Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Background Rare variants ingenecodingregions likely have agreater impactondisease-relatedphenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-basedexome array analyses of15,449genes infivelarge incidence cohortsof individualswith type 1diabetes andproteinuriawere analyzedfor survival time toESKD, testing the top gene in a sixth cohort (n52372/1115 events all cohorts) and replicating in two retrospective case-control studies (n51072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17- b dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n54196; P value53.331027). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions HSD17B14 gene ismechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.Peer reviewe

Essences in Metabolic Engineering of Lignan Biosynthesis

Lignans are structurally and functionally diverse phytochemicals biosynthesized in diverse plant species and have received wide attentions as leading compounds of novel drugs for tumor treatment and healthy diets to reduce of the risks of lifestyle-related non-communicable diseases. However, the lineage-specific distribution and the low-amount of production in natural plants, some of which are endangered species, hinder the efficient and stable production of beneficial lignans. Accordingly, the development of new procedures for lignan production is of keen interest. Recent marked advances in the molecular and functional characterization of lignan biosynthetic enzymes and endogenous and exogenous factors for lignan biosynthesis have suggested new methods for the metabolic engineering of lignan biosynthesis cascades leading to the efficient, sustainable, and stable lignan production in plants, including plant cell/organ cultures. Optimization of light conditions, utilization of a wide range of elicitor treatments, and construction of transiently gene-transfected or transgenic lignan-biosynthesizing plants are mainly being attempted. This review will present the basic and latest knowledge regarding metabolic engineering of lignans based on their biosynthetic pathways and biological activities, and the perspectives in lignan production via metabolic engineering

Metrics of the <i>de novo</i> assembly of the <i>Forsythia koreana</i> transcriptome.

<p>Metrics of the <i>de novo</i> assembly of the <i>Forsythia koreana</i> transcriptome.</p

Metrics of the <i>de novo</i> assembly of the <i>Linum flavum</i>, <i>Linum usitatissimum</i>, and <i>Podophyllum hexandrum</i> transcriptomes.

<p>Metrics of the <i>de novo</i> assembly of the <i>Linum flavum</i>, <i>Linum usitatissimum</i>, and <i>Podophyllum hexandrum</i> transcriptomes.</p

A typical example of the probability scores (blue line) and read counts (histogram) for VP-seq of <i>Forsythia</i> UGT7.

<p>The elongated sequence with VP-seq was indicated in red.</p

Summary of clusters generated by cuttree.

<p>Summary of clusters generated by cuttree.</p

Summary of the assembly of metabolism-related contigs from <i>Forsythia koreana</i> by Trinity or virtual primer-based sequence assembly (VP-seq).

<p>Summary of the assembly of metabolism-related contigs from <i>Forsythia koreana</i> by Trinity or virtual primer-based sequence assembly (VP-seq).</p

The sequence length (A) and FPKM value (B) distributions of Trinity- and virtual primer-based sequence assembly (VP-seq)-based contigs.

<p>The sequence length (A) and FPKM value (B) distributions of Trinity- and virtual primer-based sequence assembly (VP-seq)-based contigs.</p

<i>Forsythia koreana</i>-specific clusters and cluster annotation from Blast2GO.

<p><i>Forsythia koreana</i>-specific clusters and cluster annotation from Blast2GO.</p