RESUMEN
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
Asunto(s)
Anorexia Nerviosa/genética , Pueblo Asiatico/genética , Calcineurina/genética , Proteínas Portadoras/genética , Estudios de Casos y Controles , Proteínas Cullin/genética , Femenino , Estudio de Asociación del Genoma Completo , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Japón , Masculino , Metaanálisis como Asunto , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
The aetiology of multiple sclerosis (MS) is unknown. Autoimmune mechanisms are most probably involved. Loss of immunological tolerance to self-antigens is a common feature of autoimmune disorders. Response to X-linked self-antigens could be influenced by X-chromosome inactivation, and contribute to the gender bias observed in autoimmune disorders. Previous studies have indicated an association between skewed X inactivation and autoimmune thyroid disease and scleroderma. To investigate a potential role of X inactivation in MS, we compared the X-inactivation pattern in 568 female MS patients with controls. We found no difference in degree of skewing between patients (median 64%) and controls (median 65%) (P = 0.474). The X-inactivation pattern did thus not explain the female predominance of MS patients in general. As the aetiology of different subgroups of MS may differ, patients were grouped according to disease course: relapsing-remitting (RR-MS), secondary progressive (SP-MS) and primary progressive (PP-MS). A comparison of the X-inactivation pattern between subgroups indicated a possible difference in degree of skewing between patients with a progressive versus a relapsing course (P = 0.05).
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Inactivación del Cromosoma X/genética , Adulto , Factores de Edad , Anciano , Interpretación Estadística de Datos , Femenino , Variación Genética/genética , Humanos , Persona de Mediana Edad , Modelos Genéticos , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Factores SexualesRESUMEN
The X chromosome inactivation pattern in peripheral blood cells becomes more skewed after age 55, and a genetic effect on this age-related skewing has been reported. We investigated the effect of age on X inactivation phenotype in blood, buccal cells and tissue from duodenal biopsies in 80 females aged 19-90 years. The X inactivation pattern correlated positively with age in blood (r = 0.238, P = 0.034) and buccal cells (r = 0.260, P = 0.02). The mean degree of skewing was higher in the elderly (>/=55 years) than in the young (<55 years) in blood (70.1 and 63.5%, respectively, P = 0.013) and in buccal cells (64.7 and 59.0%, respectively, P = 0.004). Correlation of X inactivation between the different tissues was high in all tissues with a tendency to increase with age for blood and buccal cells (P = 0.082). None of the duodenal biopsies had a skewed X inactivation, and the mean degree of skewing was similar in the two age groups. The tendency for the same X chromosome to be the preferentially active X in both blood and buccal cells with advancing age is in agreement with a genetic effect on age-related skewing and indicates that genes other than those involved in hematopoiesis should be investigated in the search for genes contributing to age related skewing.
Asunto(s)
Envejecimiento , Células Sanguíneas/citología , Cromosomas Humanos X , Inactivación del Cromosoma X , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Mejilla , ADN/metabolismo , Duodeno/metabolismo , Femenino , Humanos , Persona de Mediana Edad , FenotipoRESUMEN
The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.
Asunto(s)
Huesos/anomalías , Diafragma/fisiopatología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Mutación/genética , Proteínas Tirosina Fosfatasas/genética , Adulto , Preescolar , Análisis Mutacional de ADN , Diafragma/patología , Femenino , Lateralidad Funcional/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Heterocigoto , Humanos , Recién Nacido , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Debilidad Muscular/patología , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/fisiopatología , Linaje , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras , Inactivación del Cromosoma X/genéticaRESUMEN
BACKGROUND: A higher frequency of skewed X chromosome inactivation has been reported in a consecutive series of young patients with breast cancer compared with controls of a similar age. OBJECTIVE: To investigate the X inactivation pattern in patients with familial non-BRCA1/BRCA2 breast cancer (n = 272), BRCA1/BRCA2 germline mutations (n = 35), and sporadic breast cancer (n = 292). METHODS: X inactivation pattern was determined by polymerase chain reaction analysis of the highly polymorphic CAG repeat in the androgen receptor (AR) gene. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially expressed one X chromosome. RESULTS: Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation (11.2%) than young controls (2.7%) (p = 0.001). There was also a strong tendency for middle aged patients with sporadic breast cancer to be more skewed than middle aged controls (13.6% v 4.4%) (p = 0.02). No association between skewed X inactivation and breast cancer was found for the BRCA1/BRCA2 patients . CONCLUSIONS: Skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X linked genes.