Candidate gene studies of human pain mechanisms - Methods for optimizing choice of polymorphisms and sample size
Candidate gene studies of human pain mechanisms - Methods for optimizing choice of polymorphisms and sample size
复制标题
DOI：
10.1097/00000542-200406000-00032
复制
发表时间：
2004-06-01
期刊：
影响因子：
8.8
通讯作者：
Max, MB
中科院分区：
文献类型：
--
作者：
Belfer, I;Wu, TX;Max, MB
人类基因组和蛋白质组的阐明为临床研究人员提供了在一项研究中检验数千种假设的机会。1肿瘤学、糖尿病和心血管疾病等成熟领域的临床研究人员抓住了这个机会。例如，在PubMed中，使用多态性和人类这两个术语搜索疾病名称，癌症的引文超过10,000条，糖尿病或高血压的引文超过2,000条。虽然有许多研究检查宏观结构疾病的遗传风险因素的变化，可能会引发疼痛，如冠状动脉狭窄，类风湿性关节炎，或腰椎间盘突出症临床疼痛研究人员很少利用这些基因组财富来研究疼痛处理的变化，给定一个统一的初始损伤。临床疼痛遗传学研究的可行性得到了最近发现的支持，这些发现表明近交系小鼠品系对20多种不同的急性和慢性疼痛条件的行为反应存在重大差异，包括皮肤和内脏的热和化学刺激以及神经损伤。2-4这些结果表明，影响疼痛处理的遗传变异在哺乳动物群体中是常见和保守的。也许疼痛研究者忽视了临床遗传学，因为除了少数罕见的，他们没有注意到疼痛综合征的明显家族遗传。然而，家族遗传仅在相对危险度（RR）为50或更高的等位基因中才变得明显。关联研究，其中常见的等位基因变异的频率进行了比较，在案件和控制，可能会发现相对较小的增加RR。这些研究已经检测到阿尔茨海默病、克罗恩病、静脉血栓形成、糖尿病、精神分裂症、退行性骨折和其他常见医学疾病的RR改变。7基于等位基因的关联研究与基于基因座的家族遗传学研究在几个方面不同。在家族研究中，受试者共享整个染色体或其大部分，通过染色体的几百个遗传标记足以搜索整个基因组的易感性基因座。几个标记将与疾病易感基因在同一个保存的染色体片段上。关联性研究通常是在不相关的个体中进行的，这些个体只有很短的DNA片段是共享的，因此在任何长度的DNA上研究的标记密度必须比家族研究高1,000倍。相反，关联研究的两个优点是，它们比家族连锁研究更有能力检测轻微到中等大小的遗传效应，8并且在选择无关受试者方面具有广泛的自由度，以优化临床表型并标准化环境暴露和测量方法。遗传关联研究有助于研究疼痛研究中最令人困惑的问题，即在各种组织明显相同的结构损伤后，大多数患者的疼痛迅速消退，而其他患者的疼痛持续存在。研究充分的例子包括带状疱疹、糖尿病性神经病变、脊柱变性、截肢、乳房切除术、开胸术或挥鞭样损伤。只有一小部分疼痛持续性的差异可以用年龄、损伤的严重程度、
THE elucidation of the human genome and proteome offers the clinical researcher the opportunity to test thousands of hypotheses in a single study. 1 Clinical researchers in established areas such as oncology, diabetes, and cardiovascular disease have seized this opportunity. For example, PubMed searches of the disease name with the terms polymorphism and human yield more than 10,000 citations for cancer and 2,000 for diabetes or hypertension. Although there are many studies examining the genetic risk factors for variations in macroscopic structural disease that may trigger pain—eg, coronary stenosis, rheumatoid arthritis, or lumbar disc herniation—clinical pain researchers have made little use of these genomic riches to study variations in pain processing, given a uniform initiating injury. The plausibility of clinical pain genetic studies is supported by the recent findings of major differences between inbred mouse strains in the behavioral response to more than 20 different acute and chronic pain conditions, including thermal and chemical stimulation of the skin and viscera and nerve injury. 2–4 These results suggest that genetic variants affecting pain processing are common and conserved in mammalian populations. Perhaps pain researchers have neglected clinical genetics because, apart from a few rarities, 5, 6 they have not noticed obvious familial inheritance of pain syndromes. However, familial inheritance only becomes obvious for alleles conferring a relative risk (RR) of 50 or more. Association studies, in which the frequencies of common allelic variants are compared in cases and controls, may detect relatively small increases in RR. Such studies have detected alterations in RR in Alzheimer disease, Crohn disease, venous thrombosis, diabetes, schizophrenia, osteoporotic fractures, and other common medical disorders. 7Allele-based association studies differ from locus-based family genetic studies in several ways. In family studies, in which the subjects share whole chromosomes or large portions thereof, several hundred genetic markers through the chromosome are sufficient to search the entire genome for a susceptibility locus. Several markers will be on the same preserved chromosome fragment as the disease susceptibility gene. Association studies are generally performed in unrelated individuals in whom only short segments of DNA are shared, so the density of markers studied over any length of DNA must be up to 1,000 times greater than in family studies. Conversely, two advantages of association studies are that they have greater power than family linkage studies to detect genetic effects of slight to modest size, 8 and one has broad latitude in selecting unrelated subjects in a way to optimize the clinical phenotype and to standardize environmental exposures and measurement methods. Genetic association studies lend themselves to the study of the most perplexing problem in pain research, that after apparently identical structural injuries to a variety of tissues, pain resolves rapidly in most patients and persists in others. Well-studied examples include shingles, diabetic neuropathy, spinal degeneration, limb amputation, mastectomy, thoracotomy, or whiplash injury. Only a small part of the variance in pain persistence has been explained by age, severity of the injury, per-