Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Summary, in English

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/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). 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/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), 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 = 8.4610 29, 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 x 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 x 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 x 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.

• Författare: John R. B. Perry; Benjamin F. Voight; Loic Yengo; Najaf Amin; Josee Dupuis; Martha Ganser; Harald Grallert; Pau Navarro; Man Li; Lu Qi; Valgerdur Steinthorsdottir; Robert A. Scott; Peter Almgren; Dan E. Arking; Yurii Aulchenko; Beverley Balkau; Rafn Benediktsson; Richard N. Bergman; Eric Boerwinkle; Lori Bonnycastle; Noel P. Burtt; Harry Campbell; Guillaume Charpentier; Francis S. Collins; Christian Gieger; Todd Green; Samy Hadjadj; Andrew T. Hattersley; Christian Herder; Albert Hofman; Andrew D. Johnson; Anna Kottgen; Peter Kraft; Yann Labrune; Claudia Langenberg; Alisa K. Manning; Karen L. Mohlke; Andrew P. Morris; Ben Oostra; James Pankow; Ann-Kristin Petersen; Peter P. Pramstaller; Inga Prokopenko; Wolfgang Rathmann; William Rayner; Michael Roden; Igor Rudan; Denis Rybin; Laura J. Scott; Gunnar Sigurdsson; Rob Sladek; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Jaakko Tuomilehto; Andre G. Uitterlinden; Sidonie Vivequin; Michael N. Weedon; Alan F. Wright; Frank B. Hu; Thomas Illig; Linda Kao; James B. Meigs; James F. Wilson; Kari Stefansson; Cornelia van Duijn; David Altschuler; Andrew D. Morris; Michael Boehnke; Mark I. McCarthy; Philippe Froguel; Colin N. A. Palmer; Nicholas J. Wareham; Leif Groop; Timothy M. Frayling; Stephane Cauchi
• Avdelning/ar: Translationell Muskel Forskning; EXODIAB: Excellence of Diabetes Research in Sweden
• Publiceringsår: 2012
• Språk: Engelska
• Publikation/Tidskrift/Serie: PLoS Genetics
• Volym: 8
• Issue: 5
• Fulltext: - 792 kB; Download statistics
• Länkar: http://dx.doi.org/10.1371/journal.pgen.1002741
• Dokumenttyp: Artikel i tidskrift
• Förlag: Public Library of Science (PLoS)
• Ämne: Endocrinology and Diabetes
• Status: Published
• Forskningsgrupp: Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Övrigt: ISSN: 1553-7404