Krawitt E L, Kilby A E, Albertini R J, Schanfield M S, Chastenay B F, Harper P C, Mickey R M, McAuliffe T L
Department of Medicine, University of Vermont, Burlington 05405.
Hepatology. 1987 Nov-Dec;7(6):1305-10. doi: 10.1002/hep.1840070621.
The strategy of assigning a surrogate phenotype, defined as the presence of antinuclear and/or antismooth muscle antibodies to disease-free first degree relatives of index cases was used to search for a postulated disease susceptibility gene in autoimmune chronic active hepatitis. In addition to determining circulating autoantibody status, 10 patients, 51 first-degree relatives and 6 spouses of index chronic active hepatitis patients, each ascertained by the single patient, were genotyped for HLA (A, B and DR loci) and immunoglobulin allotype (G1m, G2m, G3m and A2m loci) haplotypes. Among the 10 chronic active hepatitis patients, 6 had HLA haplotypes B8 and DR3, and 3 of these patients had, in addition, the immunoglobulin allotype haplotype Gm a,x;g. Circulating autoantibodies defining the surrogate phenotype was found in 39% of the first-degree relatives. However, segregation analysis offered no support for either single autosomal dominant or recessive inheritance for the autoantibody-positive phenotype. Linkage between the postulated disease susceptibility locus and either the HLA (Chromosome 6) or immunoglobulin (Chromosome 14) locus was excluded by several analyses. Furthermore, logistic regression indicated that neither immunogenetic marker was statistically associated with autoantibody positively in these families. Therefore, despite the occurrence of autoantibody positivity in first-degree relatives of autoimmune chronic active hepatitis patients, we found no evidence that this trait has a simple genetic basis, or that it is an alternative manifestation of a postulated disease susceptibility gene for chronic active hepatitis.
将替代表型定义为在指数病例的无病一级亲属中存在抗核抗体和/或抗平滑肌抗体，采用该策略在自身免疫性慢性活动性肝炎中寻找假定的疾病易感基因。除了确定循环自身抗体状态外，对10例患者、51名一级亲属以及指数慢性活动性肝炎患者的6名配偶（均由单一患者确定）进行了HLA（A、B和DR位点）和免疫球蛋白同种异型（G1m、G2m、G3m和A2m位点）单倍型基因分型。在10例慢性活动性肝炎患者中，6例具有HLA单倍型B8和DR3，其中3例患者还具有免疫球蛋白同种异型单倍型Gm a,x;g。在39%的一级亲属中发现了定义替代表型的循环自身抗体。然而，分离分析不支持自身抗体阳性表型的常染色体显性或隐性单基因遗传。通过多项分析排除了假定的疾病易感位点与HLA（第6号染色体）或免疫球蛋白（第14号染色体）位点之间的连锁关系。此外，逻辑回归表明，在这些家族中，这两种免疫遗传标记与自身抗体阳性均无统计学关联。因此，尽管自身免疫性慢性活动性肝炎患者的一级亲属中出现了自身抗体阳性，但我们没有发现证据表明该特征具有简单的遗传基础，或者它是慢性活动性肝炎假定疾病易感基因的另一种表现形式。
