Konstantin Kahnert

All Publications

• Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk. JAMA cardiology Vad, O. B., Monfort, L. M., Paludan-Muller, C., Kahnert, K., Diederichsen, S. Z., Andreasen, L., Lotta, L. A., Nielsen, J. B., Lundby, A., Svendsen, J. H., Olesen, M. S., Geisinger MyCode Community Health Initiative and the Regeneron Genetics Center (RGC) Research Team, Baras, A., Abecasis, G., Ferrando, A., Cantor, M., Coppola, G., Deubler, A., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Siminovitch, K., Portnoy, J., Jones, M. B., Mitnaul, L., Fenney, A., Marchini, J., Ferreira, M. A., Ghoussaini, M., Nafde, M., Salerno, W., Beechert, C., Brian, E. D., Cremona, L. M., Du, H., Forsythe, C., Gu, Z., Guevara, K., Lattari, M., Lopez, A., Manoochehri, K., Challa, P., Pradhan, M., Reynoso, R., Schiavo, R., Padilla, M. S., Wang, C., Wolf, S. E., Averitt, A., Banerjee, N., Li, D., Malhotra, S., Mower, J., Sarwar, M., Sharma, D., Staples, J. C., Yu, S., Zhang, A., Aqeel, M., Mitra, G., Gokhale, S., Bunyea, A., Punuru, K. P., Sreeram, S., Eom, G., Sultan, B., Lanche, R., Mahajan, V., Austin, E., O'Keeffe, S., Panea, R., Polanco, T., Rasool, A., Bai, X., Zhang, L., Boutkov, B., Edelstein, E., Gorovits, A., Guan, J., Habegger, L., Hawes, A., Krasheninina, O., Zarate, S., Mansfield, A. J., Maxwell, E. K., Balasubramanian, S., Bao, S., Sun, K., Zhang, C., Karuppaiya, V. R., Backman, J., Burch, K., Campos, A., Chen, L., Choi, S., Damask, A., Ganel, L., Gaynor, S., Geraghty, B., Ghosh, A., Martinez, S. R., Gillies, C., Gurski, L., Herman, J., Jorgenson, E., Joseph, T., Kessler, M., Kosmicki, J., Lin, N., Locke, A., Nakka, P., Landheer, K., Delaneau, O., Marcketta, A., Mbatchou, J., Moscati, A., Pandey, A., Pandit, A., Paulding, C., Ross, J., Sidore, C., Stahl, E., Suciu, M., Thornton, T., VandeHaar, P., Vedantam, S., Vrieze, S., Zhang, J., Wang, R., Wu, K., Ye, B., Zhang, B., Ziyatdinov, A., Zou, Y., Watanabe, K., Tang, M., Wendt, F., Hobbs, B., Silver, J., Palmer, W., Guerreiro, R., Joshi, A., Baldassari, A., Willer, C., Graham, S., Mayerhofer, E., Haas, M., Verweij, N., Hindy, G., Bovijn, J., De, T., Akbari, P., Sun, L., Sosina, O., Gilly, A., Dornbos, P., Rodriguez-Flores, J., Riaz, M., Kapoor, M., Tzoneva, G., Jallow, M. W., Alkelai, A., Ayer, A., Rajagopal, V., Gelfman, S., Kumar, V., Otto, J., Parikshak, N., Guvenek, A., Bras, J., Alvarez, S., Brown, J., He, J., Khiabanian, H., Revez, J., Skead, K., Zavala, V., Sul, J. S., Chen, E., LeBlanc, M. G., Mighty, J., Nishtala, N., Rana, N., Rico-Varela, J., Hernandez, J., Schwartz, R., Hankins, J., Hart, S., Perez-Beals, A., Solari, G., Rivera-Picart, J., Pagan, M., Siceron, S., Buchanan, A., Carey, D. J., Martin, C. L., Meyer, M., Retterer, K., Rolston, D. 2024

  Abstract

  Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).Design, Setting, and Participants: This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.Exposures: Rare pLOF variants and an AF PRS.Main Outcomes and Measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis.Results: A total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and Relevance: Rare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

  View details for DOI 10.1001/jamacardio.2024.1528

  View details for PubMedID 38922602

• Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction CARDIOVASCULAR RESEARCH Kahnert, K., Soattin, L., Mills, R., Wilson, C., Maurya, S., Sorrentino, A., Al-Othman, S., Tikhomirov, R., van de Vegte, Y., Hansen, F., Achter, J., Hu, W., Zi, M., Smith, M., van der Harst, P., Olesen, M., Olsen, K., Banner, J., Jensen, T., Zhang, H., Boyett, M., D'Souza, A., Lundby, A. 2024

  Abstract

  In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND.We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND.Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

  View details for DOI 10.1093/cvr/cvae054

  View details for Web of Science ID 001207875900001

  View details for PubMedID 38661182