RESUMEN
OBJECTIVE: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. METHOD: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. RESULTS: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). DISCUSSION: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.
Asunto(s)
Anorexia Nerviosa/genética , Peso Corporal/genética , Bulimia Nerviosa/genética , Leptina/genética , Melanocortinas/genética , Factores de Crecimiento Nervioso/genética , Adulto , Proteína Relacionada con Agouti/genética , Anorexia Nerviosa/fisiopatología , Índice de Masa Corporal , Bulimia Nerviosa/fisiopatología , Estudios de Casos y Controles , Femenino , Técnicas de Genotipaje , Humanos , Glicoproteínas de Membrana , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Quinasas/genética , Proteínas Tirosina Quinasas , Receptor trkBRESUMEN
RATIONALE: Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target, which imposes therapeutic constraints that are generally relevant to the translational potential of many kinases. OBJECTIVE: To study the cardioprotective properties of the activation-resistant, non-oncogenic, mutation of ILK (ILK(R211A)) against experimental MI in vivo and Doxorubicin induced apoptosis in vitro and it's relationships to stress induced heat shock proteins. METHODS/RESULTS: The transgenic mouse heart over-expressing a point mutation in the ILK pleckstrin homology (PH) domain (Tg(R211A)) exhibits a highly cardioprotective phenotype based on LAD-ligation-induced MI reduction in vivo, and on protection against doxorubicin (DOX)-induced cardiomyocyte apoptosis when overexpressed in human induced pluripotent stem cell (iPS)-derived cardiomyocytes in vitro. Intriguingly, the degree of cardioprotection seen with the ILK(R211A) mutation exceeded that with the ILK(S343D) mutation. Microarray and immunoprecipitation analyses revealed upregulation of expression levels and specific binding of ILK(WT), ILK(S343D) and ILK(R211A) to both constitutively active heat-shock protein 70 (Hsc70) and inducible Hsp70 in response to MI, and to acute ILK overexpression in iPSC-cardiomyocytes. ILK-mediated cardioprotection was shown to depend upon Hsp70 ATPase activity. CONCLUSIONS: These findings indicate that wild type ILK and the non-oncogenic ILK(R211A) mutation comprise a cardioprotective module with Hsp/c70. These results advance a novel target discovery theme in which kinase mutations can be safely engineered to enhance cardioprotective effects.
Asunto(s)
Proteínas del Choque Térmico HSC70/metabolismo , Mutación Missense , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Sustitución de Aminoácidos , Animales , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Proteínas del Choque Térmico HSC70/genética , Humanos , Ratones , Ratones Transgénicos , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/patología , Proteínas Serina-Treonina Quinasas/genética , ConejosRESUMEN
The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first- to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS.
Asunto(s)
Cardiopatías Congénitas/genética , Adulto , Síndrome de DiGeorge/genética , Composición Familiar , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética , Humanos , MasculinoRESUMEN
BACKGROUND: tetralogy of Fallot (TOF) is a complex congenital heart disease with clinical and genetic heterogeneity. Of the few known causes, 22q11.2 deletion syndrome (22q11DS) is the most common. We sought to define other clinical subgroups by focusing on cardiac and extracardiac features. METHODS: we prospectively screened a cohort of adults with TOF using an established protocol by which subjects were categorized as "syndromic" if they had at least 2 of 3 features: dysmorphic facies, learning difficulties, or voice abnormalities. We then compared the prevalence of cardiac and extracardiac features between subjects in the syndromic group (n = 56) and 112 age- and gender-matched subjects who did not meet our syndromic criteria. RESULTS: the syndromic group was more likely than the nonsyndromic group to have pulmonary atresia and/or major aortopulmonary collateral arteries (25% vs 13%, P = .04). There was a trend toward a higher prevalence of one or more major congenital extracardiac anomalies, primarily involving the musculoskeletal and genitourinary systems (25% vs 13%, P = .06). Later-onset conditions, including neuropsychiatric disorders (32% vs 17%, P = .03), thyroid disorders (20% vs 4%, P = .001), and hearing deficits (20% vs 0, P < .001), were more common in the syndromic group. The syndromic group tested (n = 50) had neither 22q11.2 deletions nor karyotypic anomalies. CONCLUSION: similar to 22q11DS, adults with TOF meeting screening criteria for a possible genetic syndrome are enriched for more severe cardiac disease and late-onset extracardiac features. Increased awareness of this subgroup with a multisystem condition may be helpful for identifying individuals for referral to medical genetics and optimizing management.