HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F25%3A10507327" target="_blank" >RIV/00064165:_____/25:10507327 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10507327

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=zooNcyRRjO" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=zooNcyRRjO</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1073/pnas.2513989122" target="_blank" >10.1073/pnas.2513989122</a>

Jazyk výsledku

angličtina

Název v původním jazyce

HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity

Popis výsledku v původním jazyce

Type 1 narcolepsy (T1N), an autoimmune disease associated with a disruption of hypocretin/orexin neurons, has conserved genetic effects transcending cultures and ethnicities. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic genome-wide association study (GWAS) on age of onset. Only one strong GWAS significant effect was observed across all ethnicities, summarized by the presence of human leukocyte antigen (HLA)-DQB1*03:01, and centered around the coding region of this gene. In contrast, HLA-DQB1*06:02-positive heterodimer (DQ0602) dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The HLA-DQB1*03:01 effect (mean -3.47 y, P = 1.7 x 10&lt;sup&gt;-18&lt;/sup&gt;) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in cis of HLA-DQB1*03:01 (DQA1*03:03; DQA1*05:05; DQA1*06:01). This effect may be due to a peptide being presented by all DQ0301 heterodimers (which are tolerant at the P1 binding position), or it may stem from genetic effects of HLA on T cell receptor genes TCRA and TCRB usage that influence the TCR repertoire. Using bulk and single-cell RNA sequencing data across Chinese and Caucasians, who have distinct patterns of linkage disequilibrium around DQB1*03:01, we found that HLA-DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2α, CDR2β, and CDR3β loops. These results illustrate the remarkable conservation of genetic effects in narcolepsy across ethnicity. The identification of the disease-causing T cells will be crucial for elucidating how this finding relates to the underlying pathophysiology.

Název v anglickém jazyce

HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity

Popis výsledku anglicky

Type 1 narcolepsy (T1N), an autoimmune disease associated with a disruption of hypocretin/orexin neurons, has conserved genetic effects transcending cultures and ethnicities. We pooled data from 5,339 cases from China, Europe, Korea, Japan, and the United States to conduct the first transethnic genome-wide association study (GWAS) on age of onset. Only one strong GWAS significant effect was observed across all ethnicities, summarized by the presence of human leukocyte antigen (HLA)-DQB1*03:01, and centered around the coding region of this gene. In contrast, HLA-DQB1*06:02-positive heterodimer (DQ0602) dosage did not strongly affect onset, and other known narcolepsy-associated genetic loci had minor effects. The HLA-DQB1*03:01 effect (mean -3.47 y, P = 1.7 x 10&lt;sup&gt;-18&lt;/sup&gt;) showed no heterogeneity across ethnic groups and was independent of common allelic variation at HLA-DQA1 in cis of HLA-DQB1*03:01 (DQA1*03:03; DQA1*05:05; DQA1*06:01). This effect may be due to a peptide being presented by all DQ0301 heterodimers (which are tolerant at the P1 binding position), or it may stem from genetic effects of HLA on T cell receptor genes TCRA and TCRB usage that influence the TCR repertoire. Using bulk and single-cell RNA sequencing data across Chinese and Caucasians, who have distinct patterns of linkage disequilibrium around DQB1*03:01, we found that HLA-DQB1*03:01 alters TCR repertoire at specific positions, most significantly within the CDR2α, CDR2β, and CDR3β loops. These results illustrate the remarkable conservation of genetic effects in narcolepsy across ethnicity. The identification of the disease-causing T cells will be crucial for elucidating how this finding relates to the underlying pathophysiology.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Proceedings of the National Academy of Sciences of the United States of America

ISSN

0027-8424

e-ISSN

1091-6490

Svazek periodika

122

Číslo periodika v rámci svazku

50

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

e2513989122

Kód UT WoS článku

001674896100001

EID výsledku v databázi Scopus

2-s2.0-105024386016