Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.
Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.
复制标题
DOI：
10.1371/journal.pmed.1002548
复制
发表时间：
2018-04
期刊：
影响因子：
15.8
通讯作者：
TEDDY Study Group
中科院分区：
文献类型：
--
作者：
Bonifacio E;Beyerlein A;Hippich M;Winkler C;Vehik K;Weedon MN;Laimighofer M;Hattersley AT;Krumsiek J;Frohnert BI;Steck AK;Hagopian WA;Krischer JP;Lernmark Å;Rewers MJ;She JX;Toppari J;Akolkar B;Oram RA;Rich SS;Ziegler AG;TEDDY Study Group
大约0.3%的新生儿在儿童时期会对胰腺β细胞产生自身免疫，随后在成年前发展为1型糖尿病。1型糖尿病的一级预防需要对遗传风险婴儿进行早期干预。这项研究的目的是确定遗传评分（两个先前的遗传评分和一个合并的遗传评分）在多大程度上可以改善1型糖尿病的预测。年轻人糖尿病的环境决定因素（TEDDY）研究从出生起每隔3到6个月跟踪遗传风险儿童，以了解胰岛自身抗体和1型糖尿病的发展。婴儿在2004年9月1日至2010年2月28日期间入组，并监测至2016年5月31日。风险（阳性预测值）用于产生多种胰岛自身抗体在4，543名没有1型糖尿病一级亲属且具有杂合HLA DR 3和DR 4-DQ 8风险基因型或纯合DR 4-DQ 8基因型的儿童中确定了1型糖尿病（症状前1型糖尿病）和1型糖尿病，其中498名儿童的遗传评分是根据41个单核苷酸多态性计算的。在具有HLA风险基因型的儿童中，6岁时发生多种胰岛自身抗体的风险为5.8%（95%CI 5.0%-6.6%），10岁时发生糖尿病的风险为3.7%（95%CI 3.0%-4.4%）。合并遗传评分>14.4（上四分位数; n = 907）的儿童发生多种胰岛自身抗体的风险为11.0%（95%CI 8.7%-13.3%），而遗传评分≤14.4（n = 2,591）的儿童发生多种胰岛自身抗体的风险为4.1%（95%CI 3.3%-4.9%，P < 0.001）。合并评分>14.4的儿童在10岁时患糖尿病的风险为7.6%（95%CI 5.3%-9.9%），而评分≤14.4的儿童为2.7%（95%CI 1.9%-3.6%）（P < 0.001）。在173名6岁时患有多种胰岛自身抗体的儿童和107名10岁时患有糖尿病的儿童中，分别有82名（敏感性，47.4%; 95%CI 40.1%-54.8%）和52名（敏感性，48.6%，95%CI 39.3%-60.0%）评分>14.4。欧洲儿童的评分高于美国儿童（P = 0.003）。在合并评分>14.4的儿童中，多种胰岛自身抗体的风险相似，在欧洲和美国均>10%;男性的风险高于女性（P = 0.01）。该研究的局限性包括遗传评分最初是从主要是欧洲人的临床糖尿病病例对照研究中发展而来的。因此，它可能不适合所有人群。1型糖尿病遗传评分确定了没有1型糖尿病家族史的婴儿，他们有超过10%的1型糖尿病症状前风险，并且比仅通过高风险HLA基因型确定的儿童高出近2倍。这一发现扩大了儿童参与1型糖尿病一级预防试验的可能性。Anette-Gabriele齐格勒及其同事报告了他们新的遗传风险评分，用于识别患有1型糖尿病的高风险婴儿。预防儿童疾病，如1型糖尿病，具有重要的医学意义。预防1型糖尿病可能最好通过在胰岛自身抗体产生之前进行干预来实现，胰岛自身抗体定义了症状前疾病阶段。早期干预需要一些工具，如识别未来病例的遗传风险措施。在没有家族史的情况下，1型糖尿病的风险目前通过HLA基因分型来确定，最大确定风险达到约5%。来自多个危险基因座的遗传评分可能会改善症状前1型糖尿病的风险分层。在TEDDY队列研究中，计算了3,000多名没有1型糖尿病家族史但具有2种最高风险HLA基因型之一（杂合子DR 3和DR 4-DQ 8或纯合子DR 4-DQ 8）的儿童的2种先前提出的1型糖尿病风险遗传评分，该队列研究前瞻性地从出生起跟踪儿童胰岛自身抗体和糖尿病的发展。我们发现，两种遗传评分，以及结合两者特征的合并遗传评分，对儿童胰岛自身抗体和糖尿病的风险进行了分层。合并遗传评分的上四分位数与多个胰岛自身抗体的症状前阶段的风险>10%相关，并且几乎一半发展为症状前或症状性糖尿病的儿童通过该评分确定。结合来自多个风险基因座的遗传信息可以改善对1型糖尿病等疾病的预测。提出了一种遗传风险评分模型，可用于招募婴儿参加早期1型糖尿病一级预防试验。该模型提供了一种新的模式，用于遗传筛查和选择高危婴儿，再加上家族史和HLA基因分型，可以从不到1%的新生儿中识别出高达25%的未来1型糖尿病儿童病例。
Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%–4.9%, P < 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%–54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%–60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials. Anette-Gabriele Ziegler and colleagues report their novel genetic risk score for identifying infants with a high risk of developing type 1 diabetes. Prevention of childhood diseases such as type 1 diabetes is of medical importance. Prevention of type 1 diabetes might be best achieved by intervention prior to the development of islet autoantibodies, which define a pre-symptomatic disease stage. Early intervention requires tools such as measures of genetic risk that identify future cases. Risk for type 1 diabetes in the absence of a family history is currently identified by HLA genotyping, with maximum identified risk reaching around 5%. Genetic scores derived from multiple risk loci may improve risk stratification for pre-symptomatic type 1 diabetes. Two previously proposed genetic scores for type 1 diabetes risk were calculated for over 3,000 children without a family history of type 1 diabetes but with 1 of the 2 highest-risk HLA genotypes (heterozygous DR3 and DR4-DQ8 or homozygous DR4-DQ8) participating in the TEDDY cohort study, which prospectively follows children from birth for the development of islet autoantibodies and diabetes. We found that both of the genetic scores, and a merged genetic score that combined the features of both, stratified the risk for islet autoantibodies and diabetes in the children. The upper quartile of the merged genetic score was associated with a >10% risk for the pre-symptomatic stage of multiple islet autoantibodies, and almost half the children who developed pre-symptomatic or symptomatic diabetes were identified by this score. Combining genetic information from multiple risk loci can improve the prediction of diseases such as type 1 diabetes. A genetic risk score model is proposed that could be used to recruit infants into early type 1 diabetes primary prevention trials. The model provides a new paradigm for genetic screening and selection of at-risk infants that, together with family history and HLA genotyping, could identify up to 25% of future childhood cases of type 1 diabetes from less than 1% of newborns.
登录
查看更多内容
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
158.5
作者：
Lionetti, Elena;Castellaneta, Stefania;Catassi, Carlo
通讯作者：
Catassi, Carlo
影响因子：
120.7
作者：
Bonifacio, Ezio;Ziegler, Anette-G.;Achenbach, Peter
通讯作者：
Achenbach, Peter
影响因子：
4.5
作者：
Clayton DG
通讯作者：
Clayton DG
影响因子：
15.8
作者：
Sudlow C;Gallacher J;Allen N;Beral V;Burton P;Danesh J;Downey P;Elliott P;Green J;Landray M;Liu B;Matthews P;Ong G;Pell J;Silman A;Young A;Sprosen T;Peakman T;Collins R
通讯作者：
Collins R