27 research outputs found

    Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

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    Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∌20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

    Com o diabo no corpo: os terrĂ­veis papagaios do Brasil colĂŽnia

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    Desde a Antiguidade, papagaios, periquitos e afins (Psittacidae) fascinaram os europeus por seu vivo colorido e uma notĂĄvel capacidade de interação com seres humanos. A descoberta do Novo Mundo nada faria alĂ©m de acrescentar novos elementos ao trĂĄfico de animais exĂłticos hĂĄ muito estabelecido pelos europeus com a África e o Oriente. Sem possuir grandes mamĂ­feros, a AmĂ©rica tropical participaria desse comĂ©rcio com o que tinha de mais atrativo, essencialmente felinos, primatas e aves - em particular os papagaios, os quais eram embarcados em bom nĂșmero. Contudo, a julgar pelos documentos do Brasil colĂŽnia, esses volĂĄteis podiam inspirar muito pouca simpatia, pois nenhum outro animal - exceto as formigas - foi tantas vezes mencionado como praga para a agricultura. AlĂ©m disso, alguns psitĂĄcidas mostravam-se tĂŁo loquazes que inspiravam a sĂ©ria desconfiança de serem animais demonĂ­acos ou possessos, pois sĂł trĂȘs classes de entidades - anjos, homens e demĂŽnios - possuĂ­am o dom da palavra. Nos dias de hoje, vĂĄrios representantes dos Psittacidae ainda constituem uma ameaça para a agricultura, enquanto os indivĂ­duos muito faladores continuam despertando a suspeita de estarem possuĂ­dos pelo demĂŽnio. Transcendendo a mera curiosidade, essa crença exemplifica o quĂŁo intrincadas podem ser as relaçÔes do homem com o chamado “mundo natural”, revelando um universo mais amplo e multifacetado do que se poderia supor a princĂ­pio. Nesse sentido, a existĂȘncia de aves capazes de falar torna essa relação ainda mais complexa e evidencia que as dificuldades de estabelecer o limite entre o animal e o humano se estendem alĂ©m dos primatas e envolvem as mais inusitadas espĂ©cies zoolĂłgicas.Since ancient times, parrots and their allies (Psittacidae) have fascinated Europeans by their striking colors and notable ability to interact with human beings. The discovery of the New World added new species to the international exotic animal trade, which for many centuries had brought beasts to Europe from Africa and the Orient. Lacking large mammals, tropical America participated in this trade with its most appealing species, essentially felines, primates and birds - especially parrots - which were shipped in large numbers. It should be noted, however, that at times these birds were not well liked. In fact, according to documents from colonial Brazil, only the ants rank higher than parrots as the animals most often mentioned as agricultural pests. On the other hand, some of these birds were so chatty that people suspected them to be demonic or possessed animals, since only three classes of beings - angels, men and demons - have the ability to speak. Nowadays, several Psittacidae still constitute a threat to agriculture, and the suspicion that extremely talkative birds were demon possessed has also survived. More than a joke or a mere curiosity, this belief exemplifies how intricate man’s relationships with the “natural world” may be. In this sense, the existence of birds that are able to speak adds a further twist to these relationships, demonstrating that the problem of establishing a boundary between the animal and the human does not only involve primates, but also includes some unusual zoological species

    X Chromosome Dose and Sex Bias in Autoimmune Diseases:Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

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    OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX , 1 in ~1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren’s syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls. METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR). RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ~404 SLE women and ~344 SS women. 47,XXX was present in excess among SLE and SS subjects. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ~2.5 and ~2.9 times higher than in 46,XX women and ~25 and ~41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity
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