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Diabetologia:父母2型糖尿病风险与后代出生体重和胎盘重量之间的联系

2022-09-06 从医路漫漫 MedSci原创

低体重和二型糖尿病易感性是同一基因型的表型。

背景:观察性研究已经在多个独立人群中确定了低出生体重(BW)和二型糖尿病病之间的一致关联。假设这种联系是遗传介导的,低体重和二型糖尿病易感性是同一基因型的表型。根据胎儿胰岛素假说,通过胰岛素的作用,影响葡萄糖代谢(以及后来的糖尿病)的多态性也与胎儿生长受损相关。事实上,在全基因组显著水平上,与BW相关的多个基因座也与晚年生活中的二型糖尿病、空腹血糖和空腹胰岛素等性状呈反向遗传相关。母体二型糖尿病风险等位基因也影响这种关系,影响子宫内葡萄糖稳态并增加后代体重。

尽管在揭示早期发育和糖尿病之间的关系方面取得了进展,但大多数调查父母糖尿病和后代出生结果之间联系的流行病学研究仅涉及母亲-后代对。很少有研究包括父亲,这允许研究由胎儿表达的父亲变异的影响,独立于母亲的血糖状态。此外,胎盘重量(PW)很少被考虑,尽管它是胎儿生长所依赖的组织。此外,回顾性研究通常包括出生记录的质量和细节以及随访时间的折衷。许多使用老年人群的研究依赖于自我报告的出生测量,对随访无反应或丢失的个体可能会引入选择偏差。

Walker群收集了上世纪50年代和60年代详尽的出生记录,总部设在苏格兰的邓迪。第二次世界大战定量配给后,这支队伍建立在这个工业化的城市地区。在近20年的时间里,超过48,000例住院分娩(占该时期邓迪所有分娩的75%)由临床工作人员详细记录,他们直接在出生卡上记录大量测量值,如BW和PW。这些卡片还包括婴儿父母的信息,允许识别完整的家庭三人组。通过数据链接,可以获得沃克父母超过70年的纵向医疗保健信息,这是一个具有显著二型糖尿病发病率和总死亡率的人群。Walker队列代表了一个有价值的数据集,从中我们可以深入了解胎儿生长和父母疾病之间的联系。由于先前报道的二型糖尿病和BW之间的遗传联系,我们假设糖尿病后代BW和PW将通过二型糖尿病风险等位基因的遗传与父母患二型糖尿病病的风险在表型上相关。为了研究这些关联,为Walker队列中的父母独立构建了父母二型糖尿病病诊断风险(针对竞争性死亡风险进行调整)和死亡风险的生存模型,由后代BW和PW建模。

目的:我们假设后代体重和胎盘重量与父母二型糖尿病风险相关,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队列研究收集了苏格兰邓迪地区20世纪50年代和60年代的出生记录,通过将BW和PW测量值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。我们对双亲二型糖尿病风险和竞争性死亡风险进行了精细-灰色生存分析,并对死亡风险进行了Cox回归分析,独立于母体和父体数据集,由后代BW和PW建模。

结果:我们发现父方二型糖尿病风险增加与后代体重(亚分布风险比[SHR] 0.92 [95% CI 0.87,0.98])和PW (SHR 0.87 [95% CI 0.81,0.94])降低之间有显著相关性。母体二型糖尿病风险与后代体重或PW的相关性不显著。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,在对体重进行调整后,较高的后代体重与孕产妇死亡风险增加相关(HR 1.08 [95% CI 1.04,1.13])。

表1总结了感兴趣的变量以及患二型糖尿病和未患的父母之间的差异

图1后代BW(A)和PW(B)的小提琴曲线图,按亲代2型糖尿病的后期发展。包括垂直的盒子和胡须的情节。每对样本之间的均数差异的p值采用Welch两样本t检验计算(*p<0.05)。T2D,2型糖尿病

图2母亲和父亲患2型糖尿病的累积百分比,按年龄和子女体重和体重四分位数分列。(a,b)母亲患2型糖尿病的累积百分比,按(A)子女体重和(B)子女体重分组。(c,d)父亲患2型糖尿病的累积百分比,按(C)子女体重和(D)子女体重分组。T2D,2型糖尿病

图3按年龄和后代体重和体重四分位数分列的已故母亲和父亲的累积百分比。(a,b)按(a)后代体重和(b)后代PW分组的已故母亲的累积百分比。(c,d)已故父亲的累积百分比,按(c)后代体重和(d)后代PW分组

表2Z转换后代体重和PW四分位数的母体相关变量汇总

表3按Z转换后代体重和PW四分位汇总感兴趣的父系变量

图4按年龄和子代BW和PW四分位估计的父母二型糖尿病和死亡的累积发生率曲线。为了清楚起见,仅绘制了四分之一1和4。p值使用格雷等式检验计算(*p<0.05,**p<0.01,***p<0.001)。(a,b)按(a)子代BW和(b)子代PW分组的二型糖尿病和死亡的累积产妇发病率。(c,d)按(c)子代BW和(d)子代PW分组的父代二型糖尿病和死亡的累积发生率。二型糖尿病T2D

表4产妇二型糖尿病和死亡的生存分析

结论:我们确定了子代体重与父代二型糖尿病风险降低之间的相关性,这很可能是由于常见的二型糖尿病易感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。此外,我们确定了子代PW和降低父代二型糖尿病风险之间的新关联,这种关系也可能是由糖尿病易感性变异的遗传引起的。我们发现了后代体重和PW与父母死亡风险之间的不同联系。这些结果为使用后代体重和PW作为母亲和父亲未来二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。

原文出处:Sánchez-Soriano C,  Pearson ER,  Reynolds RM,Associations between parental type 2 diabetes risk and offspring birthweight and placental weight: a survival analysis using the Walker cohort.Diabetologia 2022 Aug 11

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