Assessing the role of HLA-linked and unlinked determinants of disease.
Assessing the role of HLA-linked and unlinked determinants of disease.
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发表时间：
1987
影响因子：
9.8
通讯作者：
N. Risch
中科院分区：
文献类型：
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作者：
N. Risch
研究了亲属中相对于人群患病率的风险增加（λ R = KR/K）与受影响亲属对在连锁基因座（如HLA）上共有血统相同（ibd）的零标记等位基因的概率之间的关系。对于一个假设单个疾病易感基因座或一组基因座与标记基因座紧密连锁的模型，这种关系非常简单和普遍。也就是说，如果phi R是亲属对共享零标记等位基因的先验概率，那么P（共享0个标记/两个亲属都受到影响）就是phi R/lambda R。或者，λ AR，由于与标记基因座A紧密连锁的疾病基因座导致相对R的人群患病率增加的风险，等于相对对共享零A等位基因ibd的先验概率除以它们共享零等位基因ibd的后验概率，假设它们都受到影响。例如，对于受影响的同胞对，P（共有0个标记/两个同胞都受影响）= 0.25/λ S。这个公式适用于疾病位点上任何数量的等位基因及其频率、等位基因频率和人群患病率。对于共享一个和两个标记，推导出类似的公式。这些公式应用于几个充分研究的HLA相关疾病产生以下结果：对于多发性硬化症，胰岛素依赖型糖尿病，腹腔疾病，一个单一的基因座模型的疾病易感性被拒绝，这意味着存在额外的非连锁的家族决定因素。对于所有三种疾病，HLA连锁基因座对家族性的影响都很小：对于多发性硬化症，它只占同胞患病风险的2.5倍，而观察值为20;对于乳糜泻，它占同胞患病风险的约5.25倍，而观察值为60;对于胰岛素依赖型糖尿病，它使同胞兄弟姐妹的风险增加了3.42倍，而观察值为15。在所有情况下，次要决定簇必须在HLA区域之外。对于结核样麻风，一个非连锁的家族决定因素也牵涉其中（由于HLA的同胞风险增加= 1.49;观察值= 2.38）。对于血色素沉着症和霍奇金病，很少有证据表明HLA无关的家族决定因素。利用这个公式，还可以通过比较λ AS与由于相关等位基因而增加的同胞风险来检验多效性与连锁不平衡的假设。（400字处删节）
The relationship between increased risk in relatives over population prevalence (lambda R = KR/K) and probability of sharing zero marker alleles identical by descent (ibd) at a linked locus (such as HLA) by an affected relative pair is examined. For a model assuming a single disease-susceptibility locus or group of loci tightly linked to a marker locus, the relationship is remarkably simple and general. Namely, if phi R is the prior probability for the relative pair to share zero marker alleles identical by descent, then P (sharing 0 markers/both relatives are affected) is just phi R/lambda R. Alternatively, lambda AR, the increased risk over population prevalence to a relative R due to a disease locus tightly linked to marker locus A, equals the prior probability that the relative pair share zero A alleles ibd divided by the posterior probability that they share zero alleles ibd, given that they are both affected. For example, for affected sib pairs, P (sharing 0 markers/both sibs are affected) = .25/lambda S. This formula holds true for any number of alleles at the disease locus and for their frequencies, penetrances, and population prevalence. Similar formulas are derived for sharing one and two markers. Application of these formulas to several well-studied HLA-associated diseases yields the following results: For multiple sclerosis, insulin-dependent diabetes mellitus, and coeliac disease, a single-locus model of disease susceptibility is rejected, implying the existence of additional unlinked familial determinants. For all three diseases, the effect of the HLA-linked locus on familiality is minor: for multiple sclerosis, it accounts for only a 2.5-fold increased risk to sibs over the population prevalence, compared to an observed value of 20; for coeliac disease, it accounts for approximately a 5.25-fold increased risk to sibs, while the observed value is on the order of 60; for insulin-dependent diabetes mellitus, it accounts for a 3.42-fold increased risk in sibs, while the observed value is 15. In all cases, the secondary determinants must be outside the HLA region. For tuberculoid leprosy, an unlinked familial determinant is also implicated (increased risk to sibs due to HLA = 1.49; observed value = 2.38). For hemochromatosis and Hodgkin's disease, there is little evidence for HLA-unlinked familial determinants. With this formula, it is also possible to examine the hypothesis of pleiotropy versus linkage dis-equilibrium by comparing lambda AS with the increased risk to sibs due to the associated allele(s).(ABSTRACT TRUNCATED AT 400 WORDS)