Xiao Jiang

Cytochrome P450 2D6 ( CYP2D6 ) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinct CYP2D6 star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups (∼5%) compared to European and East Asian groups (∼2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carrying CYP2D6 structural variations and predicted the CYP2D6 ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the current CYP2D6 star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study of CYP2D6 to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.

Aims: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. Methods and results: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13–16% and 21–26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. Conclusions: Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Aims: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)—the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Conclusion: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Objective: To examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease. Design: Conventional observational and Mendelian randomisation study. Setting: UK Biobank and international genome-wide association studies. Participants: Approximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies. Main outcome measures: Estimated glomerular filtration, blood urea nitrogen, kidney health index, chronic kidney disease, hypertensive renal disease, renal failure, acute renal failure, other disorders of kidney and ureters, IgA nephropathy and diabetic nephropathy. Results: The Mendelian randomisation analysis indicated that increasing values of genetically predicted body mass index (BMI) and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration and increased blood urea nitrogen in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals. One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0·86; 95%CI: 0·82-0·92; P=9·18×10 ^-6 for BMI and OR=0·82; 95%CI: 0·75-0·90; P=2·12×10 ^-5 for waist circumference, respectively). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease and diabetic nephropathy. Conclusions: These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease. What is already known on this topic: - Several previous studies reported associations between increasing adiposity/obesity and either a decline in kidney function or the increased risk of specific kidney disorders. - High blood pressure and diabetes represent the two most common aetiologies of chronic kidney disease and co-exist with obesity. - It is not clear to what extent these associations may reflect cause-effect relationships. What this study adds: - Our results show a consistent pattern of causation between obesity and kidney health and disease, across different biochemical parameters of kidney function and a broad spectrum of kidney health/disease. - We further demonstrate that the causal effect of obesity on kidney health is partially mediated by blood pressure and largely independent of type 2 diabetes. - We provide evidence for a causal relationship between two clinical indices of obesity and specific renal disorders including hypertensive renal disease, acute renal failure, chronic kidney disease and diabetic nephropathy.

Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

To uncover the gene expression mechanisms underpinning the associations between over 800 single nucleotide polymorphisms (SNPs) and blood pressure (BP) in genome-wide association studies. We combined genotype information with RNA-sequencing-derived transcriptomic profiles of 430 human kidneys from 5 studies [TRANScriptome of renaL humAn TissuE (TRANSLATE) study, Tissue Cancer Genome Atlas (TCGA), moleculAr analysis of human kiDney-Manchester renal tIssue pRojEct (ADMIRE) study, Molecular analysis of mechanisms regulating gene expression in postischemic injury to renal allograft (REPAIR) and Renal gEne expreSsion and PredispOsition to cardiovascular and kidNey Disease (RESPOND)] for the purpose of cis-expression quantitative trait (cis-eQTL) analysis. After correction for multiple testing we identified 903,870 transcriptionally active kidney SNPs (eSNPs) partnering with a total of 7,348 kidney genes (renal eGenes) in the combined resource of 430 kidneys. Through an overlap analysis between our eQTL catalogue and a list of 821 independent sentinel BP GWAS SNPs we identified 252 independent BP GWAS kidney eSNPs together with their 418 expression partners (kidney eGenes). In the analysis of 48 non-renal human tissues from the Genotype-Tissue Expression (GTEx) project (either directly or through proxy) we determined that 32% of BP GWAS kidney eSNPs exhibit some degree of specificity to the kidney. Using summarised chromatin states from adult human kidney (RoadMap Epigenomics), we found that BP GWAS kidney eSNPs showed significant enrichment for promoter regions (1.5-fold) and transcribed region (2.7-fold) of the kidney. These data indicate that 31% BP GWAS loci operate as transcriptionally active variants in the human kidney and their effects on renal gene expression programmes may explain inter-individual differences in susceptibility to hypertension.