title: Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease.
abstract: Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m(2) higher BMI, odds ratio [OR] 1.05, 95% CI 1.03-1.07, P < 0.001), and lower odds of ESRD (OR 0.95, 95% CI 0.93-0.97, P < 0.001). Mendelian randomization analysis showed a 1 kg/m(2) higher BMI conferring an increased risk in macroalbuminuria (OR 1.28, 95% CI 1.11-1.45, P = 0.001), ESRD (OR 1.43, 95% CI 1.20-1.72, P < 0.001), and DKD (OR 1.33, 95% CI 1.17-1.51, P < 0.001). Our results provide genetic evidence for a causal link between obesity and DKD in type 1 diabetes. As obesity prevalence rises, this finding predicts an increase in DKD prevalence unless intervention should occur.
authors: Division of Endocrinology, Boston Children's Hospital, Boston, MA Department of Pediatrics, Harvard Medical School, Boston, MA.
authors: Jennifer N
authors: JN
authors: Todd
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors: Emma H
authors: EH
authors: Dahlström
authors: Division of Endocrinology, Boston Children's Hospital, Boston, MA Department of Pediatrics, Harvard Medical School, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors: Rany M
authors: RM
authors: Salem
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors: Niina
authors: N
authors: Sandholm
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Carol
authors: C
authors: Forsblom
authors: Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland.
authors: Amy J
authors: AJ
authors: McKnight
authors: Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland Regional Nephrology Unit, Belfast City Hospital, Belfast, Northern Ireland.
authors: Alexander P
authors: AP
authors: Maxwell
authors: Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors: Eoin
authors: E
authors: Brennan
authors: Mater Misericordiae University Hospital, Dublin, Ireland.
authors: Denise
authors: D
authors: Sadlier
authors: Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors: Catherine
authors: C
authors: Godson
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Per-Henrik
authors: PH
authors: Groop
authors: Division of Endocrinology, Boston Children's Hospital, Boston, MA Department of Pediatrics, Harvard Medical School, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors: Joel N
authors: JN
authors: Hirschhorn
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Department of Medicine, Harvard Medical School, Boston, MA Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA jcflorez@partners.org.
authors: Jose C
authors: JC
authors: Florez
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D015992:Body Mass Index; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005387:Finland / Q000453:epidemiology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D015995:Prevalence; D012307:Risk Factors