The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency

Rupar, Nina (avtor), Šelb, Julij (avtor), Košnik, Mitja (avtor), Zidarn, Mihaela (avtor), Andrejević, Slađana (avtor), Čulav, Ljerka (avtor), Grivčeva-Panovska, Vesna (avtor), Korošec, Peter (avtor), Rijavec, Matija (avtor)

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A, and ZNF790). We selected variants in CC2D2B and PLCL1, which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07-14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH.

• Jezik: Angleški jezik
• Ključne besede: hereditary angioedema, C1 inhibitor deficiency, genetic modifiers, clinical phenotype, genotype-phenotype correlation, genetic variant, SERPING1, CC2D2B
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta ; FFA - Fakulteta za farmacijo ; BF - Biotehniška fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 11 str.
• Številčenje: Vol. 919, art. 148496
• PID: 20.500.12556/RUL-156333
• UDK: 66
• ISSN pri članku: 1879-0038
• DOI: 10.1016/j.gene.2024.148496
• COBISS.SI-ID: 194844163
• Datum objave v RUL: 20.05.2024

Gradivo je del revije

• Naslov: Gene
• Skrajšan naslov: Gene
• Založnik: Elsevier
• ISSN: 1879-0038
• COBISS.SI-ID: 23394309

Licence

• Licenca: CC BY-NC 4.0, Creative Commons Priznanje avtorstva-Nekomercialno 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc/4.0/deed.sl
• Opis: Licenca Creative Commons, ki prepoveduje komercialno uporabo, vendar uporabniki ne rabijo upravljati materialnih avtorskih pravic na izpeljanih delih z enako licenco.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: hereditarni angioedem, pomanjkanje zaviralca C1, geni modifikatorji, klinični fenotip, povezave genotip-fenotip, genetska varianta, SERPING1, CC2D2B

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P3-0360
• Naslov: Celostna obravnava alergijskih bolezni in astme v Sloveniji: od epidemiologije do genetike

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: J3-2532
• Naslov: Bradikininski angioedem: novi biološki označevalci in genetska predispozicija