Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition

Despite impressive results in restoring physical performance in rodent models, treatment with renin–angiotensin system (RAS) inhibitors, such as Lisinopril, have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs, such as RAS inhibitors, remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila melanogaster, we tested the effects of Lisinopril on age-specific climbing speed and endurance. Our data show that functional response and sensitivity to Lisinopril treatment ranges from significant protection against physical decline to increased weakness depending on genotype and age. Furthermore, genome-wide analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in physical performance traits and sensitivity to Lisinopril treatment. Genetic knockdown of genes in the WNT signaling pathway, Axin, frizzled, nemo, and wingless, diminished or abolished the effects of Lisinopril treatment on climbing speed traits. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and because they have orthologs in humans, they are potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age- and sex-dependent responses to any type of pharmaceutical treatment.

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Genes Contributing to Resilience and Sensitivity to Lisinopril at Old Age: Clinical Translation of GWA in Drosophila

Innovation in Aging ◽

10.1093/geroni/igab046.2550 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 683-684

Author(s):

Mariann M Gabrawy ◽

Nick Khosravian ◽

George S Morcos ◽

Meagan Jezek ◽

Jeremy D Walston ◽

...

Keyword(s):

Old Age ◽

Wnt Signaling Pathway ◽

Renin Angiotensin System ◽

Human Populations ◽

Network Analyses ◽

Specific Effects ◽

Conserved Genes ◽

Genomic Studies ◽

Drug Treatments ◽

Ras Inhibitors

Abstract Despite impressive results in restoring physical performance in rodent models, treatment with Renin-Angiotensin System (RAS) inhibitors such as Lisinopril have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs such as RAS inhibitors remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila, we tested the effects of Lisinopril on climbing speed and endurance at young and old age (N=14,310). Our data show that functional response and sensitivity to Lisinopril ranges from significant protection against physical decline (8–100% faster, P< 0.0001) to increased weakness (P< 0.0001) depending on both genotype and age (P< 0.0001). Genome-wide analyses revealed little to no overlap in candidate polymorphisms influencing sensitivity between ages nor between treatments within each age. Furthermore, network analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in sensitivity to Lisinopril. Genetic knockdown of Axin, frizzled, nemo, and wingless, genes with human orthologs AXIN1, FZD1, NLK, and WNT1, respectively, abolished the effects of Lisinopril treatment. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and as potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age-dependent responses to pharmaceutical treatments.

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Minireview: The Wnt Signaling Pathway Effector TCF7L2 and Type 2 Diabetes Mellitus

Molecular Endocrinology ◽

10.1210/me.2008-0135 ◽

2008 ◽

Vol 22 (11) ◽

pp. 2383-2392 ◽

Cited By ~ 115

Author(s):

Tianru Jin ◽

Ling Liu

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Genome Wide ◽

Glucagon Like Peptide 1 ◽

The Relationship

Abstract Since the relationship between TCF7L2 (also known as TCF-4) polymorphisms and type 2 diabetes mellitus was identified in 2006, extensive genome-wide association examinations in different ethnic groups have further confirmed this relationship. As a component of the bipartite transcription factor β-catenin/TCF, TCF7L2 is important in conveying Wnt signaling during embryonic development and in regulating gene expression during adulthood. Although we still do not know mechanistically how the polymorphisms within the intron regions of TCF7L2 affect the risk of type 2 diabetes, this transcriptional regulator was shown to be involved in stimulating the proliferation of pancreatic β-cells and the production of the incretin hormone glucagon-like peptide-1 in intestinal endocrine L cells. In this review, we introduce background knowledge of TCF7L2 as a component of the Wnt signaling pathway, summarize recent findings demonstrating the association between TCF7L2 polymorphisms and the risk of type 2 diabetes, outline experimental evidence of the potential function of TCF7L2 in pancreatic and intestinal endocrine cells, and present our perspective views.

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Whole Genome Level Analysis of the Wnt and DIX Gene Families in Mice and Their Coordination Relationship in Regulating Cardiac Hypertrophy

Frontiers in Genetics ◽

10.3389/fgene.2021.608936 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhongchao Gai ◽

Yujiao Wang ◽

Lu Tian ◽

Guoli Gong ◽

Jieqiong Zhao

Keyword(s):

Cardiac Hypertrophy ◽

Wnt Signaling ◽

Signaling Pathway ◽

Early Stage ◽

Biological Activities ◽

Wnt Signaling Pathway ◽

Gene Families ◽

Wnt Proteins ◽

Genome Wide ◽

Genome Level

The Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays essential roles in embryonic development, organogenesis, and many other biological activities. Both Wnt proteins and DIX proteins are important components of Wnt signaling. Systematic studies of Wnt and DIX families at the genome-wide level may provide a comprehensive landscape to elucidate their functions and demonstrate their relationships, but they are currently lacking. In this report, we describe the correlations between mouse Wnt and DIX genes in family expansion, molecular evolution, and expression levels in cardiac hypertrophy at the genome-wide scale. We observed that both the Wnt and DIX families underwent more expansion than the overall average in the evolutionarily early stage. In addition, mirrortree analyses suggested that Wnt and DIX were co-evolved protein families. Collectively, these results would help to elucidate the evolutionary characters of Wnt and DIX families and demonstrate their correlations in mediating cardiac hypertrophy.

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