Gupta Meenal, Bhatnagar Pallav, Grover Sandeep, Kaur Harpreet, Baghel Ruchi, Bhasin Yasha, Chauhan Chitra, Verma Binuja, Manduva Vallikiran, Mukherjee Odity, Purushottam Meera, Sharma Abhay, Jain Sanjeev, Brahmachari Samir K, Kukreti Ritushree
Institute of Genomics and Integrative Biology, Delhi, India.
Pharmacogenomics. 2009 Mar;10(3):385-97. doi: 10.2217/14622416.10.3.385.
We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication.
MATERIALS & METHODS: Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment.
The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: chi(2) = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03-3.15; and rs4680: chi(2) = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01-3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response.
The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.
我们研究了儿茶酚-O-甲基转移酶（COMT）基因，该基因是精神分裂症及抗精神病药物治疗反应的一个强大的功能和位置候选基因。
利用来自印度南部一个同质人群的398例精神分裂症患者和241名健康个体中的7个COMT基因多态性，对COMT基因与精神分裂症及抗精神病治疗反应进行了单基因座以及基于单倍型的详细关联分析。使用临床总体印象量表（CGI）对117例精神分裂症患者的利培酮治疗反应进行了进一步评估。共有69例CGI评分≤2的患者符合良好反应者标准，48例患者CGI评分持续≥3，被归类为利培酮治疗反应不佳者。
在进行多重检验校正后，单核苷酸多态性（SNP）rs4680与精神分裂症的关联不再显著。单倍型分析显示7种COMT标记单倍型与精神分裂症高度显著相关（CLUMP T4 p值 = 0.0001）。我们的结果还表明，在进行多重校正之前，两个SNP与药物反应存在初步显著的等位基因关联（rs4633：χ² = 4.36，p值 = 0.036，比值比（OR）：1.80，95%置信区间（CI）：1.03 - 3.15；以及rs4680：χ² = 4.02，p值 = 0.044，OR：1.76，95% CI：1.01 - 3.06）。我们采用双标记滑动窗口分析进行单倍型关联分析，观察到位于内含子1和内含子2之间的标记（rs737865，rs6269：CLUMP T4 p值 = 0.021）；以及外显子4中的标记（rs4818，rs4680：CLUMP T4 p值 = 0.028）与药物反应显著相关。
本研究因此表明，COMT基因多态性之间的相互作用效应可能影响精神分裂症患者的疾病状态和对利培酮的反应。然而，该研究需要在更大样本集中重复以进行确认，随后进行功能研究。
