Ethnicity-Specific Skeletal Muscle Transcriptional Signatures and Their Relevance to Insulin Resistance in Singapore

Amelia Li Min Tan (1, 2) , Chee Fan Tan (3, 4) , Jin Fang Chai (5) , Chin Meng Khoo (2, 1, 6) , Melvin Khee-Shing Leow (2, 7, 8, 9) , Eric Yin Hao Khoo (1, 6) , Suresh Anand Sadananthan (7) , S Sendhil Velan (7, 10) , Kavita Venkataraman (5) , Yap Seng Chong (7, 1) , Yung Seng Lee (7, 1, 11) , Xueling Sim (5) , Walter Stünkel (12) , Mei Hui Liu (13) , E Shyong Tai (1, 2, 6) , Amelia Li (13) , Min Tan (13) , Sarah R Langley (2, 14) , Fan Chee (4) , Jin Fang Chai (13) , Chin Meng Khoo (13) , Melvin Khee (2) , Shing Leow (2) , Eric Yin (13) , Hao Khoo (13) , Aida Moreno-Moral (2) , Michal Pravenec (15) , Maxime Rotival (16) , Enrico Petretto (17)

1 Yong Loo Lin School of Medicine [Singapore]
2 Duke-National University of Singapore Graduate Medical School
3 Institute for Health Technologies [Singapor]
4 Nanyang Technological University [Singapour]
5 Saw Swee Hock School of Public Health [Singapore, Singapore]
6 Division of Endocrinology [NUHS, Singapore]
7 Singapore Institute for Clinical Sciences
8 Tan Tock Seng Hospital
9 Lee Kong Chian School of Medicine
10 SBIC - Singapore Bioimaging Consortium [Singapore]
11 Division of Paediatrics Endocrinology [Singapore]
12 A*STAR - Agency for science, technology and research [Singapore]
13 NUS - National University of Singapore
14 NHCS - National Heart Centre Singapore
15 Institute of Physiology [Prague]
16 Génétique Evolutive Humaine - Human Evolutionary Genetics
17 Duke-NUS Medical School [Singapore]

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. Trial registration: ClinicalTrials.gov NCT00988819.

Domaines: Génétique humaine; Génétique des populations [q-bio.PE]

Amelia Li Min Tan, Chee Fan Tan, Jin Fang Chai, Chin Meng Khoo, Melvin Khee-Shing Leow, et al.. Ethnicity-Specific Skeletal Muscle Transcriptional Signatures and Their Relevance to Insulin Resistance in Singapore. Journal of Clinical Endocrinology and Metabolism, 2019, 104 (2), pp.465-486. ⟨10.1210/jc.2018-00309⟩. ⟨pasteur-02869029⟩