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Diabetes. 2016 Oct;65(10):2980-9. doi: 10.2337/db16-0522. Epub 2016 Jul 18.

Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity.

Author information

1
Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden hong.jiao@ki.se ingrid.dahlman@ki.se.
2
Lipid Laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
3
Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
4
Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm, Sweden.
5
Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
6
Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden.
7
Lipid Laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden hong.jiao@ki.se ingrid.dahlman@ki.se.

Abstract

Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole-exome sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit β3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 control subjects with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 control subjects, rs2076349 showed strong association with obesity (P = 9.67 × 10(-5); odds ratio 1.84). This variant was also associated with BMI and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. This gene may be involved in the development of excess body fat.

PMID:
27431458
DOI:
10.2337/db16-0522
[Indexed for MEDLINE]
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