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Genomewide association study of C-peptide surfaces key regulatory genes in Indians

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Abstract

Insulin is a commonly used measure of pancreatic \(\upbeta \)-cell function but exhibits a short half-life in the human body. During biosynthesis, insulin release is accompanied by C-peptide at an equimolar concentration which has a much higher plasma half-life and is therefore projected as a precise measure of \(\upbeta \)-cell activity than insulin. Despite this, genetic studies of metabolic traits have neglected the regulatory potential of C-peptide for therapeutic intervention of type-2 diabetes. The present study is aimed to search genomewide variants governing C-peptide levels in genetically diverse and high risk population for metabolic diseases—Indians. We performed whole genome genotyping in 877 healthy Indians of Indo-European origin followed by replication of variants with \(P \le 1 \times 10^{-3}\) in an independent sample-set of 1829 Indians. Lead-associated signals were also tested in-silico in 773 Hispanics. To secure biological rationale for observed association, we further carried out DNA methylation quantitative trait loci analysis in 233 Indians and publicly available regulatory data was mined. We discovered novel lncRNA gene AC073333.8 with the strongest association with C-peptide levels in Indians that however missed genomewide significance. Also, noncoding genes, RP1-209A6.1 and RPS3AP5; protein gene regulators, ZNF831 and ETS2; and solute carrier protein gene SLC15A5 retained robust association with C-peptide after meta-analysis. Integration of methylation data revealed ETS2 and ZNF831 single-nucleotide polymorphisms as significant meth-QTLs in Indians. All genes showed reasonable expression in the human lung, signifying alternate important organs for C-peptide biology. Our findings mirror polygenic nature of C-peptide where multiple small-effect size variants in the regulatory genome principally govern the trait biology.

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Acknowledgements

The authors are grateful to all the study participants. We acknowledge the support and participation of members of the INDICO consortium in data generation. We also thank VIVA LA FAMILIA study for providing the summary statistics for meta-analysis. KB acknowledges CSIR for Senior Research Fellowship (CSIR-SRF). GP acknowledges UGC for Senior Research Fellowship. This work was supported by the Council of Scientific and Industrial Research (CSIR), Government of India through Centre for Cardiovascular and Metabolic Disease Research (CARDIOMED) project (grant no. BSC0122-(14)). This work was also funded by the Department of Science and Technology-PURSE- II (DST/SR/PURSE PhaseII/11).

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Authors and Affiliations

  1. Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110 020, India

    Khushdeep Bandesh, Gauri Prasad & Anil Kumar Giri

  2. Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110 020, India

    Khushdeep Bandesh, Gauri Prasad, Anil Kumar Giri & Dwaipayan Bharadwaj

  3. Department of Nutrition and UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, 28081, USA

    V. Saroja Voruganti

  4. USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Nancy F. Butte

  5. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    Shelley A. Cole & Anthony G. Comuzzie

  6. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, 110 029, India

    Nikhil Tandon

  7. Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110 067, India

    Dwaipayan Bharadwaj

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  1. Khushdeep Bandesh
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  2. Gauri Prasad
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Indico Consortium

Corresponding authors

Correspondence to Nikhil Tandon or Dwaipayan Bharadwaj.

Additional information

Corresponding editor: Indrajit Nanda

\(^\dag \)Members of the INDICO consortium are listed in the supplementary data.

\(^*\)KB researched the data and wrote the manuscript. KB and GP performed the analysis. AKG performed DNA methylation study. VSV, NFB, SAC and AGC provided summary statistics data for lead variants to perform meta-analysis in Hispanic population. VSV also analytically reviewed the manuscript. NT provided intellectual inputs. DB conceived, supervised the study and critically evaluated the manuscript.

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Bandesh, K., Prasad, G., Giri, A.K. et al. Genomewide association study of C-peptide surfaces key regulatory genes in Indians. J Genet 98, 8 (2019). https://doi.org/10.1007/s12041-018-1046-1

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