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A rare missense variant in the milk fat globule-EGF factor 8 (MFGE8) increases T2DM susceptibility and cardiovascular disease risk with population-specific effects

Acta Diabetologica volume 57, pages 733–741 (2020)Cite this article

Abstract

Aims

The milk fat globule-epidermal growth factor 8 (MFGE8), also called lactadherin, is an integrin ligand and a known mediator of inflammation and atherosclerosis in T2DM in studies using animal models. However, its role in the pathophysiology of human T2DM, obesity, and cardiovascular disease has been poorly explored. Aim of this study  was to investigate the role of a missense variant (rs371227978 C/T: Arg148His) in the MFGE8 gene identified through exome sequencing for its association with T2DM and cardiometabolic traits.

Methods

Exome-wide sequencing was performed using DNA samples from 68 Sikh individuals from multi-generation pedigrees affected with diabetes on Illumina’s GAIIx using “SureSelect Human All Exon” panels. We further replicated this variant by de novo genotyping in a total of 4242 individuals of the Asian Indian Diabetic Heart Study/Sikh Diabetes Study using custom TaqMan genotyping assay. We also measured circulating concentrations of Mfge8 using frozen serum aliquots by enzyme-linked immunosorbent assay.

Results

Overall, only 1.78% of 4242 individuals were carriers of this variant with MAF being 0.009. Except for the significant correlation of this variant with T2DM and triglycerides, no other quantitative risk phenotype was significant. The minor per allele-associated increased risk for T2DM showed odds ratio of 1.95 (95% CI 1.18–3.23; p = 0.008) in unadjusted model and was 1.73 (95% CI 1.02–2.93; p = 0.043) after adjusting for the age, gender, and BMI. However, there was a strong correlation between serum Mfge8 concentrations with T2DM, (r2 = 0.38; p = 0.001), fasting glucose (r2= 0.36; p = 0.002), and triglycerides (r2 = 0.33; p = 0.005). Our data revealed a significant dose-related increase in MFGE8 genotypes for affecting serum Mfge8 (p = 2.1 × 10−3) and triglyceride concentrations (p = 3.2 × 10−3). For a per risk allele-associated increase of 4.74 ng/ml ± SD of 1.62 ng/ml of the Mfge8 concentration was found to increase T2DM risk to 1.7 fold (95% CI from 1 to 3 fold).

Conclusions

Here, we report for the first time a novel population-specific rare variant in the MFGE8 gene linked with the increased Mfge8 concentrations and the risk for developing T2DM and cardiovascular risk factors in a population of Punjabi Sikhs from India. In view of a strong evidence from animal studies supporting the role of Mfge8 in obesity, insulin resistance, and the development of atherosclerosis in T2DM, our findings are important and timely. If validated in a large independent dataset, early screening of Mfge8 in blood levels may especially benefit those patients with genetically elevated Mfge8 levels to preventing or reducing the risk of T2DM and cardiovascular disease.

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Acknowledgements

Authors thank all the participants of AIDHS/SDS who made this study possible. We thankfully acknowledge Dr. Piers Blackett for reviewing the manuscript review and suggestions.

Funding

The Sikh Diabetes Study/Asian Indian Diabetic Heart Study was supported by NIH Grants-R01DK082766 (NIDDK) and NOT-HG-11-009 (NHGRI) and Grants from Presbyterian Health Foundation; and Harold Hamm Diabetes Center, Oklahoma City, USA.

Author information

Affiliations

  1. Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, Oklahoma City, OK, 73104, USA

    Bishwa R. Sapkota & Dharambir K. Sanghera

  2. Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dharambir K. Sanghera

  3. Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dharambir K. Sanghera

  4. Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dharambir K. Sanghera

  5. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dharambir K. Sanghera

Authors
  1. Bishwa R. Sapkota
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  2. Dharambir K. Sanghera
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Contributions

DKS conceived and designed the experiments; BRS contributed to data analysis, SNP genotyping for replication analysis, ELISA, and bioinformatics. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dharambir K. Sanghera.

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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Ethical approval

The study was reviewed and approved by the University of Oklahoma Health Sciences Center’s Institutional Review Board, as well as the Human Subject Protection Committees at the participating hospitals and institutes in India.

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All participants provided a written informed consent for investigations.

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Sapkota, B.R., Sanghera, D.K. A rare missense variant in the milk fat globule-EGF factor 8 (MFGE8) increases T2DM susceptibility and cardiovascular disease risk with population-specific effects. Acta Diabetol 57, 733–741 (2020). https://doi.org/10.1007/s00592-019-01463-x

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Keywords

  • MFGE8
  • Exome sequencing
  • Population-specific rare variant
  • Type 2 diabetes mellitus
  • Hypertriglyceridemia
  • Punjabi Sikhs