glucose transporter 2 ( 78 )], Reg3a/b [regenerating islet-derived protein 3 alpha/beta ( 79 )], Ffa2 [free fatty acid receptor 2 ( 80 )], Trib3 [tribbles homolog 3 ( 81 )], PP [pancreatic polypeptide ( 82 )], Sesn1 [sestrin 1 ( 83 )], Glo1 [glyoxylase 1 ( 84 )], and Lars2 [leucyl-tRNA synthetase 2, mitochondrial ( 85 )]. Using “pancreas-specific” tissue database signaling investigation with IPA, we applied Disease/Bio-Function annotation to the GIT2KO islet transcriptome data (Table S15 in Supplementary Material).…”

Section: Resultsmentioning

confidence: 99%

GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging

et al. 2016

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Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional “keystone” role in regulating the aging process by coordinating somatic responses to energy deficits.

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“…A study in 7836 individuals from the Netherlands and Denmark identified a pathogenic missense H324Q variant in the LARS2 gene, encoding mitochondrial leucyl-tRNA synthetase which catalyses the aminoacylation of mt-tRNA Leu (UUR) , as associated with T2D [75]. This initial association could, however, not be replicated in a much larger follow-up study [137]. The importance of preserved tRNA aminoacylation for proper β-cell function is illustrated by the association between impaired mt-tRNA Leu (UUG) charging and MIDD [138][139][140].…”

Section: Pathogenic Variants In Aarssmentioning

confidence: 99%

tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

Arroyo

Green²,

Cnop³

et al. 2021

IJMS

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The global rise in type 2 diabetes results from a combination of genetic predisposition with environmental assaults that negatively affect insulin action in peripheral tissues and impair pancreatic β-cell function and survival. Nongenetic heritability of metabolic traits may be an important contributor to the diabetes epidemic. Transfer RNAs (tRNAs) are noncoding RNA molecules that play a crucial role in protein synthesis. tRNAs also have noncanonical functions through which they control a variety of biological processes. Genetic and environmental effects on tRNAs have emerged as novel contributors to the pathogenesis of diabetes. Indeed, altered tRNA aminoacylation, modification, and fragmentation are associated with β-cell failure, obesity, and insulin resistance. Moreover, diet-induced tRNA fragments have been linked with intergenerational inheritance of metabolic traits. Here, we provide a comprehensive review of how perturbations in tRNA biology play a role in the pathogenesis of monogenic and type 2 diabetes.

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Genetic association analysis of LARS2 with type 2 diabetes

Cited by 10 publications

References 25 publications

Placental genomics mediates genetic associations with complex health traits and disease

Placental genomics mediates genetic associations with complex health traits and disease

GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging

tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

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