RESUMO
We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição TCF/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Estudos de Coortes , Dinamarca , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Humanos , Íntrons , Repetições de Microssatélites , Dados de Sequência Molecular , Valores de Referência , Proteína 2 Semelhante ao Fator 7 de TranscriçãoRESUMO
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.
Assuntos
Fibrilação Atrial/genética , Cromossomos Humanos Par 4/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Fibrilação Atrial/diagnóstico , Feminino , Frequência do Gene , Genoma Humano/genética , Haplótipos/genética , Hong Kong , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Suécia , Estados Unidos , População Branca/genéticaRESUMO
Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.
Assuntos
Aneurisma da Aorta Abdominal/genética , Cromossomos Humanos Par 9 , Variação Genética , Aneurisma Intracraniano/genética , Infarto do Miocárdio/genética , Adulto , Idoso , Alelos , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/fisiopatologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Marcadores Genéticos , Haplótipos , Homozigoto , Humanos , Aneurisma Intracraniano/fisiopatologia , Funções Verossimilhança , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Prevalência , Probabilidade , Fatores de Risco , Análise de Sequência de DNA , População BrancaRESUMO
Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene, MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor-like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.