Larsson H E, Lynch K, Lernmark B, Nilsson A, Hansson G, Almgren P, Lernmark A, Ivarsson S-A
Department of Clinical Sciences, University Hospital MAS, Lund University, Malmö, Sweden.
Diabetologia. 2005 Aug;48(8):1484-91. doi: 10.1007/s00125-005-1813-4. Epub 2005 Jul 1.
AIMS/HYPOTHESIS: The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight.
HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW).
Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08-1.33], p=0.0006). The HLA-DQB10603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB10603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56-0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors.
CONCLUSIONS/INTERPRETATION: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.
目的/假设：我们研究的目的是检验这一假设，即与糖尿病风险、脐带血自身抗体或两者相关的HLA基因型与出生体重增加有关。
在斯科讷糖尿病预测（DiPiS）研究中，对总共16709名健康母亲所生儿童的脐带血干血斑进行HLA基因型测定，该研究是一项基于人群的新生儿观察性临床调查。排除母亲患有糖尿病或妊娠糖尿病的儿童。采用标准放射性配体结合试验测定谷氨酸脱羧酶（GAD65Ab）和胰岛素瘤相关蛋白2的自身抗体。出生体重根据胎龄进行调整，并分为四分位数。上四分位数定义为高相对出生体重（HrBW），下四分位数定义为低相对出生体重（LrBW）。
与1型糖尿病风险相关的基因型与相对出生体重（rBW）密切相关（p = 0.01）。高危HLA - DQ2/8、DQ8/0604和DQ8/X基因型与HrBW相关（优势比[OR][95%置信区间]=1.20[1.08 - 1.33]，p = 0.0006）。与1型糖尿病呈负相关的HLA - DQB10603等位基因也与HrBW相关（p = 0.025），证实了先前关于DQB10603连锁的HLA - DR13的报道。GAD65Ab与HrBW呈负相关（OR[95%置信区间]=0.72[0.56 - 0.93]，p = 0.01）。回归分析表明，HLA相关的rBW增加独立于混杂因素。
结论/解读：HLA基因型可能与子宫内生长有关，独立于1型糖尿病风险。高出生体重是1型糖尿病风险因素这一流行病学观察结果可能是由于赋予糖尿病高风险的HLA基因型对子宫内生长的调节作用所致。
