Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
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Authors
Perry, John R BVoight, Benjamin F
Yengo, Loïc
Amin, Najaf
Dupuis, Josée
Ganser, Martha
Grallert, Harald
Navarro, Pau
Li, Man
Qi, Lu
Steinthorsdottir, Valgerdur
Scott, Robert A
Almgren, Peter
Arking, Dan E
Aulchenko, Yurii
Balkau, Beverley
Benediktsson, Rafn
Bergman, Richard N
Boerwinkle, Eric
Bonnycastle, Lori
Burtt, Noël P
Campbell, Harry
Charpentier, Guillaume
Collins, Francis S
Gieger, Christian
Green, Todd
Hadjadj, Samy
Hattersley, Andrew T
Herder, Christian
Hofman, Albert
Johnson, Andrew D
Kottgen, Anna
Kraft, Peter
Labrune, Yann
Langenberg, Claudia
Manning, Alisa K
Mohlke, Karen L
Morris, Andrew P
Oostra, Ben
Pankow, James
Petersen, Ann-Kristin
Pramstaller, Peter P
Prokopenko, Inga
Rathmann, Wolfgang
Rayner, William
Roden, Michael
Rudan, Igor
Rybin, Denis
Scott, Laura J
Sigurdsson, Gunnar
Sladek, Rob
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Tuomilehto, Jaakko
Uitterlinden, Andre G
Vivequin, Sidonie
Weedon, Michael N
Wright, Alan F
Hu, Frank B
Illig, Thomas
Kao, Linda
Meigs, James B
Wilson, James F
Stefansson, Kari
van Duijn, Cornelia
Altschuler, David
Morris, Andrew D
Boehnke, Michael
McCarthy, Mark I
Froguel, Philippe
Palmer, Colin N A
Wareham, Nicholas J
Groop, Leif
Frayling, Timothy M
Cauchi, Stéphane
Issue Date
2012-05
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PLoS Genet. 2012, 8(5):e1002741Abstract
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 (P = 8.4×10⁻⁹, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [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 (P = 1.3×10⁻⁸, OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [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 P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2×10⁻¹⁴. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10⁻¹⁶. 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.Description
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http://dx.doi.org/10.1371/journal.pgen.1002741http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364960/
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Archived with thanks to PLoS geneticsae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1002741
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