Centre for Cardiovascular Science, Deanery of Molecular, Genetic and Population Health Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK.
Diabetologia. 2022 Dec;65(12):2084-2097. doi: 10.1007/s00125-022-05776-5. Epub 2022 Aug 11.
AIMS/HYPOTHESIS: Low birthweight (BW) is associated with the development of type 2 diabetes. Genome-wide analyses have identified a strong genetic component to this association, with many BW-associated loci also involved in glucose metabolism. We hypothesised that offspring BW and placental weight (PW) are correlated with parental type 2 diabetes risk, reflecting the inheritance of diabetes risk alleles that also influence fetal growth.
The Walker cohort, a collection of birth records from Dundee, Scotland, from the 1950s and the 1960s was used to test this hypothesis by linking BW and PW measurements to parental health outcomes. Using data from SCI-Diabetes and the national death registry, we obtained health records for over 20,000 Walker parents. We performed Fine-Gray survival analyses of parental type 2 diabetes risk with competing risk of death, and Cox regression analyses of risk of death, independently in the maternal and paternal datasets, modelled by offspring BW and PW.
We found significant associations between increased paternal type 2 diabetes risk and reduced offspring BW (subdistribution hazard ratio [SHR] 0.92 [95% CI 0.87, 0.98]) and PW (SHR 0.87 [95% CI 0.81, 0.94]). The association of maternal type 2 diabetes risk with offspring BW or PW was not significant. Lower offspring BW was also associated with increased risk of death in both mothers (HR 0.91 [95% CI 0.89, 0.94]) and fathers (HR 0.95 [95% CI 0.92, 0.98]), and higher offspring PW was associated with increased maternal mortality risk (HR 1.08 [95% CI 1.04, 1.13]) when adjusted for BW.
CONCLUSIONS/INTERPRETATION: We identified associations between offspring BW and reduced paternal type 2 diabetes risk, most likely resulting from the independent effects of common type 2 diabetes susceptibility alleles on fetal growth, as described by the fetal insulin hypothesis. Moreover, we identified novel associations between offspring PW and reduced paternal type 2 diabetes risk, a relationship that might also be caused by the inheritance of diabetes predisposition variants. We found differing associations between offspring BW and PW and parental risk of death. These results provide novel epidemiological support for the use of offspring BW and PW as predictors for future risk of type 2 diabetes and death in mothers and fathers.
目的/假设：低出生体重（BW）与 2 型糖尿病的发展有关。全基因组分析已经确定了这种关联的强烈遗传成分，许多与 BW 相关的基因座也与葡萄糖代谢有关。我们假设后代的 BW 和胎盘重量（PW）与父母 2 型糖尿病风险相关，反映了影响胎儿生长的糖尿病风险等位基因的遗传。
我们使用来自苏格兰邓迪市 20 世纪 50 年代和 60 年代的出生记录的 Walker 队列，通过将 BW 和 PW 测量值与父母的健康结果联系起来，来检验这一假设。利用来自 SCI-Diabetes 和国家死亡登记处的数据，我们获得了超过 20,000 名 Walker 父母的健康记录。我们在母体和父体数据集的独立模型中，对父母 2 型糖尿病风险进行 Fine-Gray 生存分析，以死亡为竞争风险，以及对死亡风险进行 Cox 回归分析，模型由后代的 BW 和 PW 组成。
我们发现，父亲的 2 型糖尿病风险增加与后代 BW（亚分布危险比 [SHR]0.92[95%CI0.87,0.98]）和 PW（SHR0.87[95%CI0.81,0.94]）降低之间存在显著关联。母亲的 2 型糖尿病风险与后代 BW 或 PW 之间的关联不显著。后代 BW 降低也与母亲（HR0.91[95%CI0.89,0.94]）和父亲（HR0.95[95%CI0.92,0.98]）的死亡风险增加相关，而后代 PW 升高与母亲死亡率风险增加相关（HR1.08[95%CI1.04,1.13]），当调整 BW 时。
结论/解释：我们发现后代 BW 与父亲 2 型糖尿病风险降低之间存在关联，这很可能是由于常见 2 型糖尿病易感性等位基因对胎儿生长的独立影响，正如胎儿胰岛素假说所描述的那样。此外，我们还发现了后代 PW 与父亲 2 型糖尿病风险降低之间的新关联，这种关系也可能是由于糖尿病易感性变异的遗传。我们发现后代 BW 和 PW 与父母死亡风险之间存在不同的关联。这些结果为后代 BW 和 PW 作为母亲和父亲未来 2 型糖尿病和死亡风险的预测因子提供了新的流行病学支持。
