Genetic variants of PKLR are associated with acute pain in sickle cell disease.
Genetic variants of PKLR are associated with acute pain in sickle cell disease.
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DOI：
10.1182/bloodadvances.2021006668
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发表时间：
2022-06-14
期刊：
影响因子：
7.5
通讯作者：
Thein, Swee Lay
中科院分区：
文献类型：
--
作者：
Wang, Xunde;Gardner, Kate;Tegegn, Mickias B.;Dalgard, Clifton L.;Alba, Camille;Menzel, Stephan;Patel, Hamel;Pirooznia, Mehdi;Fu, Yi-Ping;Seifuddin, Fayaz T.;Thein, Swee Lay
PKLR内含子变异与镰状细胞病急性疼痛住院率相关等位基因特异性表达分析表明，变异体影响PKLR活性，为该关联提供了功能基础。急性疼痛是镰状细胞病（SCD）最突出的并发症，由缺氧红细胞（RBC）的镰状化引发的血管闭塞引起。RBC中2，3-二磷酸甘油酸（2，3-DPG）的浓度通过优先结合HbS的低亲和力T构象促进脱氧。2，3-DPG是糖酵解途径中的中间底物，其中丙酮酸激酶（基因PKLR，蛋白PKR）是限速酶; PKLR的变体可能影响PKR活性、RBC中的2，3-DPG水平、RBC镰状化和急性疼痛发作（APE）。我们使用2个队列进行了一项候选基因关联研究：242例成人SCD-HbSS患者和977例SCD-HbSS或SCD-HbSβ0地中海贫血儿童。在成人队列中评估的47种PKLR变异中有7种与住院相关：内含子4，rs 2071053;内含子2，rs 8177970，rs 116244351，rs 114455416，rs 12741350，rs3020781和rs 8177964。所有7种变体在两个队列中显示出一致的效应方向，并且在成人和儿科队列的加权Fisher荟萃分析中保持显著性，使用P < .0071作为阈值以校正多重检验。对52名SCD成人的独立队列进行的等位基因特异性表达分析表明，内含子变异可能通过影响PKLR的表达来影响APE，尽管因果变异和机制尚未确定。
Intronic variants of PKLR are associated with hospitalization rate for acute pain in sickle cell disease. Allele-specific expression analysis suggests that variants influence PKLR activity, providing a functional basis for the association. Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSβ0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P < .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
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影响因子：
20.3
作者：
Eaton, William A.;Bunn, H. Franklin
通讯作者：
Bunn, H. Franklin
影响因子：
20.3
作者：
POILLON, WN;KIM, BC;KARK, JA
通讯作者：
KARK, JA
在泰国人群中，丙酮酸激酶（PKLR）变体对疟疾表型的调节。
影响因子：
3.7
作者：
van Bruggen R;Gualtieri C;Iliescu A;Louicharoen Cheepsunthorn C;Mungkalasut P;Trape JF;Modiano D;Sirima BS;Singhasivanon P;Lathrop M;Sakuntabhai A;Bureau JF;Gros P
通讯作者：
Gros P
影响因子：
10.1
作者：
Bianchi P;Fermo E
通讯作者：
Fermo E
DOI：
10.1146/annurev-biodatasci-021621-122219
发表时间：
2021-01-01
期刊：
ANNUAL REVIEW OF BIOMEDICAL DATA SCIENCE, VOL 4
影响因子：
--
作者：
Cleary, Siobhan;Seoighe, Cathal
通讯作者：
Seoighe, Cathal