Pugliese A, Bugawan T, Moromisato R, Awdeh Z L, Alper C A, Jackson R A, Erlich H A, Eisenbarth G S
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver 80262.
J Clin Invest. 1994 Jun;93(6):2447-52. doi: 10.1172/JCI117253.
Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles deriving from the evolutionary lineage 4 (*0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (*0101, *0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles were IAA-positive, with lower levels than relatives with lineage 1-3 alleles (mean = 55 +/- 15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0.004). The amino acid sequences of lineage 1-3 alleles uniquely share glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (often DQA1 *0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer recessive low responsiveness to insulin.
胰岛素自身抗体（IAA）水平在胰岛素依赖型糖尿病患者的不同一级亲属中有所不同，提示存在基因调控。我们之前报道过，在有患病风险的DR4阳性亲属中IAA水平升高。在本研究中，82名有患病风险的亲属中有72名IAA呈阳性，其中75%（54/72）携带DR4，而IAA阴性亲属中这一比例为20%（2/10）（P = 0.0004）。然而，69%（18/26）的DR4阴性亲属IAA呈阳性。由于DR4不能解释所有IAA阳性情况，我们分析了DQA1和DQB1等位基因。源自进化谱系4（*0401、*0501、*0601）的DQA1等位基因纯合与低IAA水平相关，而谱系1 - 3等位基因（*0101、*0102、*0103、*0201、*0301）则与较高水平相关。大多数（93%，65/70）携带谱系1 - 3等位基因的亲属IAA呈阳性（平均值 = 360 ± 63 SEM nU/ml）。携带谱系4等位基因纯合的亲属中只有7/12的IAA呈阳性，且水平低于携带谱系1 - 3等位基因的亲属（平均值 = 55 ± 15 SEM nU/ml，P < 0.0001；7/12对比65/70，P = 0.004）。谱系1 - 3等位基因的氨基酸序列在第40和51位独特地共享谷氨酸（E）和苯丙氨酸（F）（EF等位基因）。谱系4等位基因在这些位置有甘氨酸（G）和亮氨酸（L）（GL等位基因）。90%（65/72）的IAA阳性亲属有一个EF等位基因，而只有75%（54/72）有DR4（P = 0.01）。GL等位基因纯合（通常在DR3单倍型上为DQA1 *0501）与对胰岛素几乎没有或没有体液反应相关。因此，HLA - DQB1 GL等位基因，或携带这些DQA1等位基因的单倍型上的其他基因（如DR3），可能赋予对胰岛素的隐性低反应性。
