Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden

医学 锂(药物) 队列 肾功能 人口 内科学 双相情感障碍 队列研究 儿科 环境卫生
作者
Vincent Millischer,Granville J. Matheson,Sarah E. Bergen,Brandon J. Coombes,Katja Ponzer,Fredrik Wikström,Karolina Jagiełło,Martin Lundberg,Peter Stenvinkel,Joanna M. Biernacka,Olof Breuer,Lina Martinsson,Mikael Landén,Lena Backlund,Catharina Lavebratt,Martin Schalling
出处
期刊:The Lancet Psychiatry [Elsevier]
卷期号:9 (6): 447-457 被引量:13
标识
DOI:10.1016/s2215-0366(22)00100-6
摘要

Background Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. Methods We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. Findings 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17–89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin–aldosterone–angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; β=–0·053 [95% CI –0·071 to –0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. Interpretation Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Funding Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
围城发布了新的文献求助10
刚刚
刚刚
上官若男应助Star1983采纳,获得10
刚刚
不懈奋进应助我直接狂学采纳,获得30
2秒前
bkagyin应助远航采纳,获得10
3秒前
Kair发布了新的文献求助10
4秒前
Winfred完成签到,获得积分10
5秒前
trevor完成签到,获得积分20
5秒前
研友_VZG7GZ应助神勇的曼文采纳,获得10
5秒前
凌志发布了新的文献求助30
5秒前
飘逸的麦片完成签到,获得积分10
5秒前
共享精神应助grace采纳,获得10
6秒前
zhao完成签到,获得积分10
7秒前
量子星尘发布了新的文献求助10
8秒前
ComVivas完成签到,获得积分10
9秒前
9秒前
桐桐应助凌志采纳,获得10
9秒前
bkagyin应助王若琪采纳,获得10
10秒前
Galen完成签到,获得积分20
11秒前
dorkoom发布了新的文献求助10
12秒前
远航完成签到,获得积分10
12秒前
14秒前
14秒前
trevor发布了新的文献求助10
15秒前
李治稳发布了新的文献求助10
15秒前
Jasper应助000采纳,获得10
17秒前
Hello应助老迟到的沛萍采纳,获得10
17秒前
Holly12345应助内向寒云采纳,获得10
18秒前
yyy完成签到,获得积分10
19秒前
cbx完成签到,获得积分10
21秒前
打打应助九卫采纳,获得10
21秒前
令宏发布了新的文献求助10
21秒前
香蕉觅云应助ning采纳,获得10
22秒前
三年三班三井寿完成签到,获得积分10
22秒前
天天快乐应助shinn采纳,获得10
23秒前
岛不言完成签到,获得积分10
24秒前
NexusExplorer应助学者宫Sir采纳,获得10
25秒前
26秒前
成功i吃u官方完成签到,获得积分20
27秒前
情怀应助H7采纳,获得10
28秒前
高分求助中
Picture Books with Same-sex Parented Families: Unintentional Censorship 700
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
Effective Learning and Mental Wellbeing 300
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3975339
求助须知:如何正确求助?哪些是违规求助? 3519670
关于积分的说明 11199199
捐赠科研通 3256002
什么是DOI,文献DOI怎么找? 1798043
邀请新用户注册赠送积分活动 877386
科研通“疑难数据库(出版商)”最低求助积分说明 806305