The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders


Autoři: 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: 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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