A simple estimate of the general population frequency of the MHC susceptibility gene for autoimmune polygenic disease.

C A Alper, D P Dubey, E J Yunis, Z Awdeh
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引用次数: 12

Abstract

We wished to determine the frequencies of the MHC and non-MHC susceptibility genes for polygenic autoimmune diseases like type 1 diabetes (IDDM). We used Mendelian inheritance and the Hardy-Weinberg equilibrium to calculate the frequencies of mating pairs and susceptible offspring under classical recessive and dominant inheritance of the MHC susceptibility gene. We then analyzed the distribution of haplotype sharing by affected sib pairs of the 4 MHC haplotypes in each of the kinds of mating pairs in terms of the frequency of the disease susceptibility gene. For IDDM, the analysis was consistent with a recessive, but not a dominant, MHC susceptibility gene of frequency 0.525 at a distribution of 55, 38 and 7% of affected sib pairs who share 2, 1 and 0 MHC haplotypes, respectively. A simple relationship was obtained: if inheritance is recessive, the MHC susceptibility gene frequency is the square root of the fraction of affected sib pairs who share no MHC haplotypes multiplied by 4. For recessive inheritance, affected sib pairs who share no haplotypes are solely in families where both parents are homozygous MHC-susceptible. Although homozygous MHC susceptibles represent over 25% of the population, only 2-3% of them are IDDM-susceptible at non-MHC susceptibility loci, also required for disease expression. Predictions from our analysis fit all published observations of the familial occurrence of disease. The analysis is general, simple and provides a single estimate (not a range) of the MHC susceptibility gene frequency. This approach should be applicable to other MHC-determined polygenic diseases.

自身免疫性多基因疾病的MHC易感基因的一般人群频率的简单估计。
我们希望确定MHC和非MHC易感基因在多基因自身免疫性疾病如1型糖尿病(IDDM)中的频率。利用孟德尔遗传和Hardy-Weinberg平衡计算了MHC易感基因经典隐性遗传和显性遗传下的交配对和易感子代的频率。然后,我们根据疾病易感基因的频率,分析了4种MHC单倍型的受影响兄弟姐妹在每种交配对中的单倍型共享分布。对于IDDM,分析结果与隐性(而非显性)频率0.525的MHC易感基因一致,分布在分别具有2、1和0个MHC单倍型的受影响兄弟对中,分别为55.8%、38%和7%。得到了一个简单的关系:如果遗传是隐性的,那么MHC易感基因频率就是没有MHC单倍型的受影响兄弟姐妹的比例乘以4的平方根。对于隐性遗传,只有在父母双方都是纯合的mhc易感的家庭中,没有相同单倍型的兄弟姐妹才会受到影响。尽管纯合子MHC易感人群占人口的25%以上,但其中只有2-3%的人在非MHC易感位点(也是疾病表达所必需的)对iddm易感。我们的分析预测符合所有已发表的关于家族性疾病发生的观察结果。分析是一般的,简单的,并提供MHC易感基因频率的单一估计(而不是范围)。这种方法应该适用于其他由mhc决定的多基因疾病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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