Torfs C P, King M C, Huey B, Malmgren J, Grumet F C
Am J Hum Genet. 1986 Feb;38(2):170-87.
To investigate the possible coinheritance of autoimmune diseases that are associated with the same HLA antigen, we studied 70 families in which at least two siblings had either type I diabetes mellitus (IDDM), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), or a combination of these diseases. HLA-A, B, and C typing was performed on all affected sibs in one generation or more. First, we estimated by sib-pair analysis the disease allele frequency (pD) and the mode of inheritance for each disease. According to the method of ascertainment entered into the analysis, the pD for ATD ranged from .120 to .180, for an additive (dominant) mode of inheritance. For RA, the pD ranged from .254 to .341, also for additive inheritance, although recessive inheritance could not be excluded. For IDDM, the pD ranged from .336 to .337 for recessive inheritance; additive inheritance was rejected. Second, we examined the distribution of shared parental haplotypes in pairs of siblings that were discordant for their autoimmune diseases. The results suggested that the same haplotype may predispose to both IDDM and ATD, or IDDM and RA, but not to both RA and ATD. Analysis of pedigrees supported this hypothesis. In 16 families typed for HLA-DR also, the haplotype predisposing to both IDDM and ATD was assigned from pedigree information to DR3 (44%), DR4 (39%), or DR5, DR6, or DR7 (5.5% each). In some families, these haplotypes segregated over several generations with ATD only (either clinical or subclinical), suggesting that in such families, ATD was a marker for a susceptibility to IDDM. In several families, an IDDM haplotype segregated with RA but not with ATD. This suggests that ATD- and RA-associated susceptibilities to IDDM may be biologically different and thus independently increase the risk of IDDM.
为了研究与相同HLA抗原相关的自身免疫性疾病可能的共遗传情况，我们研究了70个家庭，这些家庭中至少有两个兄弟姐妹患有I型糖尿病（IDDM）、自身免疫性甲状腺疾病（ATD）、类风湿关节炎（RA）或这些疾病的某种组合。对一代或多代中所有受影响的同胞进行了HLA - A、B和C分型。首先，我们通过同胞对分析估计了每种疾病的疾病等位基因频率（pD）和遗传模式。根据纳入分析的确定方法，对于ATD，pD范围为0.120至0.180，遗传模式为加性（显性）。对于RA，pD范围为0.254至0.341，同样为加性遗传，尽管不能排除隐性遗传。对于IDDM，隐性遗传的pD范围为0.336至0.337；加性遗传被排除。其次，我们检查了自身免疫性疾病不一致的同胞对中共享亲本单倍型的分布。结果表明，相同的单倍型可能使个体易患IDDM和ATD，或IDDM和RA，但不会使个体同时易患RA和ATD。系谱分析支持了这一假设。在同样进行了HLA - DR分型的16个家庭中，根据系谱信息，使个体易患IDDM和ATD的单倍型被确定为DR3（44%）、DR4（39%）或DR5、DR6或DR7（各占5.5%）。在一些家庭中，这些单倍型仅与ATD（临床或亚临床）在几代人中分离，这表明在这些家庭中，ATD是易患IDDM的一个标志。在几个家庭中，一个IDDM单倍型与RA分离，但不与ATD分离。这表明与ATD和RA相关的对IDDM的易感性在生物学上可能不同，因此独立增加了患IDDM的风险。
