Plasticity of the Human Plasma Lipidome is Genetically Influenced and Associated with Type 2 Diabetes in Mexican American Families
Authors: Kulkarni Hemant , Meikle Peter , Mamtani Manju , Wong Gerard , Weir Jacquelyn , Barlow Christopher , Dyer Thomas , Almasy Laura , Mahaney Michael , Comuzzie Anthony , Duggirala Ravindranath , Blangero John , Curran Joanne 
Published: June 2021

Using Shannon's entropy, we quantified the plasticity of the human plasma lipidome (defined as the extent to which the lipidome departs froma homeostatic equilibrium). Our objective was to test whether a) the plasticity is genetically influenced and b) whether it is associated with the presence of type 2 diabetes (T2D) in the high‐risk population of Mexican Americans. We used data from 1,212 pedigreed individuals (representing 40 large and extended families) recruited in the San Antonio Family Heart Study. The plasma lipidome (318 lipid species, 22 classes) was measured using a combination of high‐performance liquid chromatography and mass spectrometry. Using SOLAR software package and accounting for the kinship structure, we made three interesting observations:

Lipid class
Mean Entropy
SD Entropy
h2r
p(h2r)
ß (T2D)
p(T2D)

Dihydroceramide
2.34
0.09
0.28
1.87x10‐11
0.03
0.6033

Ceramide
1.96
0.11
0.41
1.98x10‐21
0.09
0.0972

Monohexosylceramide
2.12
0.05
0.32
3.27x10‐10
0.07
0.2094

Dihexosylceramide
1.43
0.13
0.42
9.95x10‐16
0.28
9.93x10‐7

Trihexosylceramide
1.96
0.10
0.42
1.21x10‐18
0.08
0.1638

GM3 ganglioside
2.45
0.04
0.35
3.13x10‐12
0.09
0.0948

Sphingomyelin
1.48
0.11
0.53
8.89x10‐31
0.06
0.3286

Phosphatidylcholine
3.64
0.12
0.60
2.60x10‐30
‐0.01
0.8930

Alkylphosphatidylcholine
2.83
0.11
0.43
1.26x10‐18
0.16
0.0041

Alkenylphosphatidylcholine
1.83
0.17
0.45
4.91x10‐27
0.23
3.76x10‐5

Lysophosphatidylcholine
3.44
0.17
0.31
6.82x10‐10
‐0.17
0.0053

Lysoalkylphosphaidylcholine
1.88
0.11
0.18
0.0001
0.02
0.7757

Phosphatidylethanolamine
2.02
0.09
0.36
2.62x10‐12
‐0.06
0.2637

Alkylphosphatidylethanolamine
2.98
0.14
0.15
0.0001
‐0.26
1.88x10‐6

Alkenylphosphatidylethanolamine
2.58
0.09
0.35
6.3x10‐15
0.07
0.2354

Lysophosphatidylethanolamine
1.73
0.10
0.27
7.11x10‐8
‐0.17
0.0018

Phosphatidylinositol
3.60
0.12
0.41
1.41x10‐16
‐0.06
0.2700

Phosphatidylserine
1.97
0.28
0.42
3.10x10‐16
‐0.28
4.95x10‐6

Phosphatidylglycerol
1.59
0.10
0.32
1.49x10‐9
0.02
0.6771

Cholesteryl ester
2.94
0.16
0.19
1.78x10‐5
‐0.07
0.1684

Diacylglycerol
2.74
0.11
0.37
2.04x10‐15
0.11
0.0356

Triacylglycerol
3.76
0.27
0.14
0.0008
0.16
0.0037

Overall
4.83
0.13
0.17
0.0002
‐0.06
0.2563

I) The class‐specific entropy varied widely across classes. II) All entropies were significantly heritable ranging from 0.14 (for triacylglycerols) to 0.60 (for phosphatidylcholines). III) High entropy of the five lipid classes was significantly and independently associated with T2D even after correcting for multiple testing. Our results demonstrate a strong genetic influence on the plasticity of the plasma lipidome and provide novel mechanistic insights by implicating the plasticity of five lipid classes in the pathogenesis of T2D. This work was supported in part by NIH grants, AT&T Foundation and facilities supported by NIH grants.