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

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, (r = 0.38; p = 0.001), fasting glucose (r= 0.36; p = 0.002), and triglycerides (r = 0.33; p = 0.005). Our data revealed a significant dose-related increase in MFGE8 genotypes for affecting serum Mfge8 (p = 2.1 × 10) and triglyceride concentrations (p = 3.2 × 10). 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.