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1. A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome.

Author: Gale, DP, Gross, O, Wang, F, Esteban de la Rosa, RJ, Hall, M, Sayer, JA, Appel, G, Hariri, A, Liu, S, Maski, M, Shen, Y, Zhang, Q, Iqbal, S, Kowthalam, MU, Lin, J, Ding, J, HERA Clinical Trial Group, Gale, DP, Gross, O, Wang, F, Esteban de la Rosa, RJ, Hall, M, Sayer, JA, Appel, G, Hariri, A, Liu, S, Maski, M, Shen, Y, Zhang, Q, Iqbal, S, Kowthalam, MU, Lin, J, Ding, J, and HERA Clinical Trial Group
Abstract: Key Points: • Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression. • There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint. • The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo. Background: Preclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression. Methods: This study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility. Results: Forty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1
Published: 2024

2. The 2019 and 2021 International Workshops on Alport Syndrome.

Author: Daga, S, Ding, J, Deltas, C, Savige, J, Lipska-Ziętkiewicz, BS, Hoefele, J, Flinter, F, Gale, DP, Aksenova, M, Kai, H, Perin, L, Barua, M, Torra, R, Miner, JH, Massella, L, Ljubanović, DG, Lennon, R, Weinstock, AB, Knebelmann, B, Cerkauskaite, A, Gear, S, Gross, O, Turner, AN, Baldassarri, M, Pinto, AM, Renieri, A, Daga, S, Ding, J, Deltas, C, Savige, J, Lipska-Ziętkiewicz, BS, Hoefele, J, Flinter, F, Gale, DP, Aksenova, M, Kai, H, Perin, L, Barua, M, Torra, R, Miner, JH, Massella, L, Ljubanović, DG, Lennon, R, Weinstock, AB, Knebelmann, B, Cerkauskaite, A, Gear, S, Gross, O, Turner, AN, Baldassarri, M, Pinto, AM, and Renieri, A
Published: 2022

3. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Author: Koettgen, A, Cornec-Le Gall, E, Halbritter, J, Kiryluk, K, Mallett, AJ, Parekh, RS, Rasouly, HM, Sampson, MG, Tin, A, Antignac, C, Ars, E, Bergmann, C, Bleyer, AJ, Bockenhauer, D, Devuyst, O, Florez, JC, Fowler, KJ, Franceschini, N, Fukagawa, M, Gale, DP, Gbadegesin, RA, Goldstein, DB, Grams, ME, Greka, A, Gross, O, Guay-Woodford, LM, Harris, PC, Hoefele, J, Hung, AM, Knoers, NVAM, Kopp, JB, Kretzler, M, Lanktree, MB, Lipska-Zietkiewicz, BS, Nicholls, K, Nozu, K, Ojo, A, Parsa, A, Pattaro, C, Pei, Y, Pollak, MR, Rhee, EP, Sanna-Cherchi, S, Savige, J, Sayer, JA, Scolari, F, Sedor, JR, Sim, X, Somlo, S, Susztak, K, Tayo, BO, Torra, R, van Eerde, AM, Weinstock, A, Winkler, CA, Wuttke, M, Zhang, H, King, JM, Cheung, M, Jadoul, M, Winkelmayer, WC, Gharavi, AG, Koettgen, A, Cornec-Le Gall, E, Halbritter, J, Kiryluk, K, Mallett, AJ, Parekh, RS, Rasouly, HM, Sampson, MG, Tin, A, Antignac, C, Ars, E, Bergmann, C, Bleyer, AJ, Bockenhauer, D, Devuyst, O, Florez, JC, Fowler, KJ, Franceschini, N, Fukagawa, M, Gale, DP, Gbadegesin, RA, Goldstein, DB, Grams, ME, Greka, A, Gross, O, Guay-Woodford, LM, Harris, PC, Hoefele, J, Hung, AM, Knoers, NVAM, Kopp, JB, Kretzler, M, Lanktree, MB, Lipska-Zietkiewicz, BS, Nicholls, K, Nozu, K, Ojo, A, Parsa, A, Pattaro, C, Pei, Y, Pollak, MR, Rhee, EP, Sanna-Cherchi, S, Savige, J, Sayer, JA, Scolari, F, Sedor, JR, Sim, X, Somlo, S, Susztak, K, Tayo, BO, Torra, R, van Eerde, AM, Weinstock, A, Winkler, CA, Wuttke, M, Zhang, H, King, JM, Cheung, M, Jadoul, M, Winkelmayer, WC, and Gharavi, AG
Abstract: Numerous genes for monogenic kidney diseases with classical patterns of inheritance, as well as genes for complex kidney diseases that manifest in combination with environmental factors, have been discovered. Genetic findings are increasingly used to inform clinical management of nephropathies, and have led to improved diagnostics, disease surveillance, choice of therapy, and family counseling. All of these steps rely on accurate interpretation of genetic data, which can be outpaced by current rates of data collection. In March of 2021, Kidney Diseases: Improving Global Outcomes (KDIGO) held a Controversies Conference on "Genetics in Chronic Kidney Disease (CKD)" to review the current state of understanding of monogenic and complex (polygenic) kidney diseases, processes for applying genetic findings in clinical medicine, and use of genomics for defining and stratifying CKD. Given the important contribution of genetic variants to CKD, practitioners with CKD patients are advised to "think genetic," which specifically involves obtaining a family history, collecting detailed information on age of CKD onset, performing clinical examination for extrarenal symptoms, and considering genetic testing. To improve the use of genetics in nephrology, meeting participants advised developing an advanced training or subspecialty track for nephrologists, crafting guidelines for testing and treatment, and educating patients, students, and practitioners. Key areas of future research, including clinical interpretation of genome variation, electronic phenotyping, global representation, kidney-specific molecular data, polygenic scores, translational epidemiology, and open data resources, were also identified.
Published: 2022

4. Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome

Author: Gibson, JT, Huang, M, Dabrera, MSC, Shukla, K, Rothe, H, Hilbert, P, Deltas, C, Storey, H, Lipska-Zietkiewicz, BS, Chan, MMY, Sadeghi-Alavijeh, O, Gale, DP, Cerkauskaite, A, Savige, J, Gibson, JT, Huang, M, Dabrera, MSC, Shukla, K, Rothe, H, Hilbert, P, Deltas, C, Storey, H, Lipska-Zietkiewicz, BS, Chan, MMY, Sadeghi-Alavijeh, O, Gale, DP, Cerkauskaite, A, and Savige, J
Abstract: Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3-COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
Published: 2022

5. Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy

Author: Downie ML, Gupta S, Tekman MC, Cheshire C, Arora S, Licht C, Robinson LA, Munoz M, Alvaro Madrid Aris, Al Attrach I, Brenchley PE, Gale DP, Stanescu H, Bockenhauer D, and Kleta R
Subjects: X-linked, membranous nephropathy, linkage analysis, LOD score, genetic risk score, glomerulonephritis
Abstract: INTRODUCTION: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN. METHODS: We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined. RESULTS: Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls. CONCLUSIONS: Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
Published: 2021

6. Germline selection shapes human mitochondrial DNA diversity

Author: Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract: INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.
Published: 2019
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7. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Author: French, CE, Delon, I, Dolling, H, Sanchis-Juan, A, Shamardina, O, Mégy, K, Abbs, S, Austin, T, Bowdin, S, Branco, RG, Firth, H, Tuna, S, Aitman, TJ, Ashford, S, Astle, WJ, Bennet, DL, Bleda, M, Carss, KJ, Chinnery, PF, Deevi, SVV, Fletcher, D, Gale, DP, Gräf, SF, Hu, F, James, R, Kasanicki, MA, Kingston, N, Koziell, AB, Allen, HL, Maher, ER, Markus, HS, Meacham, S, Morrell, NW, Penkett, CJ, Roberts, I, Smith, KGC, Stark, H, Stirrups, KE, Turro, E, Watkins, H, Williamson, C, Young, T, Bradley, JR, Ouwehand, WH, Raymond, FL, Agrawal, S, Armstrong, R, Beardsall, K, Belteki, G, Bohatschek, M, Broster, S, Campbell, R, Chaudhary, R, Costa, C, D’Amore, A, Fitzsimmons, A, Hague, J, Harley, J, Hoodbhoy, S, Kayani, R, Kelsall, W, Mehta, SG, O’Donnell, R, O’Hare, S, Ogilvy-Stuart, A, Papakostas, S, Park, SM, Parker, A, Pathan, N, Prapa, M, Sammut, A, Sandford, R, Schon, K, Singh, Y, Spike, K, Tavares, ALT, Wari-Pepple, D, Wong, HS, Woods, CG, Rowitch, DH, Raymond, F Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository
Subjects: Male, NICU, medicine.medical_specialty, Palliative care, Adolescent, PICU, Original, Critical Illness, Critically ill children, Genomics, Critical Care and Intensive Care Medicine, Intensive Care Units, Pediatric, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Anesthesiology, Intensive care, Intensive Care Units, Neonatal, Genetics, Medicine, Humans, Prospective Studies, Medical diagnosis, Intensive care medicine, Prospective cohort study, Child, Whole genome sequencing, Whole Genome Sequencing, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Infant, 030208 emergency & critical care medicine, 030228 respiratory system, England, FOS: Biological sciences, Child, Preschool, Female, business, Genetic Background, Cohort study
Abstract: Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.
Published: 2019

8. Expert consensus guidelines for the genetic diagnosis of Alport syndrome

Author: Savige, J, Ariani, F, Mari, F, Bruttini, M, Renieri, A, Gross, O, Deltas, C, Flinter, F, Ding, J, Gale, DP, Nagel, M, Yau, M, Shagam, L, Torra, R, Ars, E, Hoefele, J, Garosi, G, and Storey, H
Subjects: Next generation sequencing, Collagen IV genes, Pathogenic variants, urologic and male genital diseases, Alport syndrome
Abstract: Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
Published: 2019

9. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author: Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van Duijn, Cornelia M. McEniery CM, Wilkinson IB, Cockcroft JR, O'Shaughnessy KM, Newhouse SJ, Yasmin, Smith AV, Eiriksdottir G, Launer LJ, Sigurdsson S, Aspelund T, Gudnason V, De Bacquer D, Rietzschel ER, De Backer GG, Van Bortel L, De Buyzere ML, Segers P, Bekaert S, Gillebert TC, De Meyer T, Ferrucci L, Tanaka T, Johnson AD, Levy D, Benjamin EJ, Mitchell GF, Vita JA, Larson MG, Hamburg NM, Vasan RS, Isaacs A, Schut AF, Oostra BA, van Duijn CM, van Rijn MJ, Sie MP, Newman AB, Herrington DM, Andrews JS, Ding J, Sutton-Tyrrell KC, Harris TB, Howard TD, Liu Y, Parsa A, Shuldiner AR, McArdle PF, Gibson Q, Post WS, Dehghan A, Hofman A, Uitterlinden AG, Sijbrands EJ, Rivadeneira F, Mattace-Raso FU, Verwoert GC, Witteman JC, Scuteri A, Lakatta EG, Jewell E, Abecasis GR, Tarasov KV, Uda M, Najjar SS, Sanna S, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Deloukas P, Foad N, Eardman J, Goodall AH, Gracey J, Gray E, Gulde S, Gwilliams R, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Linsel-Nitschke P, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Wallace C, Kathiresan S, Reilly MP, Erdmann J, Assimes TL, Boerwinkle E, Hall A, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assime TL, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Wild P, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Chen IY, Cupples L, Demissie-Banjaw S, Folsom A, Glazer N, Harris T, Heckbert S, Lumley T, Marciante K, Morrison A, O' Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Uitterlinden A, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Lieb W, Stark K, Schreiber S, Wichmann HE, Aherrahrou Z, Bruse P, Doering A, Illig T, Klopp N, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Kleber M, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Yang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Willerson JT, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Gao X, Yang Q, O'Connell JR, Schmidt H, Ketkar S, Hwang SJ, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Siscovick D, Zillikens MC, Feitosa M, Province M, de Andrade M, Turner ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Coresh J, Schmidt R, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Felix SB, Watzinger N, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Arnett DK, Blettner M, Friedrich N, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Vollenweider P, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), University of Leicester, Department of Genetics [Leicester], Erasmus University Rotterdam, Netherlands Genomics Initiative, Department of Epidemiology and Biostatistics, School of Public Health, Zahedan University of Medical Sciences, Washington University in Saint Louis (WUSTL), Queen Mary University of London (QMUL), National Heart, Lung and Blood Institute, Partenaires INRAE, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne = University of Lausanne (UNIL), Department of Biostatistics [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Department of Epidemiology, The Netherlands Cancer Institute, Department of Mathematics, Boston University [Boston] (BU), GlaxoSmithKline, Division of Community Health Sciences, St. George's, University of South Florida [Tampa] (USF), Universität Greifswald - University of Greifswald, University of Washington [Seattle], University of Tartu, Institute of Molecular and Cell Biology, Medical Research Council, Institut de Génomique, Centre National de Génotypage, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University Medical Center Groningen, Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Massachusetts General Hospital [Boston], Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Università degli studi di Trieste = University of Trieste, Universität zu Lübeck = University of Lübeck [Lübeck], Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, The University of Western Australia (UWA), Department of Twin Research and Genetic Epidemiology, King's College London, London, University of Oxford, Medical University Graz, National Institute on Aging, Centre for population Health Sciences, University of Edinburgh, Uppsala University, Vrije Universiteit Amsterdam [Amsterdam] (VU), Western General Hospital, Harvard Medical School [Boston] (HMS), Brigham and Women's Hospital [Boston], University of Michigan System, University of Groningen, Ealing Hospital, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Medical Genetics Institute, Cedars-Sinai Medical Center, University of Tampere, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Split, The University of Texas Health Science Center at Houston (UTHealth), Johns Hopkins University (JHU), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Finnish Institute of Occupational Health, National Institute of Health and Welfare, University of Oulu, Lapland Central Hospital, University of Bristol [Bristol], Institute for Community Medicine, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), US National Institutes of Health, National Heart, Lung, and Blood Institute, European, Epidemiology, Internal Medicine, Public Health, Clinical Genetics, Université de Lausanne (UNIL), LeidenUniversity Medical Centre, University of Iceland, Università degli studi di Trieste, Universität zu Lübeck [Lübeck], University of Western Australia, University of Oxford [Oxford], VU University Amsterdam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Human genetics, Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Epidemiology and Data Science, Medical Research Council (MRC), Louise V., Wain, Germaine C., Verwoert, Paul F., O'Reilly, Gang, Shi, Toby, Johnson, Andrew D., Johnson, Murielle, Bochud, Kenneth M., Rice, Peter, Henneman, Albert V., Smith, Georg B., Ehret, Najaf, Amin, Martin G., Larson, Vincent, Mooser, David, Hadley, Marcus, Dörr, Joshua C., Bi, Thor, Aspelund, Tõnu, Esko, A. Cecile J. W., Janssen, Jing Hua, Zhao, Simon, Heath, Maris, Laan, Jingyuan, Fu, Giorgio, Pisti, Jian'An, Luan, Pankaj, Arora, Gavin, Luca, Pirastu, Nicola, Irene, Pichler, Anne U., Jackson, Rebecca J., Webster, Feng, Zhang, John F., Peden, Helena, Schmidt, Toshiko, Tanaka, Harry, Campbell, Wilmar, Igl, Yuri, Milaneschi, Jouke Jan, Hottenga, Veronique, Vitart, Daniel I., Chasman, Stella, Trompet, Jennifer L., Bragg Gresham, Behrooz Z., Alizadeh, John C., Chamber, Xiuqing, Guo, Terho, Lehtimäki, Brigitte, Kühnel, Lorna M., Lopez, Ozren, Polašek, Mladen, Boban, Christopher P., Nelson, Alanna C., Morrison, Vasyl, Pihur, Santhi K., Ganesh, Albert, Hofman, Suman, Kundu, Francesco U. S., Mattace Raso, Fernando, Rivadeneira, Eric J. G., Sijbrand, Andre G., Uitterlinden, Shih Jen, Hwang, Ramachandran S., Vasan, Thomas J., Wang, Sven, Bergmann, Peter, Vollenweider, Gérard, Waeber, Jaana, Laitinen, Anneli, Pouta, Paavo, Zitting, Wendy L., Mcardle, Heyo K., Kroemer, Uwe, Völker, Henry, Völzke, Nicole L., Glazer, Kent D., Taylor, Tamara B., Harri, Helene, Alavere, Toomas, Haller, Aime, Kei, Mari Liis, Tammesoo, Yurii, Aulchenko, Inês, Barroso, Kay Tee, Khaw, Pilar, Galan, Serge, Hercberg, Mark, Lathrop, Susana, Eyheramendy, Elin, Org, Siim, Sõber, Xiaowen, Lu, Ilja M., Nolte, Brenda W., Penninx, Tanguy, Corre, Corrado, Masciullo, Cinzia, Sala, Leif, Groop, Benjamin F., Voight, Olle, Melander, Christopher J., O'Donnell, Veikko, Salomaa, D'Adamo, ADAMO PIO, Antonella, Fabretto, Flavio, Faletra, Sheila, Ulivi, Fabiola Del Greco, M, Maurizio, Facheri, Francis S., Collin, Richard N., Bergman, John P., Beilby, Joseph, Hung, A., William Musk, Massimo, Mangino, So Youn, Shin, Nicole, Soranzo, Hugh, Watkin, Anuj, Goel, Anders, Hamsten, Pierre, Gider, Marisa, Loitfelder, Marion, Zeginigg, Dena, Hernandez, Samer S., Najjar, Pau, Navarro, Sarah H., Wild, Anna Maria, Corsi, Andrew, Singleton, Eco J. C., de Geu, Gonneke, Willemsen, Alex N., Parker, Lynda M., Rose, Brendan, Buckley, David, Stott, Marco, Orru, Manuela, Uda, Melanie M., van der Klauw, Weihua, Zhang, Xinzhong, Li, James, Scott, Yii Der Ida, Chen, Gregory L., Burke, Mika, Kähönen, Jorma, Viikari, Angela, Döring, Thomas, Meitinger, Gail, Davie, John M., Starr, Valur, Emilsson, Andrew, Plump, Jan H., Lindeman, Peter A. C., 't Hoen, Inke R., König, Janine F., Felix, Robert, Clarke, Jemma C., Hopewell, Halit, Ongen, Monique, Breteler, Stéphanie, Debette, Anita L., Destefano, Myriam, Fornage, Gary F., Mitchell, Nicholas L., Smith, Hilma, Holm, Kari, Stefansson, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Nilesh J., Samani, Michael, Preu, Igor, Rudan, Caroline, Hayward, Ian J., Deary, H., Erich Wichmann, Olli T., Raitakari, Walter, Palma, Jaspal S., Kooner, Ronald P., Stolk, J., Wouter Jukema, Alan F., Wright, Dorret I., Boomsma, Stefania, Bandinelli, Ulf B., Gyllensten, James F., Wilson, Luigi, Ferrucci, Reinhold, Schmidt, Martin, Farrall, Tim D., Spector, Lyle J., Palmer, Jaakko, Tuomilehto, Arne, Pfeufer, Gasparini, Paolo, David, Siscovick, David, Altshuler, Ruth J. F., Loo, Daniela, Toniolo, Harold, Snieder, Christian, Gieger, Pierre, Meneton, Nicholas J., Wareham, Ben A., Oostra, Andres, Metspalu, Lenore, Launer, Rainer, Rettig, David P., Strachan, Jacques S., Beckmann, Jacqueline C. M., Witteman, Jeanette, Erdmann, Ko Willems van, Dijk, Eric, Boerwinkle, Michael, Boehnke, Paul M., Ridker, Marjo Riitta, Jarvelin, Aravinda, Chakravarti, Goncalo R., Abecasi, Vilmundur, Gudnason, Christopher Newton, Cheh, Daniel, Levy, Patricia B., Munroe, Bruce M., Psaty, Mark J., Caulfield, Dabeeru C., Rao, Martin D., Tobin, Paul, Elliott, Cornelia M., van Duijn, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcu, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Mari, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, Mcardle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Tooma, Keis, Aime, Tammesoo, Mari-Lii, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Ander, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, Jame, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thoma, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andre, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willem, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van, Duijn, Cornelia M., McEniery CM, Wilkinson, Ib, Cockcroft, Jr, O'Shaughnessy, Km, Newhouse, Sj, Yasmin, Smith, Av, Eiriksdottir, G, Launer, Lj, Sigurdsson, S, Aspelund, T, Gudnason, V, De Bacquer, D, Rietzschel, Er, De Backer, Gg, Van Bortel, L, De Buyzere, Ml, Segers, P, Bekaert, S, Gillebert, Tc, De Meyer, T, Ferrucci, L, Tanaka, T, Johnson, Ad, Levy, D, Benjamin, Ej, Mitchell, Gf, Vita, Ja, Larson, Mg, Hamburg, Nm, Vasan, R, Isaacs, A, Schut, Af, Oostra, Ba, van Duijn, Cm, van Rijn, Mj, Sie, Mp, Newman, Ab, Herrington, Dm, Andrews, J, Ding, J, Sutton-Tyrrell, Kc, Harris, Tb, Howard, Td, Liu, Y, Parsa, A, Shuldiner, Ar, Mcardle, Pf, Gibson, Q, Post, 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Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Vollenweider, P, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Lightstone, L, Scott, J, Navis, G, Elliott, P, and Kooner, Js.
Subjects: Netherlands Twin Register (NTR), Linkage disequilibrium, pulse pressure, mean arterial pressure, genome-wide, [SDV]Life Sciences [q-bio], Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, RELEVANCE, CardioGram, Medicine and Health Sciences, Genetics & Heredity, ddc:616, Genetics, 0303 health sciences, Genome-wide association, 11 Medical And Health Sciences, Arteries, ADRENERGIC-RECEPTOR TRAFFICKING, Pulse pressure, EchoGen consortium, Hypertension, HEART-FAILURE, arterial pressure, Case-Control Studie, Life Sciences & Biomedicine, Human, circulatory and respiratory physiology, medicine.medical_specialty, Mean arterial pressure, Arterie, AortaGen Consortium, Cardiogenics consortium, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, Humans, cardiovascular diseases, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, HYPERTENSION, MORTALITY, Case-control study, CARDIOVASCULAR-DISEASE RISK, 06 Biological Sciences, GENE, MICE, Endocrinology, Blood pressure, CKDGen consortium, Genetic Loci, Case-Control Studies, KidneyGen consortium, CHARGE Consortium Heart Failure Working Group, LifeLines Cohort Study, Developmental Biology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Les affiliations des 100 premiers auteurs sont renseignées dans la notice. Les affiliations des autres auteurs sont disponibles à la fin de la publication.; International audience; Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Published: 2016

10. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author: Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr. , W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. 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F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Meyers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fisher M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann M, O'Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Mattha W, Knouf CW, Waterworth DM, Hakonarson HH, Walker M, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker B, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Uitterlinden AG, Willerson JT, van Duijn CM, Witteman JC, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Parsa A, Gao X, Yang Q, Smith AV, O'Connell JR, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson A, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria, Francesco, Metter J, de Boer J, Siscovick D, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turne ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan R, Felix SB, Watzinger N, Larson MG, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Stricker BH, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett D, Blettner M, Friedrich N, Benjamin EJ, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic T, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Abecasis GR, Lightstone L, Scott J, Navis G, Elliot P, Kooner JS., AII - Amsterdam institute for Infection and Immunity, Nephrology, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Epidemiology, Medical Microbiology & Infectious Diseases, Radiology & Nuclear Medicine, Cardiology, Internal Medicine, Clinical Genetics, Erasmus MC other, Obstetrics & Gynecology, International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Clinical Pharmacology and The Genome Centre, Queen Mary University of London (QMUL), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Center for Human Genetic Research, Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Harvard University-Massachusetts Institute of Technology (MIT), Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'An, Arora, Pankaj, Dehghan, Abba, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, Mcardle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthia, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johanne, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inê, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Marku, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margu, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Mckenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thoma, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, Jame, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr., W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Ander, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcu, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Pano, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Jano, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charle, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Mari, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang, H, Knowles, J, Hlatky, M, Fortmann, S, Assimes, Tl, Quertermous, T, Go, A, Iribarren, C, Absher, D, Risch, N, Meyers, R, Sidney, S, Ziegler, A, Schillert, A, Bickel, C, Sinning, C, Rupprecht, Hj, Lackner, K, Wild, P, Schnabel, R, Blankenberg, S, Zeller, T, Münzel, T, Perret, C, Cambien, F, Tiret, L, Nicaud, V, Proust, C, Dehghan, A, Hofman, A, Uitterlinden, A, van Duijn, C, Levy, D, Whitteman, J, Cupples, La, Demissie-Banjaw, S, Ramachandran, V, Smith, A, Gudnason, V, Boerwinkle, E, Folsom, A, Morrison, A, Psaty, Bm, Chen, Iy, Rotter, Ji, Bis, J, Volcik, K, Rice, K, Taylor, Kd, Marciante, K, Smith, N, Glazer, N, Heckbert, S, Harris, T, Lumley, T, Kong, A, Thorleifsson, G, Thorgeirsson, G, Holm, H, Gulcher, Jr, Stefansson, K, Andersen, K, Gretarsdottir, S, Thorsteinsdottir, U, Preuss, M, Schreiber, S, Meitinger, T, König, Ir, Lieb, W, Hengstenberg, C, Schunkert, H, Erdmann, J, Fisher, M, Grosshennig, A, Medack, A, Stark, K, Linsel-Nitschke, P, Bruse, P, Aherrahrou, Z, Peters, A, Loley, C, Willenborg, C, Nahrstedt, J, Freyer, J, Gulde, S, Doering, A, Meisinger, C, Wichmann, He, Klopp, N, Illig, T, Meinitzer, A, Tomaschitz, A, Halperin, E, Dobnig, H, Scharnagl, H, Kleber, M, Laaksonen, R, Pilz, S, Grammer, Tb, Stojakovic, T, Renner, W, März, W, Böhm, Bo, Winkelmann, Br, Winkler, K, Hoffmann, M, O'Donnell, Cj, Voight, Bf, Altshuler, D, Siscovick, D, Musunuru, K, Peltonen, L, Barbalic, M, Melander, O, Elosua, R, Kathiresan, S, Schwartz, Sm, Salomaa, V, Guiducci, C, Burtt, N, Gabriel, Sb, Stewart, Af, Wells, Ga, Chen, L, Jarinova, O, Roberts, R, Mcpherson, R, Dandona, S, Pichard, Ad, Rader, Dj, Devaney, J, Lindsay, Jm, Kent, Km, Qu, L, 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Subjects: novel loci, Kidney Disease, Polymorphism, Single Nucleotide/*genetics, [SDV]Life Sciences [q-bio], left ventricular wall thickness, LOCI, Genome-wide association study, Blood Pressure, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, RELEVANCE, Africa/ethnology, Cardiovascular Disease, genetics, Kidney Diseases/genetics, Stroke, genome wide association study, POPULATION, ta118, Blood pressure, hypertension, stroke, coronary artery disease, ddc:616, 0303 health sciences, education.field_of_study, Asia/ethnology, Multidisciplinary, Coronary Artery Disease/genetics, COMMON VARIANTS, Genetic Predisposition to Disease/*genetics, 3. Good health, Europe, Cardiovascular Diseases, Hypertension, Cardiology, Kidney Diseases, HEALTH, Human, medicine.medical_specialty, Asia, Population, Renal function, Polymorphism, Single Nucleotide, Europe/ethnology, Article, CLONING, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stroke/genetics, Internal medicine, medicine, Humans, Cardiovascular Diseases/*genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, 030304 developmental biology, RECEPTOR, genes, blood pressure, cardiovascular disease risk, medicine.disease, Africa, Blood Pressure/*genetics/physiology, Hypertension/genetics, Kidney disease, Genome-Wide Association Study
Abstract: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. ispartof: Nature vol:478 issue:7367 pages:103-109 ispartof: location:England status: published
Published: 2011

11. A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population

Author: Chatziantoniou, C, Voskarides, K, Stefanou, C, Pieri, M, Demosthenous, P, Felekkis, K, Arsali, M, Athanasiou, Y, Xydakis, D, Stylianou, K, Daphnis, E, Goulielmos, G, Loizou, P, Savige, J, Hoehne, M, Voelker, LA, Benzing, T, Maxwell, PH, Gale, DP, Gorski, M, Boeger, C, Kollerits, B, Kronenberg, F, Paulweber, B, Zavros, M, Pierides, A, Deltas, C, Chatziantoniou, C, Voskarides, K, Stefanou, C, Pieri, M, Demosthenous, P, Felekkis, K, Arsali, M, Athanasiou, Y, Xydakis, D, Stylianou, K, Daphnis, E, Goulielmos, G, Loizou, P, Savige, J, Hoehne, M, Voelker, LA, Benzing, T, Maxwell, PH, Gale, DP, Gorski, M, Boeger, C, Kollerits, B, Kronenberg, F, Paulweber, B, Zavros, M, Pierides, A, and Deltas, C
Abstract: BACKGROUND: Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on long-term follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. METHODS: We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as "Severe" or "Mild", based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. RESULTS AND CONCLUSIONS: Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10-3, OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10-3 adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10-3). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohor
Published: 2017

12. Advances and unmet needs in genetic, basic and clinical science in Alport syndrome::report from the 2015 International Workshop on Alport Syndrome

Author: Gross, O, Kashtan, CE, Rheault, MN, Flinter, F, Savige, J, Miner, JH, Torra, R, Ars, E, Deltas, C, Savva, I, Perin, L, Renieri, A, Ariani, F, Mari, F, Baigent, C, Judge, P, Knebelman, B, Heidet, L, Lagas, S, Blatt, D, Ding, J, Zhang, Y, Gale, DP, Prunotto, M, Xue, Y, Schachter, AD, Morton, LC, Blem, J, Huang, M, Liu, S, Vallee, S, Renault, D, Schifter, J, Skelding, J, Gear, S, Friede, T, Turner, AN, and Lennon, R
Subjects: Collagen Type IV, nephroprotection, Podocytes, Reviews, Nephritis, Hereditary, Genetic Therapy, Quality Improvement, hereditary kidney disease, Mutation, Animals, Humans, Alport syndrome, chronic kidney disease, guidelines, Needs Assessment
Abstract: Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the alpha 3 alpha 4 alpha 5(IV) collagen heterotrimer. AS is rare, but it accounts for > 1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis.
Published: 2016

13. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations

Author: Okada, Y, Sim, X, Go, Mj, Wu, Jy, Gu, D, Takeuchi, F, Takahashi, A, Maeda, S, Tsunoda, T, Chen, P, Lim, Sc, Wong, Ty, Liu, J, Young, Tl, Aung, T, Seielstad, M, Teo, Yy, Kim, Yj, Lee, Jy, Han, Bg, Kang, D, Chen, Ch, Tsai, Fj, Chang, Lc, Fann, Sj, Mei, H, Rao, Dc, Hixson, Je, Chen, S, Katsuya, T, Isono, M, Ogihara, T, Chambers, Jc, Zhang, W, Kooner, Js, Kidneygen, Consortium, Ckdgen, Consortium, Albrecht, E, Gugc, Consortium, Yamamoto, K, Kubo, M, Nakamura, Y, Kamatani, N, Kato, N, He, J, Chen, Yt, Cho, Ys, Tai, Es, Tanaka, T., Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, Js, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Smith, Gd, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Ferrucci, L, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, van der Heide JJ, Hepkema, Bg, Hernandez Fuentes, M, Hypponen, E, Johnson, T, de Jong PE, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Melander, O, Munroe, Pb, Nordfors, L, Parsa, A, Peltonen, L, Penninx, Bw, Perucha, E, Pouta, A, Prokopenko, I, Roderick, Pj, Ruokonen, A, Samani, Nj, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Shuldiner, Ar, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Tanaka, T, Ubink Veltmaat LJ, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Mooser, V, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliott, P, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Glazer, Nl, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Li, M, Schmidt, H, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, Ad, Dehghan, A, Teumer, A, Paré, G, Atkinson, Ej, Zeller, T, Lohman, K, Cornelis, Mc, Probst Hensch NM, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Boerwinkle, E, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer IH, Haritunians, T, Lumley, T, Siscovick, D, Psaty, Bm, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schillert, A, Ziegler, A, Wild, Ps, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, Ts, Illig, T, Klopp, N, Meisinger, C, Wichmann, He, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, Å, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Schreiber, S, Aulchenko, Ys, Felix, Jf, Rivadeneira, F, Uitterlinden, Ag, Hofman, A, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Blankenberg, S, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Wang, W, Gudnason, V, Coresh, J, Schmidt, R, Shlipak, Mg, van Duijn CM, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Witteman, Jc, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, Cs, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, M, Haller, T, Kutalik, Z, Shi, J, Middelberg, Ps, Gaffo, Al, Pirastu, N, Li, G, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, Giovanni, Lopez, Lm, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Peden, Jf, Steri, M, Tenesa, A, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Mcardle, P, Schallert, M, Martin, Ng, Montgomery, Gw, Jacobs DR Jr, Liu, K, D'Adamo, P, Ulivi, S, Rotter, Ji, Navaro, P, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Kraja, A, Zhang, Q, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, Antonio, Trabetti, Elisabetta, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Winkelmann, Br, Boehm, Bo, Lucae, S, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Mateo Leach, I, van Gilst WH, Goel, A, Ongen, H, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Sala, C, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Burnier, M, Attia, J, Laan, M, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Whitfield, Jb, Fornage, M, Gasparini, P, Siscovick, Ds, Bouatia Naji, N, Metspalu, A, Borecki, Ib, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, März, W, Watkins, H, Schipf, S, Dunlop, Mg, Ripatti, S, Toniolo, D, Raitakari, O, Ciullo, M, Caulfield, M, Gieger, C., Okada, Y, Sim, X, Go, Mj, Wu, Jy, Gu, D, Takeuchi, F, Takahashi, A, Maeda, S, Tsunoda, T, Chen, P, Lim, Sc, Wong, Ty, Liu, J, Young, Tl, Aung, T, Seielstad, M, Teo, Yy, Kim, Yj, Lee, Jy, Han, Bg, Kang, D, Chen, Ch, Tsai, Fj, Chang, Lc, Fann, Sj, Mei, H, Rao, Dc, Hixson, Je, Chen, S, Katsuya, T, Isono, M, Ogihara, T, Chambers, Jc, Zhang, W, Kooner, J, Albrecht, E, Yamamoto, K, Kubo, M, Nakamura, Y, Kamatani, N, Kato, N, He, J, Chen, Yt, Cho, Y, Tai, E, Tanaka, T, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Smith, Gd, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Ferrucci, L, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, van der Heide, Jj, Hepkema, Bg, Hernandez Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Melander, O, Munroe, Pb, Nordfors, L, Parsa, A, Peltonen, L, Penninx, Bw, Perucha, E, Pouta, A, Prokopenko, I, Roderick, Pj, Ruokonen, A, Samani, Nj, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Shuldiner, Ar, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink Veltmaat, Lj, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Mooser, V, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliott, P, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Glazer, Nl, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Li, M, Schmidt, H, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, Ad, Dehghan, A, Teumer, A, Paré, G, Atkinson, Ej, Zeller, T, Lohman, K, Cornelis, Mc, Probst Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Boerwinkle, E, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer, Ih, Haritunians, T, Lumley, T, Siscovick, D, Psaty, Bm, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schillert, A, Ziegler, A, Wild, P, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Illig, T, Klopp, N, Meisinger, C, Wichmann, He, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, Å, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Schreiber, S, Aulchenko, Y, Felix, Jf, Rivadeneira, F, Uitterlinden, Ag, Hofman, A, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Blankenberg, S, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Wang, W, Gudnason, V, Coresh, J, Schmidt, R, Shlipak, Mg, van Duijn, Cm, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Witteman, Jc, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, M, Haller, T, Kutalik, Z, Shi, J, Middelberg, P, Gaffo, Al, Pirastu, Nicola, Li, G, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Peden, Jf, Steri, M, Tenesa, A, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Mcardle, P, Schallert, M, Martin, Ng, Montgomery, Gw, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Navaro, P, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Kraja, A, Zhang, Q, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Winkelmann, Br, Boehm, Bo, Lucae, S, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Mateo Leach, I, van Gilst, Wh, Goel, A, Ongen, H, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Sala, C, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Burnier, M, Attia, J, Laan, M, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Whitfield, Jb, Fornage, M, Gasparini, Paolo, Bouatia Naji, N, Metspalu, A, Borecki, Ib, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, März, W, Watkins, H, Schipf, S, Dunlop, Mg, Ripatti, S, Toniolo, D, Raitakari, O, Ciullo, M, Caulfield, M, Gieger, C., KidneyGen Consortium, CKDGen Consortium, GUGC consortium, Chambers, J.C., Zhang, W., Lord, G.M., van der Harst, P., Lawlor, D.A., Sehmi, J.S., Gale, D.P., Wass, M.N., Ahmadi, K.R., Bakker, S.J., Beckmann, J., Bilo, H.J., Bochud, M., Brown, M.J., Caulfield, M.J., Connell, J.M., Cook, H.T., Cotlarciuc, I., Smith, G.D., de Silva, R., Deng, G., Devuyst, O., Dikkeschei, L.D., Dimkovic, N., Dockrell, M., Dominiczak, A., Ebrahim, S., Eggermann, T., Farrall, M., Ferrucci, L., Floege, J., Forouhi, N.G., Gansevoort, R.T., Han, X., Hedblad, B., van der Heide, J.J., Hepkema, B.G., Hernandez-Fuentes, M., Hypponen, E., Johnson, T., de Jong, P.E., Kleefstra, N., Lagou, V., Lapsley, M., Li, Y., Loos, R.J., Luan, J., Luttropp, K., Maréchal, C., Melander, O., Munroe, P.B., Nordfors, L., Parsa, A., Peltonen, L., Penninx, B.W., Perucha, E., Pouta, A., Prokopenko, I., Roderick, P.J., Ruokonen, A., Samani, N.J., Sanna, S., Schalling, M., Schlessinger, D., Schlieper, G., Seelen, M.A., Shuldiner, A.R., Sjögren, M., Smit, J.H., Snieder, H., Soranzo, N., Spector, T.D., Stenvinkel, P., Sternberg, M.J., Swaminathan, R., Tanaka, T., Ubink-Veltmaat, L.J., Uda, M., Vollenweider, P., Wallace, C., Waterworth, D., Zerres, K., Waeber, G., Wareham, N.J., Maxwell, P.H., McCarthy, M.I., Jarvelin, M.R., Mooser, V., Abecasis, G.R., Lightstone, L., Scott, J., Navis, G., Elliott, P., Kooner, J.S., Köttgen, A., Pattaro, C., Böger, C.A., Fuchsberger, C., Olden, M., Glazer, N.L., Gao, X., Yang, Q., Smith, A.V., O'Connell, J.R., Li, M., Schmidt, H., Isaacs, A., Ketkar, S., Hwang, S.J., Johnson, A.D., Dehghan, A., Teumer, A., Paré, G., Atkinson, E.J., Zeller, T., Lohman, K., Cornelis, M.C., Probst-Hensch, N.M., Kronenberg, F., Tönjes, A., Hayward, C., Aspelund, T., Eiriksdottir, G., Launer, L.J., Harris, T.B., Rampersaud, E., Mitchell, B.D., Arking, D.E., Boerwinkle, E., Struchalin, M., Cavalieri, M., Singleton, A., Giallauria, F., Metter, J., de Boer, I.H., Haritunians, T., Lumley, T., Siscovick, D., Psaty, B.M., Zillikens, M.C., Oostra, B.A., Feitosa, M., Province, M., de Andrade, M., Turner, S.T., Schillert, A., Ziegler, A., Wild, P.S., Schnabel, R.B., Wilde, S., Munzel, T.F., Leak, T.S., Illig, T., Klopp, N., Meisinger, C., Wichmann, H.E., Koenig, W., Zgaga, L., Zemunik, T., Kolcic, I., Minelli, C., Hu, F.B., Johansson, Å., Igl, W., Zaboli, G., Wild, S.H., Wright, A.F., Campbell, H., Ellinghaus, D., Schreiber, S., Aulchenko, Y.S., Felix, J.F., Rivadeneira, F., Uitterlinden, A.G., Hofman, A., Imboden, M., Nitsch, D., Brandstätter, A., Kollerits, B., Kedenko, L., Mägi, R., Stumvoll, M., Kovacs, P., Boban, M., Campbell, S., Endlich, K., Völzke, H., Kroemer, H.K., Nauck, M., Völker, U., Polasek, O., Vitart, V., Badola, S., Parker, A.N., Ridker, P.M., Kardia, S.L., Blankenberg, S., Liu, Y., Curhan, G.C., Franke, A., Rochat, T., Paulweber, B., Wang, W., Gudnason, V., Coresh, J., Schmidt, R., Shlipak, M.G., van Duijn, C.M., Borecki, I., Krämer, B.K., Rudan, I., Gyllensten, U., Wilson, J.F., Witteman, J.C., Pramstaller, P.P., Rettig, R., Hastie, N., Chasman, D.I., Kao, W.H., Heid, I.M., Fox, C.S., Albrecht, E., Krumsiek, J., Hundertmark, C., Pistis, G., Ruggiero, D., O'Seaghdha, M., Haller, T., Kutalik, Z., Shi, J., Middelberg, P.S., Gaffo, A.L., Pirastu, N., Li, G., Huffman, J., Yengo, L., Zhao, J.H., Demirkan, A., Feitosa, M.F., Liu, X., Malerba, G., Lopez, L.M., Li, X., Kleber, M.E., Hicks, A.A., Nolte, I.M., Johansson, A., Murgia, F., Peden, J.F., Steri, M., Tenesa, A., Salo, P., Mangino, M., Rose, L.M., Lehtimäki, T., Woodward, O.M., Okada, Y., Tin, A., Müller, C., Oldmeadow, C., Putku, M., Czamara, D., Kraft, P., Frogheri, L., Thun, G.A., Grotevendt, A., Gislason, G.K., McArdle, P., Schallert, M., Martin, N.G., Montgomery, G.W., Kubo, M., Nakamura, Y., Jacobs, D.R., Liu, K., D'Adamo, P., Ulivi, S., Rotter, J.I., Navaro, P., Balkau, B., Froguel, P., Esko, T., Salumets, A., Khaw, K.T., Langenberg, C., Kraja, A., Zhang, Q., Scott, R.J., Holliday, E.G., Org, E., Viigimaa, M., Bandinelli, S., Metter, J.E., Lupo, A., Trabetti, E., Sorice, R., Döring, A., Lattka, E., Strauch, K., Theis, F., Waldenberger, M., Davies, G., Gow, A.J., Bruinenberg, M., Stolk, R.P., Winkelmann, B.R., Boehm, B.O., Lucae, S., Curhan, G., Mudgal, P., Plenge, R.M., Portas, L., Persico, I., Kirin, M., Mateo Leach, I., van Gilst, W.H., Goel, A., Ongen, H., von Eckardstein, A., Cucca, F., Nagaraja, R., Piras, M.G., Schurmann, C., Budde, K., Ernst, F., Farrington, S.M., Theodoratou, E., Jula, A., Perola, M., Salomaa, V., Shin, S.Y., Sala, C., Kähönen, M., Viikari, J., Hengstenberg, C., Nelson, C.P., Meschia, J.F., Nalls, M.A., Sharma, P., Singleton, A.B., Kamatani, N., Burnier, M., Attia, J., Laan, M., Hillege, H.L., Kloiber, S., Choi, H., Pirastu, M., Tore, S., Whitfield, J.B., Fornage, M., Gasparini, P., Siscovick, D.S., Bouatia-Naji, N., Metspalu, A., Borecki, I.B., Gambaro, G., Deary, I.J., Wolffenbuttel, B.H., März, W., Watkins, H., Schipf, S., Dunlop, M.G., Ripatti, S., Toniolo, D., Raitakari, O., Ciullo, M., Caulfield, M., Obstetrics & Gynecology, Medical Informatics, Okada, Yukinori, Sim, Xueling, Go, Min Jin, Wu, Jer-Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su-Chi, Wong, Tien-Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Seielstad, Mark, Teo, Yik-Ying, Kim, Young Jin, Lee, Jong-Young, Han, Bok-Ghee, Kang, Daehee, Chen, Chien-Hsiun, Tsai, Fuu-Jen, Chang, Li-Ching, Cathy Fann, S. -J. C., Mei, Hao, Rao, Dabeeru C., Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Ogihara, Toshio, Chambers, John C., Zhang, Weihua, Kooner, Jaspal S., Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan-Tsong, Cho, Yoon Shin, Tai, E-Shyong, Tanaka, Toshihiro, de Silva, R Deng G, Hernandez-Fuentes, M, Ubink-Veltmaat, Lj, Probst-Hensch, Nm, Giallauria, Francesco, Pirastu, N, D'Adamo, P, Gasparini, P, and Bouatia-Naji, N
Subjects: Asian Continental Ancestry Group, kidney, Population, Renal function, Genome-wide association study, Biology, Kidney, Polymorphism, Single Nucleotide, Article, Blood Urea Nitrogen, Cohort Studies, chemistry.chemical_compound, SDG 3 - Good Health and Well-being, Asian People, loci, Asian, medicine, Humans, genetics, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, education, meta-analysis, Genome-Wide Association Study, Genetic association, Genetics, Creatinine, education.field_of_study, ta3121, medicine.disease, Uric Acid, Asian Continental Ancestry Group/genetics, Creatinine/blood, Glomerular Filtration Rate/genetics, Kidney/physiology, Renal Insufficiency, Chronic/genetics, Uric Acid/blood, medicine.anatomical_structure, chemistry, Genetic epidemiology, Cohort Studie, Human, Kidney disease, Glomerular Filtration Rate
Abstract: Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genomewide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 x 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of similar to 110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.
Published: 2012

14. Recurrence of complement factor H-related protein 5 nephropathy in a renal transplant

Author: Vernon, KA, Gale, DP, De Jorge, E Goicoechea, McLean, AG, Galliford, J, Pierides, A, Maxwell, PH, Taube, D, Pickering, MC, and Cook, HT
Subjects: Male, Complement System Proteins, Middle Aged, urologic and male genital diseases, Kidney Transplantation, 3. Good health, Glomerulonephritis, Recurrence, Complement Factor H, Cyprus, Humans, Female, Kidney Diseases, Aged
Abstract: Complement factor H-related protein 5 (CFHR5) nephropathy is a familial renal disease endemic in Cyprus. It is characterized by persistent microscopic hematuria, synpharyngitic macroscopic hematuria and progressive renal impairment. Isolated glomerular accumulation of complement component 3 (C3) is typical with variable degrees of glomerular inflammation. Affected individuals have a heterozygous internal duplication in the CFHR5 gene, although the mechanism through which this mutation results in renal disease is not understood. Notably, the risk of progressive renal failure in this condition is higher in males than females. We report the first documented case of recurrence of CFHR5 nephropathy in a renal transplant in a 53-year-old Cypriot male. Strikingly, histological changes of CFHR5 nephropathy were evident in the donor kidney 46 days post-transplantation. This unique case demonstrates that renal-derived CFHR5 protein cannot prevent the development of CFHR5 nephropathy.

15. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

Author: Connor, TM, Hoer, S, Mallett, A, Gale, DP, Gomez Duran, A, Posse, V, Antrobus, R, Moreno, P, Sciacovelli, M, Frezza, C, Duff, J, Sheerin, NS, Sayer, JA, Ashcroft, M, Wiesener, MS, Hudson, G, Gustafsson, CM, Chinnery, PF, and Maxwell, PH
Subjects: Male, Genetic Linkage, Biopsy, Phenylalanine, Fibroblasts, DNA, Mitochondrial, Polymorphism, Single Nucleotide, 3. Good health, Mitochondria, Pedigree, Quadriceps Muscle, Kidney Tubules, Oxygen Consumption, Phenotype, RNA, Transfer, Leucine, Acetylglucosaminidase, Mutation, Humans, Female, Kidney Diseases, Promoter Regions, Genetic
Abstract: Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNA$^{Phe}$, tRNA$^{Leu1}$ and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNA$^{Phe}$ (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNA$^{Phe}$.

16. Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1

Author: Nathalie Demoulin, Eric Goffin, Yves Pirson, Anna Greka, Patrick Hofmann, Uyen Huynh-Do, Olivier Devuyst, Olivier Bonny, Johann Morelle, Gregory Papagregoriou, Roser Torra, Karin Dahan, Hendrica Belge, Bruno Vogt, Constantinos Deltas, John A. Sayer, Anthony J. Bleyer, Céline Schaeffer, Kendrah Kidd, Daniel Guido Fuster, Luca Rampoldi, Eric Olinger, Stanislav Kmoch, Kateřina Hodaňová, Anne Kipp, Inès Dufour, Reto Martin Venzin, Thomas Fehr, Andreas D. Kistler, Christina Venzin, Martina Živná, Daniel P. Gale, Richard Sandford, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Olinger, E, Hofmann, P, Kidd, K, Dufour, I, Belge, H, Schaeffer, C, Kipp, A, Bonny, O, Deltas, C, Demoulin, N, Fehr, T, Fuster, Dg, Gale, Dp, Goffin, E, Hodanova, K, Hyunh-Do, U, Kistler, Ad, Morelle, J, Papagregoriou, G, Pirson, Y, Sandford, R, Sayer, Ja, Torra, R, Venzin, C, Venzin, R, Vogt, B, Živná, M, Greka, A, Dahan, K, Rampoldi, L, Kmoch, S, Bleyer AJ, Sr, and Devuyst, O
Subjects: 0301 basic medicine, Nephrology, medicine.medical_specialty, Tamm–Horsfall protein, Gout, Urinary system, 030232 urology & nephrology, 610 Medicine & health, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Diagnostic score, Internal medicine, Uromodulin, Humans, Medicine, Genetic Testing, Genetic testing, Mutation, Kidney, medicine.diagnostic_test, biology, business.industry, Mucin-1, Middle Aged, Polycystic Kidney, Autosomal Dominant, medicine.disease, Dominant kidney disease, Europe, 030104 developmental biology, medicine.anatomical_structure, biology.protein, business, Kidney disease
Abstract: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized. cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. To expand on this, we analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
Published: 2020

17. Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations

Author: Karl Lhotta, Peter J. Conlon, Daniel P. Gale, Victoria Robins, Miroslav Votruba, Kendrah Kidd, Céline Schaeffer, Dominik Steubl, Ying Maggie Chen, Catarina Silveira, Gianluca Caridi, Lauren Martin, Claudia Izzi, Antonio Amoroso, Eric Olinger, Jorge Reis Almeida, Stanislav Kmoch, Rita Raposeiro, Daniela Gianchino, Alena Vrbacká, Hannah C. Ainsworth, Martina Živná, Gian Marco Ghiggeri, Kateřina Hodaňová, Rosa J. Torres, Christine Gast, Joaquim Calado, Abbigail Taylor, Olivier Devuyst, Katherine A. Benson, Susan L. Murray, Cintia Fernandes de Souza, Eva Gombos, Emily Johnson, Francesco Scolari, Gianpiero L. Cavalleri, Petr Vylet'al, Jasmin Divers, Anthony J. Bleyer, Luca Rampoldi, Sofia C Jorge, Nelson Weller, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Centre for Toxicogenomics and Human Health (ToxOmics), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), Kidd, K, Vylet’Al, P, Schaeffer, C, Olinger, E, Živná, M, Hodaňová, K, Robins, V, Johnson, E, Taylor, A, Martin, L, Izzi, C, Jorge, Sc, Calado, J, Torres, Rj, Lhotta, K, Steubl, D, Gale, Dp, Gast, C, Gombos, E, Ainsworth, H, Chen, Ym, Almeida, Jr, Fernandes de Souza, C, Silveira, C, Raposeiro, R, Weller, N, Conlon, P, Murray, S, Benson, Ka, Cavalleri, G, Votruba, M, Vrbacká, A, Amoroso, A, Gianchino, D, Caridi, G, Ghiggeri, Gm, Divers, J, Scolari, F, Devuyst, O, Rampoldi, L, Kmoch, S, and Bleyer, A
Subjects: Oncology, medicine.medical_specialty, autosomal dominant uromodulin kidney disease, Tamm–Horsfall protein, phenotype, uromodulin, genotype, Population, 030232 urology & nephrology, 030204 cardiovascular system & hematology, lcsh:RC870-923, rs4293393, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, Mendelian randomization, medicine, Allele, education, Allele frequency, education.field_of_study, biology, business.industry, medicine.disease, lcsh:Diseases of the genitourinary system. Urology, Minor allele frequency, Ophthalmology, Nephrology, biology.protein, business, Kidney disease
Abstract: Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD. publishersversion published
Published: 2020

18. The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Author: Vivarelli M, Barratt J, Beck LH Jr, Fakhouri F, Gale DP, Goicoechea de Jorge E, Mosca M, Noris M, Pickering MC, Susztak K, Thurman JM, Cheung M, King JM, Jadoul M, Winkelmayer WC, and Smith RJH
Subjects: Humans, Biomarkers blood, Complement Inactivating Agents therapeutic use, Complement System Proteins immunology, Complement System Proteins metabolism, Congresses as Topic, Disease Progression, Kidney Glomerulus immunology, Kidney Glomerulus pathology, Complement Activation immunology, Kidney Diseases immunology, Kidney Diseases therapy, Kidney Diseases diagnosis
Abstract: Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. Although complement activation plays a causal role in atypical hemolytic uremic syndrome and C3 glomerulopathy, over the past decade, a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022, Kidney Diseases: Improving Global Outcomes (KDIGO) convened a Controversies Conference, "The Role of Complement in Kidney Disease," to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of hemolytic uremic syndrome. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified., (Copyright © 2024 Kidney Disease: Improving Global Outcomes (KDIGO). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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19. Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing.

Author: Sadeghi-Alavijeh O, Chan MM, Doctor GT, Voinescu CD, Stuckey A, Kousathanas A, Ho AT, Stanescu HC, Bockenhauer D, Sandford RN, Levine AP, and Gale DP
Subjects: Humans, Male, Female, Collagen Type IV genetics, Genetic Variation, Gene Frequency, Case-Control Studies, Genetic Predisposition to Disease, Autoantigens, Receptors, Cell Surface, Whole Genome Sequencing, Kidney Diseases, Cystic genetics
Abstract: BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODSUsing whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTSIn 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%-9% to the heritability of CyKD across European ancestries.CONCLUSIONBy providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.
Published: 2024
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20. A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome.

Author: Gale DP, Gross O, Wang F, Esteban de la Rosa RJ, Hall M, Sayer JA, Appel G, Hariri A, Liu S, Maski M, Shen Y, Zhang Q, Iqbal S, Kowthalam MU, Lin J, and Ding J
Subjects: Humans, Adult, Male, Female, Kidney physiopathology, Kidney drug effects, Glomerular Filtration Rate drug effects, Middle Aged, Treatment Outcome, Nephritis, Hereditary complications, Nephritis, Hereditary drug therapy, Nephritis, Hereditary physiopathology
Published: 2024
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21. Developing Therapies for C3 Glomerulopathy: Report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group.

Author: Nester C, Decker DA, Meier M, Aslam S, Bomback AS, Caravaca-Fontán F, Cook TH, Feldman DL, Fremeaux-Bacchi V, Gale DP, Gooch A, Johnson S, Licht C, Mathur M, Pickering MC, Praga M, Remuzzi G, Selvarajah V, Smith RJ, Tabriziani H, van de Kar N, Wang Y, Wong E, Mistry K, Lim M, Portillo C, Balogun S, Trachtman H, and Thompson A
Abstract: Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Published: 2024
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22. Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort.

Author: Wong K, Pitcher D, Braddon F, Downward L, Steenkamp R, Masoud S, Annear N, Barratt J, Bingham C, Coward RJ, Chrysochou T, Game D, Griffin S, Hall M, Johnson S, Kanigicherla D, Karet Frankl F, Kavanagh D, Kerecuk L, Maher ER, Moochhala S, Pinney J, Sayer JA, Simms R, Sinha S, Srivastava S, Tam FWK, Thomas K, Turner AN, Walsh SB, Waters A, Wilson P, Wong E, Sy KTL, Huang K, Ye J, Nitsch D, Saleem M, Bockenhauer D, Bramham K, and Gale DP
Abstract: Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR., Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census., Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P -value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P -value < 0.0001)., Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)
Published: 2024
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23. Using genomics to understand severe COVID-19.

Author: Chan MMY and Gale DP
Subjects: Humans, Severity of Illness Index, COVID-19 virology, COVID-19 genetics, Genomics methods, SARS-CoV-2 genetics
Published: 2024
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24. A Neanderthal haplotype introgressed into the human genome confers protection against membranous nephropathy.

Author: Voinescu CD, Mozere M, Genovese G, Downie ML, Gupta S, Gale DP, Bockenhauer D, Kleta R, Arcos-Burgos M, and Stanescu HC
Subjects: Humans, Animals, Haplotypes, Genome, Human, Genome-Wide Association Study, Receptors, Phospholipase A2 genetics, Neanderthals genetics, Glomerulonephritis, Membranous genetics
Abstract: Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene. We reconstructed the phylogeny of Neanderthal and modern haplotypes in this region and calculated the probability of the observed clustering being the result of introgression or common descent. We imputed variants for the participants in our previous genome-wide association study and we compared the distribution of Neanderthal variants between MN cases and controls. The region associated with the lead MN risk locus in the PLA2R1 gene was confirmed and showed that, within a 507 kb region enriched in introgressed sequence, a stringently defined 105 kb haplotype, intersecting the coding regions for PLA2R1 and ITGB6, is inherited from Neanderthals. Thus, introgressed Neanderthal haplotypes overlapping PLA2R1 are differentially represented in MN cases and controls, with enrichment In controls suggesting a protective effect., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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25. Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

Author: Wong K, Pitcher D, Braddon F, Downward L, Steenkamp R, Annear N, Barratt J, Bingham C, Chrysochou C, Coward RJ, Game D, Griffin S, Hall M, Johnson S, Kanigicherla D, Karet Frankl F, Kavanagh D, Kerecuk L, Maher ER, Moochhala S, Pinney J, Sayer JA, Simms R, Sinha S, Srivastava S, Tam FWK, Turner AN, Walsh SB, Waters A, Wilson P, Wong E, Taylor CM, Nitsch D, Saleem M, Bockenhauer D, Bramham K, and Gale DP
Subjects: Humans, Glomerular Filtration Rate, Kidney, Radar, Rare Diseases, Registries, United Kingdom epidemiology, Infant, Newborn, Infant, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic therapy, Kidney Failure, Chronic etiology, Renal Insufficiency epidemiology, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic therapy, Renal Insufficiency, Chronic complications
Abstract: Background: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure., Methods: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m 2 or more to first eGFR of less than 30 mL/min per 1·73 m 2 (the therapeutic trial window)., Findings: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases., Interpretation: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand., Funding: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity., Competing Interests: Declaration of interests ERM reports support for the current manuscript from VHL UK/Ireland and consulting fees from MSD. SM is chair of OxalEurope. MS reports support for the current manuscript from a Medical Research Council UK Precision Medicine programme grant (MR/R013942/1) and consulting fees from Travere Therapeutics. RJC reports support for the current manuscript from Kidney Research UK. JAS reports support for the current manuscript from Kidney Research UK, Northern Counties Kidney Research Fund, and the Medical Research Council UK (all payments to institution). JAS is Academic Vice President of the UK Kidney Association. FWKT reports support from the National Institute for Health and Care Research Imperial Biomedical Centre. DN is the UK Kidney Association Director of Informatics Research. DPG reports support for the current manuscript from St Peter's Trust for Kidney Bladder and Prostate Research, Medical Research Council, Kidney Research UK, Kidney Care UK, and Polycystic Kidney Disease Charity (all payments to institution). DPG chairs the Rare Diseases Committee of the UK Kidney Association and reports fees for consulting and presenting from Novartis, Alexion, Calliditas, Sanofi, Britannia, and Travere. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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26. Correction: The 2019 and 2021 International workshops on Alport syndrome.

Author: Daga S, Ding J, Deltas C, Savige J, Lipska-Ziętkiewicz BS, Hoefele J, Flinter F, Gale DP, Aksenova M, Kai H, Perin L, Barua M, Torra R, Miner JH, Massella L, Ljubanović DG, Lennon R, Weinstock AB, Knebelmann B, Cerkauskaite A, Gear S, Gross O, Turner AN, Baldassarri M, Pinto AM, and Renieri A
Published: 2024
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27. Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

Author: Cipriani V, Vestito L, Magavern EF, Jacobsen JO, Arno G, Behr ER, Benson KA, Bertoli M, Bockenhauer D, Bowl MR, Burley K, Chan LF, Chinnery P, Conlon P, Costa M, Davidson AE, Dawson SJ, Elhassan E, Flanagan SE, Futema M, Gale DP, García-Ruiz S, Corcia CG, Griffin HR, Hambleton S, Hicks AR, Houlden H, Houlston RS, Howles SA, Kleta R, Lekkerkerker I, Lin S, Liskova P, Mitchison H, Morsy H, Mumford AD, Newman WG, Neatu R, O'Toole EA, Ong AC, Pagnamenta AT, Rahman S, Rajan N, Robinson PN, Ryten M, Sadeghi-Alavijeh O, Sayer JA, Shovlin CL, Taylor JC, Teltsh O, Tomlinson I, Tucci A, Turnbull C, van Eerde AM, Ware JS, Watts LM, Webster AR, Westbury SK, Zheng SL, Caulfield M, and Smedley D
Abstract: To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.
Published: 2023
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28. Rare variants in the sodium-dependent phosphate transporter gene SLC34A3 explain missing heritability of urinary stone disease.

Author: Sadeghi-Alavijeh O, Chan MMY, Moochhala SH, Howles S, Gale DP, and Böckenhauer D
Subjects: Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Sodium, Sodium-Phosphate Cotransporter Proteins, Type IIc genetics, Urinary Calculi genetics, Urolithiasis genetics, Urologic Diseases
Abstract: Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. Here, we investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the United Kingdom 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic codes indicative of USD. Whole genome gene-based rare variant testing and polygenic risk scoring against a control population of 24,930 ancestry-matched controls was performed. We observed (and replicated in an independent dataset) exome-wide significant enrichment of monoallelic rare, predicted damaging variants in the SLC34A3 gene for a sodium-dependent phosphate transporter that were present in 5% cases compared with 1.6% of controls. This gene was previously associated with autosomal recessive disease. The effect on USD risk of having a qualifying SLC34A3 variant was greater than that of a standard deviation increase in polygenic risk derived from GWAS. Addition of the rare qualifying variants in SLC34A3 to a linear model including polygenic score increased the liability-adjusted heritability from 5.1% to 14.2% in the discovery cohort. We conclude that rare variants in SLC34A3 represent an important genetic risk factor for USD, with effect size intermediate between the fully penetrant rare variants linked with Mendelian disorders and common variants associated with USD. Thus, our findings explain some of the heritability unexplained by prior common variant genome-wide association studies., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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29. Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Author: Tam FWK, Tumlin J, Barratt J, Rovin BH, Roberts ISD, Roufosse C, Cook HT, Bhangal G, Brown AL, Busch M, Dudhiya F, Duliege AM, Fraser DJ, Gale DP, Huang CC, Lai PC, Lee M, Masuda ES, McAdoo SP, Rosenkranz AR, Sommerer C, Sunder-Plassmann G, Szeto CC, Tang SCW, Williamson DE, Willcocks L, Vielhauer V, Kim MJ, Todd L, Zayed H, Tong-Starksen S, and Lafayette R
Abstract: Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells., Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology., Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05)., Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)
Published: 2023
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30. Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice.

Author: Deltas C, Papagregoriou G, Louka SF, Malatras A, Flinter F, Gale DP, Gear S, Gross O, Hoefele J, Lennon R, Miner JH, Renieri A, Savige J, and Turner AN
Subjects: Child, Preschool, Humans, Animals, Mice, Middle Aged, Adult, Hematuria genetics, Collagen Type IV genetics, Nephritis, Hereditary genetics, Renal Insufficiency
Abstract: Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5 . Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3 / A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models.
Published: 2023
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31. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.

Author: Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, Zanoni F, Liu L, Mladkova N, Khan A, Marasa M, Zhang JY, Balderes O, Sanna-Cherchi S, Bomback AS, Canetta PA, Appel GB, Radhakrishnan J, Trimarchi H, Sprangers B, Cattran DC, Reich H, Pei Y, Ravani P, Galesic K, Maixnerova D, Tesar V, Stengel B, Metzger M, Canaud G, Maillard N, Berthoux F, Berthelot L, Pillebout E, Monteiro R, Nelson R, Wyatt RJ, Smoyer W, Mahan J, Samhar AA, Hidalgo G, Quiroga A, Weng P, Sreedharan R, Selewski D, Davis K, Kallash M, Vasylyeva TL, Rheault M, Chishti A, Ranch D, Wenderfer SE, Samsonov D, Claes DJ, Akchurin O, Goumenos D, Stangou M, Nagy J, Kovacs T, Fiaccadori E, Amoroso A, Barlassina C, Cusi D, Del Vecchio L, Battaglia GG, Bodria M, Boer E, Bono L, Boscutti G, Caridi G, Lugani F, Ghiggeri G, Coppo R, Peruzzi L, Esposito V, Esposito C, Feriozzi S, Polci R, Frasca G, Galliani M, Garozzo M, Mitrotti A, Gesualdo L, Granata S, Zaza G, Londrino F, Magistroni R, Pisani I, Magnano A, Marcantoni C, Messa P, Mignani R, Pani A, Ponticelli C, Roccatello D, Salvadori M, Salvi E, Santoro D, Gembillo G, Savoldi S, Spotti D, Zamboli P, Izzi C, Alberici F, Delbarba E, Florczak M, Krata N, Mucha K, Pączek L, Niemczyk S, Moszczuk B, Pańczyk-Tomaszewska M, Mizerska-Wasiak M, Perkowska-Ptasińska A, Bączkowska T, Durlik M, Pawlaczyk K, Sikora P, Zaniew M, Kaminska D, Krajewska M, Kuzmiuk-Glembin I, Heleniak Z, Bullo-Piontecka B, Liberek T, Dębska-Slizien A, Hryszko T, Materna-Kiryluk A, Miklaszewska M, Szczepańska M, Dyga K, Machura E, Siniewicz-Luzeńczyk K, Pawlak-Bratkowska M, Tkaczyk M, Runowski D, Kwella N, Drożdż D, Habura I, Kronenberg F, Prikhodina L, van Heel D, Fontaine B, Cotsapas C, Wijmenga C, Franke A, Annese V, Gregersen PK, Parameswaran S, Weirauch M, Kottyan L, Harley JB, Suzuki H, Narita I, Goto S, Lee H, Kim DK, Kim YS, Park JH, Cho B, Choi M, Van Wijk A, Huerta A, Ars E, Ballarin J, Lundberg S, Vogt B, Mani LY, Caliskan Y, Barratt J, Abeygunaratne T, Kalra PA, Gale DP, Panzer U, Rauen T, Floege J, Schlosser P, Ekici AB, Eckardt KU, Chen N, Xie J, Lifton RP, Loos RJF, Kenny EE, Ionita-Laza I, Köttgen A, Julian BA, Novak J, Scolari F, Zhang H, and Gharavi AG
Subjects: Animals, Mice, Genome-Wide Association Study, Immunoglobulin A genetics, Glomerulonephritis, IGA drug therapy, Glomerulonephritis, IGA genetics, Glomerulonephritis, IGA diagnosis
Abstract: IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2023
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32. Long-Term Outcomes in IgA Nephropathy.

Author: Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, Steenkamp R, Wong K, Turner AN, Wang K, Gale DP, and Barratt J
Subjects: Adult, Child, Humans, Glomerular Filtration Rate, Kidney, Proteinuria etiology, Disease Progression, Retrospective Studies, Glomerulonephritis, IGA complications, Glomerulonephritis, IGA epidemiology, Kidney Failure, Chronic therapy
Abstract: Background: IgA nephropathy can progress to kidney failure, and risk assessment soon after diagnosis has advantages both for clinical management and the development of new therapeutics. We present relationships among proteinuria, eGFR slope, and lifetime risks for kidney failure., Methods: The IgA nephropathy cohort (2299 adults and 140 children) of the UK National Registry of Rare Kidney Diseases (RaDaR) was analyzed. Patients enrolled had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 ml/min per 1.73 m 2 . Incident and prevalent populations and a population representative of a typical phase 3 clinical trial cohort were studied. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope., Results: The median (Q1, Q3) follow-up was 5.9 (3.0, 10.5) years; 50% of patients reached kidney failure or died in the study period. The median (95% confidence interval [CI]) kidney survival was 11.4 (10.5 to 12.5) years; the mean age at kidney failure/death was 48 years, and most patients progressed to kidney failure within 10-15 years. On the basis of eGFR and age at diagnosis, almost all patients were at risk of progression to kidney failure within their expected lifetime unless a rate of eGFR loss ≤1 ml/min per 1.73 m 2 per year was maintained. Time-averaged proteinuria was significantly associated with worse kidney survival and more rapid eGFR loss in incident, prevalent, and clinical trial populations. Thirty percent of patients with time-averaged proteinuria of 0.44 to <0.88 g/g and approximately 20% of patients with time-averaged proteinuria <0.44 g/g developed kidney failure within 10 years. In the clinical trial population, each 10% decrease in time-averaged proteinuria from baseline was associated with a hazard ratio (95% CI) for kidney failure/death of 0.89 (0.87 to 0.92)., Conclusions: Outcomes in this large IgA nephropathy cohort are generally poor with few patients expected to avoid kidney failure in their lifetime. Significantly, patients traditionally regarded as being low risk, with proteinuria <0.88 g/g (<100 mg/mmol), had high rates of kidney failure within 10 years., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Published: 2023
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33. Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome.

Author: Downie ML, Gupta S, Chan MMY, Sadeghi-Alavijeh O, Cao J, Parekh RS, Diz CB, Bierzynska A, Levine AP, Pepper RJ, Stanescu H, Saleem MA, Kleta R, Bockenhauer D, Koziell AB, and Gale DP
Subjects: Child, Humans, Genome-Wide Association Study, Steroids, Risk Factors, Nephrotic Syndrome diagnosis, Nephrotic Syndrome drug therapy, Nephrotic Syndrome genetics, Nephrosis, Lipoid diagnosis, Nephrosis, Lipoid drug therapy, Nephrosis, Lipoid genetics, Glomerulosclerosis, Focal Segmental diagnosis, Glomerulosclerosis, Focal Segmental drug therapy, Glomerulosclerosis, Focal Segmental genetics, Glomerulonephritis, Membranous
Abstract: Background: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways., Methods: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls., Results: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS., Conclusions: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)
Published: 2023
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34. Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.

Author: Downie ML, Gupta S, Voinescu C, Levine AP, Sadeghi-Alavijeh O, Dufek-Kamperis S, Cao J, Christian M, Kari JA, Thalgahagoda S, Ranawaka R, Abeyagunawardena A, Gbadegesin R, Parekh R, Kleta R, Bockenhauer D, Stanescu HC, and Gale DP
Abstract: Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non- HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry., Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls., Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10 -27 , odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10 -8 , OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3., Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)
Published: 2023
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35. Genomics in the kidney clinic.

Author: Doctor GT, Gale DP, and Chan MM
Subjects: Humans, Genomics, Kidney, Mutation, Kidney Failure, Chronic, Nephritis, Hereditary diagnosis, Nephritis, Hereditary genetics, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant genetics
Abstract: Inherited diseases are a frequent cause of end-stage kidney disease and often seen in the kidney clinic. Clinical genomic testing is increasingly available in the UK and eligible patients in England can be referred through the NHS Genomic Medicine Service. Testing is useful for diagnosis, prognostication and management of conditions such as autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, autosomal dominant tubulointerstitial kidney disease (ADTKD) and focal segmental glomerulosclerosis (FSGS). As more patients undergo genomic testing and newer technologies such as whole genome sequencing are applied, we are developing a greater appreciation of the full phenotypic spectrum of inherited kidney diseases and the challenges associated with the interpretation of clinically significant variants., (© Royal College of Physicians 2023. All rights reserved.)
Published: 2023
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36. A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy.

Author: Gupta S, Downie ML, Cheshire C, Dufek-Kamperis S, Levine AP, Brenchley P, Hoxha E, Stahl R, Ashman N, Pepper RJ, Mason S, Norman J, Bockenhauer D, Stanescu HC, Kleta R, and Gale DP
Abstract: Introduction: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1 , HLA-DRB1 , HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states., Methods: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome., Results: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive ( N = 372) compared with both the unaffected control ( N = 4,929) and anti-THSD7A-positive ( N = 31) groups ( p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset ( p = 0.009). Further, the GRS in the dual antibody-negative group ( N = 355) was intermediate between controls and the PLA2R1-positive group ( p < 0.0001)., Conclusion: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)
Published: 2023
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37. Segregation analysis identifies specific alpha-defensin (DEFA1A3) SNP-CNV haplotypes in predisposition to IgA nephropathy.

Author: Shwan NAA, Moise EC, Necsoiu PE, Farr AJ, Gale DP, Barratt J, and Armour JAL
Subjects: Humans, Haplotypes, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Disease Susceptibility, Genetic Predisposition to Disease, Peptides, Cyclic genetics, alpha-Defensins genetics, Glomerulonephritis, IGA genetics
Abstract: Background: Immunoglobulin A (IgA) nephropathy is a disorder of the immune system affecting kidney function, and genome-wide association studies (GWAS) have defined numerous loci with associated variation, all implicating components of innate or adaptive immunity. Among these, single nucleotide polymorphisms (SNPs) in a region including the multiallelic copy number variation (CNV) of DEFA1A3 are associated with IgA nephropathy in both European and Asian populations. At present, the precise factors underlying the observed associations at DEFA1A3 have not been defined, although the key alleles differ between Asian and European populations, and multiple independent factors may be involved even within a single population., Methods: In this study, we measured DEFA1A3 copy number in UK family trios with an offspring affected by IgA nephropathy, used the population distributions of joint SNP-CNV haplotypes to infer the likely segregation in trios, and applied transmission disequilibrium tests (TDT) to examine joint SNP-CNV haplotypes for over- or undertransmission into affected offspring from heterozygous parents., Results and Conclusions: We observed overtransmission of 3-copy class 2 haplotypes (raw p = 0.029) and some evidence for under-transmission of 3-copy class 1 haplotypes (raw p = 0.051), although these apparent effects were not statistically significant after correction for testing of multiple haplotypes., (© 2022 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)
Published: 2023
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38. A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.

Author: Mingardo E, Beaman G, Grote P, Nordenskjöld A, Newman W, Woolf AS, Eckstein M, Hilger AC, Dworschak GC, Rösch W, Ebert AK, Stein R, Brusco A, Di Grazia M, Tamer A, Torres FM, Hernandez JL, Erben P, Maj C, Olmos JM, Riancho JA, Valero C, Hostettler IC, Houlden H, Werring DJ, Schumacher J, Gehlen J, Giel AS, Buerfent BC, Arkani S, Åkesson E, Rotstein E, Ludwig M, Holmdahl G, Giorgio E, Berettini A, Keene D, Cervellione RM, Younsi N, Ortlieb M, Oswald J, Haid B, Promm M, Neissner C, Hirsch K, Stehr M, Schäfer FM, Schmiedeke E, Boemers TM, van Rooij IALM, Feitz WFJ, Marcelis CLM, Lacher M, Nelson J, Ure B, Fortmann C, Gale DP, Chan MMY, Ludwig KU, Nöthen MM, Heilmann S, Zwink N, Jenetzky E, Odermatt B, Knapp M, and Reutter H
Subjects: Humans, Animals, Mice, Genome-Wide Association Study, Transcriptome, Ephrin-A1 genetics, Bladder Exstrophy genetics, Bladder Exstrophy complications, Urinary Bladder Neoplasms genetics
Abstract: Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility., (© 2022. The Author(s).)
Published: 2022
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39. Digenic Alport Syndrome.

Author: Savige J, Renieri A, Ars E, Daga S, Pinto AM, Rothe H, Gale DP, Aksenova M, Cerkauskaite A, Bielska O, Lipska-Zietkiewicz B, and Gibson JT
Subjects: Humans, Male, Female, Pedigree, Autoantigens genetics, Collagen Type IV genetics, Proteinuria, Mutation, Nephritis, Hereditary genetics, Nephritis, Hereditary pathology
Abstract: Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4 Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant "severity," and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α 3 α 4 α 5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome ( in cis ) or recessive when they affect different chromosomes ( in trans ). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes., (Copyright © 2022 by the American Society of Nephrology.)
Published: 2022
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40. Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.

Author: Chan MMY, Sadeghi-Alavijeh O, Lopes FM, Hilger AC, Stanescu HC, Voinescu CD, Beaman GM, Newman WG, Zaniew M, Weber S, Ho YM, Connolly JO, Wood D, Maj C, Stuckey A, Kousathanas A, Kleta R, Woolf AS, Bockenhauer D, Levine AP, and Gale DP
Subjects: Cell Adhesion Molecules genetics, Child, Chromatin, Humans, Male, Receptor Protein-Tyrosine Kinases genetics, Transcription Factors genetics, Genome-Wide Association Study, T-Box Domain Proteins genetics, Urinary Tract
Abstract: Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) in 132 unrelated male PUV cases and 23,727 controls of diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (p=7.8 × 10 -12 ; OR 0.4) and rare variants at 6p21.1 (p=2.0 × 10 -8 ; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4151 controls. Fine mapping and functional genomic data mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7 , respectively, the encoded proteins of which were detected in the developing urinary tract of human embryos. We also observed enrichment of rare structural variation intersecting with candidate cis -regulatory elements, particularly inversions predicted to affect chromatin looping (p=3.1 × 10 -5 ). These findings represent the first robust genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate how a diverse ancestry seqGWAS can be used for disease locus discovery in a rare disease., Competing Interests: MC, OS, FL, AH, HS, CV, GB, WN, MZ, SW, YH, JC, DW, CM, AS, AK, RK, AW, DB, AL, DG No competing interests declared, (© 2022, Chan et al.)
Published: 2022
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41. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements.

Author: Dixon PH, Levine AP, Cebola I, Chan MMY, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J, Chambers J, Syngelaki A, Donnelly J, Cooley S, Geary M, Nicolaides K, Thorsell M, Hague WM, Estiu MC, Marschall HU, Gale DP, and Williamson C
Subjects: Bile Acids and Salts, Female, Genome-Wide Association Study, Humans, Infant, Newborn, Pregnancy, Cholestasis, Intrahepatic genetics, Pregnancy Complications genetics, Premature Birth
Abstract: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility., (© 2022. The Author(s).)
Published: 2022
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42. Pathogenicity of missense variants affecting the collagen IV α5 carboxy non-collagenous domain in X-linked Alport syndrome.

Author: Gibson JT, Sadeghi-Alavijeh O, Gale DP, Rothe H, and Savige J
Subjects: Collagen Type IV chemistry, Humans, Male, Renal Insufficiency, Collagen Type IV genetics, Mutation, Missense, Nephritis, Hereditary genetics, Nephritis, Hereditary pathology
Abstract: X-linked Alport syndrome is a genetic kidney disease caused by pathogenic COL4A5 variants, but little is known of the consequences of missense variants affecting the NC1 domain of the corresponding collagen IV α5 chain. This study examined these variants in a normal (gnomAD) and other databases (LOVD, Clin Var and 100,000 Genomes Project) to determine their pathogenicity and clinical significance. Males with Cys substitutions in the collagen IV α5 NC1 domain reported in LOVD (n = 25) were examined for typical Alport features, including age at kidney failure. All NC1 variants in LOVD (n = 86) were then assessed for structural damage using an online computational tool, Missense3D. Variants in the ClinVar, gnomAD and 100,000 Genomes Project databases were also examined for structural effects. Predicted damage associated with NC1 substitutions was then correlated with the level of conservation of the affected residues. Cys substitutions in males were associated with the typical features of X-linked Alport syndrome, with a median age at kidney failure of 31 years. NC1 substitutions predicted to cause structural damage were overrepresented in LOVD (p < 0.001), and those affecting Cys residues or 'buried' Gly residues were more common than expected (both p < 0.001). Most NC1 substitutions in gnomAD (88%) were predicted to be structurally-neutral. Substitutions affecting conserved residues resulted in more structural damage than those affecting non-conserved residues (p < 0.001). Many pathogenic missense variants affecting the collagen IV α5 NC1 domain have their effect through molecular structural damage and 3D modelling is a useful tool in their assessment., (© 2022. The Author(s).)
Published: 2022
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43. Hematuria and Proteinuria in a Patient With Recurrent Pulmonary Illnesses: A Quiz.

Author: Liang KV, Ellis BK, Stokes MB, Smith RJ, Gu X, and Gale DP
Subjects: Humans, Proteinuria diagnosis, Proteinuria etiology, Glomerulonephritis, IGA, Hematuria diagnosis, Hematuria etiology
Published: 2022
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44. The 2019 and 2021 International Workshops on Alport Syndrome.

Author: Daga S, Ding J, Deltas C, Savige J, Lipska-Ziętkiewicz BS, Hoefele J, Flinter F, Gale DP, Aksenova M, Kai H, Perin L, Barua M, Torra R, Miner JH, Massella L, Ljubanović DG, Lennon R, Weinstock AB, Knebelmann B, Cerkauskaite A, Gear S, Gross O, Turner AN, Baldassarri M, Pinto AM, and Renieri A
Subjects: Collagen Type IV, Female, Humans, Male, Nephritis, Hereditary diagnosis, Nephritis, Hereditary genetics, Nephritis, Hereditary therapy
Published: 2022
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45. Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants.

Author: Mohamed M, Tellez J, Bergmann C, Gale DP, Sayer JA, and Olinger E
Subjects: Autoantigens genetics, Humans, Male, Mutation, Pedigree, Collagen Type IV genetics, Nephritis, Hereditary diagnosis, Nephritis, Hereditary genetics, Nephritis, Hereditary pathology, Renal Insufficiency
Abstract: Alport syndrome is a genetic disorder affecting the basement membranes of the kidney, ear and eye, and represents a leading cause of monogenic kidney disease. Alport syndrome is genetically heterogeneous with three key genes involved (COL4A3-5) and several transmission patterns, including monogenic X-linked, autosomal recessive/dominant and digenic. We report a consanguineous family where 13 individuals presented variable features of Alport syndrome including kidney failure on two generations and male-to-male transmission, suggesting autosomal dominant inheritance. COL4A3-5 gene panel analysis surprisingly reveals two distinct, confirmed splice-altering variants in COL4A3 (NM_000091.4: c.1150+5G>A and c.4028-3C>T) present in homozygous or compound heterozygous state in individuals with kidney failure. This adds a further mode of transmission for Alport syndrome where, in a consanguineous family, the independent segregation of two variants at the same locus may create a pseudodominant transmission pattern. These findings highlight the importance of a molecular diagnosis in Alport syndrome for genetic risk counselling, given the variable modes of inheritance, but also the pitfalls of assuming identity by descent in consanguineous families., (© 2021 John Wiley & Sons Ltd/University College London.)
Published: 2022
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46. Identification of a novel genetic locus associated with immune-mediated thrombotic thrombocytopenic purpura.

Author: Stubbs MJ, Coppo P, Cheshire C, Veyradier A, Dufek S, Levine AP, Thomas M, Patel V, Connolly JO, Hubank M, Benhamou Y, Galicier L, Poullin P, Kleta R, Gale DP, Stanescu H, and Scully MA
Subjects: ADAMTS13 Protein genetics, Genetic Loci, Genome-Wide Association Study, Glucosyltransferases genetics, Humans, Purpura, Thrombocytopenic, Idiopathic genetics, Purpura, Thrombotic Thrombocytopenic genetics
Abstract: Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, life-threatening disorder, mediated through severe ADAMTS13 deficiency causing multi-system micro-thrombi formation, and has specific human leukocyte antigen associations. We undertook a large genome-wide association study to investigate additional genetically distinct associations in iTTP. We compared two iTTP patient cohorts with controls, following standardized genome-wide quality control procedures for single-nucleotide polymorphisms and imputed HLA types. Associations were functionally investigated using expression quantitative trait loci (eQTL), and motif binding prediction software. Independent associations consistent with previous findings in iTTP were detected at the HLA locus and in addition a novel association was detected on chromosome 3 (rs9884090, P=5.22x10-10, odds ratio 0.40) in the UK discovery cohort. Meta-analysis, including the French replication cohort, strengthened the associations. The haploblock containing rs9884090 is associated with reduced protein O-glycosyltransferase 1 (POGLUT1) expression (eQTL P<0.05), and functional annotation suggested a potential causative variant (rs71767581). This work implicates POGLUT1 in iTTP pathophysiology and suggests altered post-translational modification of its targets may influence disease susceptibility.
Published: 2022
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47. Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome.

Author: Gibson JT, Huang M, Shenelli Croos Dabrera M, Shukla K, Rothe H, Hilbert P, Deltas C, Storey H, Lipska-Ziętkiewicz BS, Chan MMY, Sadeghi-Alavijeh O, Gale DP, Cerkauskaite A, and Savige J
Subjects: Adult, Databases, Genetic, Deafness complications, Deafness genetics, Female, Genetic Variation, Hematuria complications, Hematuria genetics, Heterozygote, Humans, Logistic Models, Male, Mutation, Missense, Nephritis, Hereditary complications, Nephritis, Hereditary epidemiology, Prevalence, Proportional Hazards Models, Renal Insufficiency complications, Renal Insufficiency genetics, Risk Factors, Young Adult, Amino Acid Substitution genetics, Autoantigens genetics, Collagen Type IV genetics, Genetic Association Studies, Glycine genetics, Nephritis, Hereditary genetics
Abstract: Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3-COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome., (© 2022. The Author(s).)
Published: 2022
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48. Kidney organoids recapitulate human basement membrane assembly in health and disease.

Author: Morais MRPT, Tian P, Lawless C, Murtuza-Baker S, Hopkinson L, Woods S, Mironov A, Long DA, Gale DP, Zorn TMT, Kimber SJ, Zent R, and Lennon R
Subjects: Animals, Biopsy, Cell Culture Techniques, Three Dimensional methods, Cell Line, Child, Preschool, Collagen Type IV genetics, Extracellular Matrix Proteins genetics, Female, Humans, Kidney pathology, Kidney Diseases genetics, Male, Mice, Pluripotent Stem Cells physiology, Proteomics methods, Basement Membrane pathology, Basement Membrane physiology, Kidney physiology, Kidney Diseases pathology, Organoids physiology
Abstract: Basement membranes (BMs) are complex macromolecular networks underlying all continuous layers of cells. Essential components include collagen IV and laminins, which are affected by human genetic variants leading to a range of debilitating conditions including kidney, muscle, and cerebrovascular phenotypes. We investigated the dynamics of BM assembly in human pluripotent stem cell-derived kidney organoids. We resolved their global BM composition and discovered a conserved temporal sequence in BM assembly that paralleled mammalian fetal kidneys. We identified the emergence of key BM isoforms, which were altered by a pathogenic variant in COL4A5 . Integrating organoid, fetal, and adult kidney proteomes, we found dynamic regulation of BM composition through development to adulthood, and with single-cell transcriptomic analysis we mapped the cellular origins of BM components. Overall, we define the complex and dynamic nature of kidney organoid BM assembly and provide a platform for understanding its wider relevance in human development and disease., Competing Interests: MM, PT, CL, SM, LH, SW, AM, DL, DG, TZ, SK, RZ, RL No competing interests declared, (© 2022, Morais et al.)
Published: 2022
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49. Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation.

Author: Khalil Y, Carrino S, Lin F, Ferlin A, Lad HV, Mazzacuva F, Falcone S, Rivers N, Banks G, Concas D, Aguilar C, Haynes AR, Blease A, Nicol T, Al-Shawi R, Heywood W, Potter P, Mills K, Gale DP, and Clayton PT
Subjects: Animals, Brain metabolism, Cytochrome P450 Family 2 metabolism, Cytochrome P450 Family 4 metabolism, Fatty Acids metabolism, Female, Gene Knockout Techniques, Kidney metabolism, Liver metabolism, Male, Mice, Oxidation-Reduction, Phytanic Acid analogs & derivatives, Phytanic Acid metabolism, Phytol pharmacology, Carbon-Carbon Lyases genetics, Lipidomics methods, Peroxisomes metabolism, Phytol administration & dosage, Proteomics methods
Abstract: Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1 -/- mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1 -/- liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1 -/- mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1 -/- mice in better understanding disease mechanism in fatty acid α-oxidation disorders.
Published: 2022
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50. C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

Author: Wong EKS, Marchbank KJ, Lomax-Browne H, Pappworth IY, Denton H, Cooke K, Ward S, McLoughlin AC, Richardson G, Wilson V, Harris CL, Morgan BP, Hakobyan S, McAlinden P, Gale DP, Maxwell H, Christian M, Malcomson R, Goodship THJ, Marks SD, Pickering MC, Kavanagh D, Cook HT, and Johnson SA
Subjects: Adolescent, Child, Child, Preschool, Complement C3 genetics, Complement C3b immunology, Complement C4 metabolism, Complement Factor B immunology, Complement Factor H immunology, Disease Progression, Female, Follow-Up Studies, Glomerular Filtration Rate, Glomerulonephritis, Membranoproliferative pathology, Glomerulonephritis, Membranoproliferative therapy, Graft Survival, Humans, Kaplan-Meier Estimate, Kidney Failure, Chronic etiology, Kidney Failure, Chronic surgery, Kidney Transplantation, Male, Prognosis, Proportional Hazards Models, Prospective Studies, Recurrence, Registries, Risk Factors, Autoantibodies blood, Complement C3 metabolism, Glomerulonephritis, Membranoproliferative blood, Glomerulonephritis, Membranoproliferative etiology, Phenotype
Abstract: Background and Objectives: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data., Design, Setting, Participants, & Measurements: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method., Results: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P< 0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen., Conclusions: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure., (Copyright © 2021 by the American Society of Nephrology.)
Published: 2021
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