The endocrine system is crucial for maintaining whole‐body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart‐derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart‐derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well‐established clinical observation that children with heart diseases often develop FTT.
DNA mismatch repair, known as a fundamentally biological pathway, plays key roles in maintaining genomic stability, eliminating mismatch bases and preventing both mutagenesis in the short term and cancerogenesis in the long term. Polymorphisms of MLH1 in individuals may have an effect on the DNA repair capacity and therefore on cancer risk. Recently, emerging studies have been done to evaluate the association between MLH1 -93 G/A polymorphism and cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. In this meta-analysis, we assessed reported studies of association between the MLH1 -93 G/A polymorphism and cancer risk including 13 691 cancer cases and 14 068 controls from 17 published studies. A borderline significant association between the MLH1 -93 G/A polymorphism and cancer risk was observed in overall analysis [heterozygote: odds ratio (OR) = 1.15; 95% confidence interval (CI) 1.05-1.26; homozygote: OR = 1.21; 95% CI, 1.04-1.40; dominant model: OR = 1.13; 95% CI 1.01-1.26; recessive model: OR = 1.21; 95% CI 1.07-1.35, respectively]. In subgroup analysis by ethnicity, significantly increased risks were found in Asian population and mixed population but not in Caucasian population. After stratified analysis according to the quality of literature, increased cancer risks were observed in the studies of lower quality but not in the studies of higher quality. Similarly, elevated cancer risks were observed in hospital-based studies but not in population-based studies. These findings showed no persuasive evidence that MLH1 -93 G/A polymorphism was associated with an increased risk of cancer. On the conservative standpoint, well-designed population-based studies with larger sample size in different ethnic groups should be performed to further confirm these results.
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