Obesity is a major risk factor for Type 2 Diabetes (T2D) yet the majority of obese subjects never develop T2D and their metabolic tissues never lose insulin sensitivity. This suggests a key role of genetic predisposition to T2D development in obesity. We have assessed for the first time if single nucleotide variants (SNVs) within three genes, i.e., PIKFYVE, SAC3/FIG4 and ARPIKFYVE/VAC14, proposed to control glucose homeostasis, are associated with development of T2D in obesity. Assembled in a complex, the protein products of the 3 genes regulate synthesis and turnover of 2 signaling lipids, i.e., PtdIns (3,5) P2 and PtdIns5P. We performed exome sequencing using abdominal fat derived from bariatric surgeries of morbidly obese men (n=32) and morbidly obese women (n=64) with or without T2D (48 subjects/group) . The two groups were with similar mean BMI and age. Out of a total of 942 SNVs identified in the three genes, 7 were associated with T2D in obesity via logistic regression analysis: 2 in PIKFYVE (rs6755550, rs12624141) , 2 in SAC3/FIG4 (rs17612996, rs9386844) and 3 in ARPIKFYVE/VAC14 (rs1875941, rs2242126, rs7201952) (p<0.05; n=48) , all located in noncoding regions of the three genes and yet unlinked to a disease. Notably, the PIKFYVE SNVs were more frequently associated with T2D in the group of women (n=32) than that of men (n=16) . Further analysis of women’s group uncovered two additional T2D-associated SNVs located in the adipose super-enhancer of the PIKFYVE gene (rs2118296, rs10208655) . A constellation of the latter two and the PIKFYVE SNV rs6755550 was seen in 25% of the morbidly obese women with T2D but not in those without T2D (n=32) . Together, our data indicate for the first time that SNVs in the three genes may be associated with development of T2D in morbidly obese patients. Our finding for certain T2D-associated SNVs located in the PIKFYVE adipose super-enhancer suggests a mechanism whereby faulty PIKfyve expression in fat tissue could lead to T2D in morbid obesity.
D. Sbrissa: None. B. Seyoum: None. W. Liu: None.
Department of Defense, Peer Reviewed Medical Research Program (W81XWH-17-1-0060)