The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders
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Mette K. Andersen aff001; Emil Jørsboe aff002; Line Skotte aff003; Kristian Hanghøj aff002; Camilla H. Sandholt aff001; Ida Moltke aff002; Niels Grarup aff001; Timo Kern aff001; Yuvaraj Mahendran aff001; Bolette Søborg aff003; Peter Bjerregaard aff005; Christina V. L. Larsen aff005; Inger K. Dahl-Petersen aff005; Hemant K. Tiwari aff007; Bjarke Feenstra aff003; Anders Koch aff003; Howard W. Wiener aff009; Scarlett E. Hopkins aff010; Oluf Pedersen aff001; Mads Melbye aff003; Bert B. Boyer aff010; Marit E. Jørgensen aff005; Anders Albrechtsen aff002; Torben Hansen aff001
Působiště autorů:
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
aff001; The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark
aff002; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
aff003; PEPperPRINT GmbH, Heidelberg, Germany
aff004; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
aff005; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland
aff006; Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
aff007; Department of Infectious Diseases, Rigshospitalet University Hospital, Copenhagen, Denmark
aff008; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
aff009; Department of Obstetrics and Gynecology, Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, United States of America
aff010; Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America
aff011; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
aff012; Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America
aff013; Steno Diabetes Center Copenhagen, Gentofte, Denmark
aff014; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
aff015
Vyšlo v časopise:
The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008544
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008544
Souhrn
The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup’ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup’ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.
Klíčová slova:
Alaska – Body Mass Index – Europe – Fats – Genetic loci – Insulin resistance – Metaanalysis – Obesity
Zdroje
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