Husemoen Lise Lotte N, Skaaby Tea, Jørgensen Torben, Thyssen Jacob P, Meldgaard Michael, Szecsi Pal B, Stender Steen, Johansen Jeanne Duus, Linneberg Allan
Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark.
Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark ; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2013 Dec 18;8(12):e84293. doi: 10.1371/journal.pone.0084293. eCollection 2013.
Common loss-of-function mutations in the filaggrin gene (FLG) are a major predisposing risk factor for atopic disease due to reduced epidermal filaggrin protein levels. We previously observed an association between these mutations and type 2 diabetes and hypothesized that an inherited impairment of skin barrier functions could facilitate low-grade inflammation and hence increase the risk of diabetes and cardiovascular disease. We examined the association between loss-of-function mutations in FLG and diabetes, stroke, ischemic heart disease (IHD), and all-cause mortality in the general population.
The R501X and 2282del4 loss-of function mutations in FLG were genotyped in four Danish study populations including a total of 13373 adults aged 15-77 years. Two of the studies also genotyped the R2447X mutation. By linkage to Danish national central registers we obtained information for all participants on dates of diagnoses of diabetes, stroke, and IHD, as well as all-cause mortality. Data were analyzed by Cox proportional hazard models and combined by fixed effect meta-analyses.
In meta-analyses combining the results from the four individual studies, carriage of loss-of-function mutations in FLG was not associated with incident diabetes (hazard ratio (HR) (95% confidence intervals (CI)) = 0.95 (0.73, 1.23), stroke (HR (95% CI) = 1.27 (0.97, 1.65), ischemic heart disease (HR (95%CI) = 0.92 (0.71, 1.19), and all-cause mortality (HR (95%CI) = 1.02 (0.83, 1.25)). Similar results were obtained when including prevalent cases in logistic regression models.
Our results suggest that loss-of-function mutations in FLG are not associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. However, larger studies with longer follow-up are needed to exclude any associations.
由于表皮中间丝相关蛋白水平降低，中间丝相关蛋白基因（FLG）常见的功能丧失突变是特应性疾病的主要诱发危险因素。我们之前观察到这些突变与2型糖尿病之间存在关联，并推测皮肤屏障功能的遗传性损害可能会促进低度炎症，从而增加患糖尿病和心血管疾病的风险。我们研究了普通人群中FLG功能丧失突变与糖尿病、中风、缺血性心脏病（IHD）和全因死亡率之间的关联。
在四个丹麦研究人群中对FLG的R501X和2282del4功能丧失突变进行基因分型，这些人群共有13373名年龄在15 - 77岁的成年人。其中两项研究还对R2447X突变进行了基因分型。通过与丹麦国家中央登记处建立联系，我们获得了所有参与者关于糖尿病、中风和IHD诊断日期以及全因死亡率的信息。数据通过Cox比例风险模型进行分析，并通过固定效应荟萃分析进行合并。
在对四项独立研究结果进行的荟萃分析中，FLG功能丧失突变的携带与新发糖尿病（风险比（HR）（95%置信区间（CI））= 0.95（0.73，1.23））、中风（HR（95%CI）= 1.27（0.97, 1.65））、缺血性心脏病（HR（95%CI）= 0.92（0.71, 1.19））和全因死亡率（HR（95%CI）= 1.02（0.83, 1.25））均无关联。当在逻辑回归模型中纳入现患病例时，也得到了类似结果。
我们的结果表明，FLG功能丧失突变与2型糖尿病、心血管疾病和全因死亡率无关。然而，需要更大规模、随访时间更长的研究来排除任何关联。
