Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease

被引:1
作者
Heitzer, Andrew M. [1 ]
Rashkin, Sara R. [2 ]
Trpchevska, Ana [1 ]
Longoria, Jennifer N. [1 ]
Rampersaud, Evadnie [3 ]
Olufadi, Yunusa [4 ]
Wang, Winfred C. [2 ]
Raches, Darcy [1 ]
Potter, Brian [1 ]
Steinberg, Martin H. [5 ]
King, Allison A. [6 ,7 ,8 ]
Kang, Guolian [4 ]
Takemoto, Clifford M. [2 ]
Hankins, Jane S. [2 ,9 ]
机构
[1] St Jude Childrens Res Hosp, Dept Psychol, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN USA
[3] St Jude Childrens Res Hosp, Ctr Appl Bioinformat, Memphis, TN USA
[4] St Jude Childrens Res Hosp, Biostat Dept, Memphis, TN USA
[5] Boston Univ, Chobanian & Avidesian Sch Med, Dept Med, Boston, MA USA
[6] Washington Univ, Program Occupat Therapy, St Louis, MO USA
[7] Washington Univ, Dept Pediat, St Louis, MO USA
[8] Washington Univ, Dept Med, St Louis, MO USA
[9] St Jude Childrens Res Hosp, Global Pediat Med, Memphis, TN USA
关键词
Sickle cell disease; Catechol O-methyltransferase; Polymorphism; Single nucleotide; Dopamine; COGNITIVE FUNCTION; VASOOCCLUSIVE PAIN; VAL(108/158) MET; GENOTYPE; POLYMORPHISM; METAANALYSIS; VARIANTS; CHILDREN; STROKE; RISK;
D O I
10.1016/j.retram.2023.103433
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Purpose Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. Patients and Methods The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGS(COMT)) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). Results In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGS(COMT) was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGS(COMT) was negatively associated with IQ performance among males but not females across all cohorts. Conclusion Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.
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