CONTEXT: Insulin resistance (IR) and obesity differ among ethnic groups in Singapore, with the Malays more obese yet less IR than Asian-Indians. However, the molecular basis underlying these differences is not clear. OBJECTIVE: As the skeletal muscle (SM) is metabolically relevant to IR, we investigated molecular pathways in SM that are associated with ethnic differences in IR, obesity, and related traits. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: We integrated transcriptomic, genomic, and phenotypic analyses in 156 healthy subjects representing three major ethnicities in the Singapore Adult Metabolism Study. PATIENTS: This study contains Chinese (n = 63), Malay (n = 51), and Asian-Indian (n = 42) men, aged 21 to 40 years, without systemic diseases. RESULTS: We found remarkable diversity in the SM transcriptome among the three ethnicities, with >8000 differentially expressed genes (40% of all genes expressed in SM). Comparison with blood transcriptome from a separate Singaporean cohort showed that >95% of SM expression differences among ethnicities were unique to SM. We identified a network of 46 genes that were specifically downregulated in Malays, suggesting dysregulation of components of cellular respiration in SM of Malay individuals. We also report 28 differentially expressed gene clusters, four of which were also enriched for genes that were found in genome-wide association studies of metabolic traits and disease and correlated with variation in IR, obesity, and related traits. CONCLUSION: We identified extensive gene-expression changes in SM among the three Singaporean ethnicities and report specific genes and molecular pathways that might underpin and explain the differences in IR among these ethnic groups.

Department of Chemistry Food Science and Technology Programme National University of Singapore Singapore

Department of Endocrinology Tan Tock Seng Hospital Singapore

Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore

Department of Obstetrics and Gynaecology Yong Loo Lin School of Medicine National University of Singapore Singapore

Department of Paediatrics Yong Loo Lin School of Medicine National University of Singapore Singapore

Division of Endocrinology Department of Medicine National University Health System Singapore

Division of Paediatrics Endocrinology Khoo Teck Puat National University Children's Medical Institute National University Hospital National University Health System Singapore

Duke National University of Singapore Medical School Singapore

Experimental Biotherapeutics Centre Agency for Science Technology and Research Singapore

Institute Of Physiology Czech Academy Of Sciences Prague Czech Republic

Lee Kong Chian School of Medicine Nanyang Technological University Singapore

Nanyang Institute of Technology in Health and Medicine Nanyang Technological University Singapore

National Heart Centre Singapore Singapore

Saw Swee Hock School of Public Health National University of Singapore Singapore

School of Biological Sciences Nanyang Technological University Singapore

Singapore Bioimaging Consortium Agency for Science Technology and Research Singapore

Singapore Institute for Clinical Sciences Agency for Science Technology and Research Singapore

Unit of Human Evolutionary Genetics Institut Pasteur Paris France

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