Simon M, Le Mignon L, Fauchet R, Yaouanq J, David V, Edan G, Bourel M
Am J Hum Genet. 1987 Aug;41(2):89-105.
We compared 609 haplotypes carrying the idiopathic hemochromatosis allele with 475 control haplotypes. Four haplotypes were more frequent in hemochromatosis: A3, B7 (actually A3, CW., B7, Bfs, DR2); A3, B14 (actually A3, CW., B14, BfF, DRW6); A11, B35; and A11, B5. The linkage disequilibrium for A3, B7 and A3, B14 (and probably also for A11, B5) was undeniably stronger in hemochromatosis than in controls. Two haplotypes--A3, B12 and A3, B15--were more frequent in hemochromatosis, without linkage disequilibrium. Four haplotypes in linkage disequilibrium in hemochromatosis--i.e., A2, B12; A1, B8; A9, B7; and A29, B12--were also found to have the same frequency and strength of linkage in controls. The dual observation (1) that haplotypes carrying A3 without either B7 or B14 were highly significantly more frequent in hemochromatosis than in controls and (2) that haplotypes carrying B7 or B14 but not A3 had the same frequency in hemochromatosis and controls led to the formal conclusion that only A3 is an independent marker for the hemochromatosis allele, B7 and B14 being involved only owing to the haplotypic mode of marking; the hemochromatosis allele can thus be mapped closer to locus A than to locus B. Our findings fit well with the hypothesis that the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.
我们将609个携带特发性血色素沉着病等位基因的单倍型与475个对照单倍型进行了比较。血色素沉着病中有四种单倍型更为常见：A3、B7（实际上是A3、CW、B7、Bfs、DR2）；A3、B14（实际上是A3、CW、B14、BfF、DRW6）；A11、B35；以及A11、B5。不可否认，血色素沉着病中A3、B7和A3、B14（可能还有A11、B5）的连锁不平衡比对照组更强。两种单倍型——A3、B12和A3、B15——在血色素沉着病中更为常见，但不存在连锁不平衡。在血色素沉着病中处于连锁不平衡的四种单倍型——即A2、B12；A1、B8；A9、B7；以及A29、B12——在对照组中也具有相同的频率和连锁强度。双重观察结果如下：（1）携带A3但不携带B7或B14的单倍型在血色素沉着病中比在对照组中显著更常见；（2）携带B7或B14但不携带A3的单倍型在血色素沉着病和对照组中的频率相同。由此得出正式结论，只有A3是血色素沉着病等位基因的独立标记，B7和B14仅因单倍型标记模式而相关；因此，血色素沉着病等位基因在基因座图谱上更靠近A基因座而非B基因座。我们的研究结果与以下假设非常吻合：血色素沉着病突变即使不是唯一的罕见事件，也是一个罕见事件，它产生了一个祖先HLA标记，随后由于迁移导致的重组和地理扩散而发生了改变。
