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.

Methods

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.

Results

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.

Graphical abstract

中文翻译：

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父母 2 型糖尿病风险与后代出生体重和胎盘重量之间的关联：使用 Walker 队列的生存分析

目标/假设

低出生体重 (BW) 与 2 型糖尿病的发生有关。全基因组分析已经确定了这种关联的强大遗传成分，许多 BW 相关位点也参与葡萄糖代谢。我们假设后代 BW 和胎盘重量 (PW) 与父母 2 型糖尿病风险相关，反映了糖尿病风险等位基因的遗传也影响胎儿生长。

方法

Walker 队列是 1950 年代和 1960 年代苏格兰邓迪出生记录的集合，用于通过将 BW 和 PW 测量与父母健康结果联系起来来检验这一假设。使用来自 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。我们对父母 2 型糖尿病风险与死亡竞争风险进行了 Fine-Gray 生存分析，并对死亡风险进行了 Cox 回归分析，独立于母本和父本数据集，由后代 BW 和 PW 建模。

结果

我们发现父亲 2 型糖尿病风险增加与后代 BW（次分布风险比 [SHR] 0.92 [95% CI 0.87, 0.98]）和 PW（SHR 0.87 [95% CI 0.81, 0.94]）降低之间存在显着关联。母亲 2 型糖尿病风险与后代 BW 或 PW 的关联不显着。较低的后代体重也与母亲 (HR 0.91 [95% CI 0.89, 0.94]) 和父亲 (HR 0.95 [95% CI 0.92, 0.98]) 的死亡风险增加相关，而较高的后代体重与母体死亡风险增加相关针对 BW 调整后的死亡风险 (HR 1.08 [95% CI 1.04, 1.13])。

结论/解释

我们确定了后代 BW 与降低的父亲 2 型糖尿病风险之间的关联，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，如胎儿胰岛素假说所述。此外，我们确定了后代 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糖尿病易感性变异的遗传引起的。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。这些结果为使用后代 BW 和 PW 作为未来 2 型糖尿病风险和母亲和父亲死亡风险的预测因子提供了新的流行病学支持。

图形概要