Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
PLoS Genet
; 8(5): e1002741, 2012 May.
Article
em En
| MEDLINE
| ID: mdl-22693455
ABSTRACT
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI≥30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (Pâ=â8.4×10â»9, ORâ=â1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (Pâ=â0.04, ORâ=â1.03 [95% CI 1.00-1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (Pâ=â1.3×10â»8, ORâ=â1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (Pâ=â0.02, ORâ=â1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial Pâ=â0.0002). In the lean analysis, we observed a weighted per-risk allele ORâ=â1.13 [95% CI 1.10-1.17], Pâ=â3.2×10⻹4. This was larger than the same model fitted in the obese analysis where the ORâ=â1.06 [95% CI 1.05-1.08], Pâ=â2.2×10⻹6. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Grupo de Alta Mobilidade
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Índice de Massa Corporal
/
Laminina
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Diabetes Mellitus Tipo 2
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Obesidade
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
PLoS Genet
Assunto da revista:
GENETICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido