Doria A, Lee J, Warram J H, Krolewski A S
Section of Epidemiology and Genetics, Joslin Diabetes Center, Boston, MA 02215, USA.
Diabetologia. 1996 May;39(5):594-9. doi: 10.1007/BF00403307.
An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.
卢卡森等人得出结论，认为胰岛素依赖型糖尿病2型（IDDM2，位于11p15.5）必定位于胰岛素（INS）基因座的一个4.1千碱基（kb）片段内，然而他们自己的数据却显示胰岛素依赖型糖尿病（IDDM）与该片段边界之外的标记之间存在统计学上的显著关联，这一矛盾现已显现。我们展示了一项针对201例IDDM患者和107例非糖尿病对照受试者的独立研究数据，这些数据同样显示与INS基因座5'端的一个标记存在显著关联。对患者和对照受试者进行了INS/+ 1140 A/C（作为INS基因调控部分可变数目串联重复序列（VNTR）多态性的替代标记）以及酪氨酸羟化酶（TH）基因5'端的一个标记TH/pINS500 - RsaI的基因分型，该标记位于VNTR的5'端10 kb处。IDDM患者中INS/+ 1140等位基因“+”的纯合子频率显著高于对照受试者（73%对45%，p < 0.001），优势比为3.3（95%置信区间（CI）：2.0 - 5.3）。对于TH/RsaI等位基因“+”的纯合子也发现了非常相似的关联（53%对31%，p < 0.001），优势比为2.6（95%CI 1.6 - 4.2）。通过多位点分析，TH/RsaI等位基因“+”确定了INS/+ 1140等位基因“+”单倍型的一个子集，该子集与IDDM的关联比等位基因 + 1140“+”整体更为特异（优势比 = 5.4，95%CI 2.9 - 10.4）。总之，与IDDM相关的11号染色体片段至少跨越INS和TH基因座。在确定IDDM2的正确边界并排除其中其他基因座作为IDDM的决定因素之前，不能合理地声称IDDM2对应于INS基因座的VNTR多态性。
