RESUMO
Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45-60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.
Assuntos
Cálcio/metabolismo , Cálculos Renais/genética , Vitamina D/metabolismo , Adulto , Idoso , Povo Asiático/genética , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão , Cálculos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas/genética , Proteínas/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Reino Unido , População Branca/genéticaRESUMO
Breast cancer is the commonest cancer in the UK. Advances in breast cancer treatment means that the sequelae of treatment are affecting more women and for a longer duration. Lymphoedema is one such sequela, with wide-ranging implications, from serious functional and psychological effects at the individual level to wider economic burdens to society. Breast cancer-related lymphoedema is principally managed by conservative therapy comprising compression garments and manual decongestive massage. This approach is effective for early stages of lymphoedema, but it is not curative and the effectiveness depends on patient compliance. Early surgical approaches were ablative, gave significant morbidity and hence, reserved for the most severe cases of refractory lymphoedema. However, recent non-ablative reconstructive surgical approaches have seen a revival of interest in the prevention or surgical management of breast cancer-related lymphoedema. This review examines the modern surgical techniques for the treatment of breast cancer-related lymphoedema. Liposuction reduces the volume and symptoms of lymphedema, but requires continual compressive therapy to avoid recurrence. Lymphatic reconstruction or bypass techniques including lymph node transfer (inguinal nodes are transferred to the affected limb), lymphatico-lymphatic bypass (lymphatics bypass the axilla using a lymph vessel graft reconstructing lymphatic flow from arm to neck) and lymphaticovenous anastomoses (lymphatics in the arm are joined to the venous system aiding lymph drainage) show promise in reducing lymphedema significantly. Further research is required, including into the role of primary lymphaticovenous anastomoses in the prevention of lymphedema at the time of axillary dissection.