Assuntos
Doenças Transmissíveis/epidemiologia , Surtos de Doenças , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Regiões Árticas/epidemiologia , Estudos de Coortes , Doenças Transmissíveis/diagnóstico , Feminino , Groenlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Distribuição por Sexo , Tuberculose/diagnóstico , Adulto JovemRESUMO
BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.
Assuntos
Tamanho Corporal/genética , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos Ômega-3/metabolismo , Mutação de Sentido Incorreto , Alelos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Groenlândia , Humanos , Inuíte/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
OBJECTIVE: This study estimates the erythema nodosum (EN) incidence in a tuberculosis (TB) endemic setting and evaluates the likelihood of a subsequent TB diagnosis among individuals with Mycobacterium tuberculosis infection (MTI) with or without EN. DESIGN: We estimated EN incidence rates (IRs) in East Greenland in 2010-2011 and conducted a cohort study following all individuals who tested positive for MTI from 1 January 2010 until 31 December 2012. A personal identifier allowed individual follow-up in the mandatory TB register. MTI was defined by a positive interferon-gamma release assay. TB incidence rate ratios (IRRs) among participants with or without EN were estimated with the Cox proportional hazard model. RESULTS: We identified 38 EN cases corresponding to an IR of 500/100,000 inhabitants/year. All cases were among individuals with MTI. The EN IR was 11.79 (95% CI 5.73-24.27) times higher for BCG-unvaccinated compared with BCG-vaccinated individuals. The TB IRR was 25 (95% CI 11-60) within 1 month of EN compared to individuals without EN. CONCLUSION: This study documents a high EN incidence in a TB endemic region. EN occurred only in individuals with MTI, and predominantly among BCG-unvaccinated individuals. EN was significantly associated with a TB diagnosis within 1 month of diagnosis.