Investigator Names and Contact Information
Simin Liu (firstname.lastname@example.org)
Recently, a new peptide hormone from white adipose tissue named Asprosin was identified by Dr. Atul Chopra's laboratory at the Baylor College of Medicine 1. Most interestingly, asprosin is the C-terminal cleavage product of profibrillin which is encoded by the so-called "skinner" gene-FBN1-whose rare loss of function mutations can cause lipodystrophy and hypoglycemia in a handful of humans around the world 2. In both mice and humans, loss of function of asprosin via immunologic or genetic means apparently causes profound glucose- and insulin-lowering effects that are secondary to reduced hepatic glucose release1 via gluconeogenesis that is well-known to play a fundamental role in insulin resistance and type 2 diabetes (T2D). Therefore, this protein may be a critical target for new therapeutics to treat cardiometabolic disorders such as obesity, insulin resistance, and T2D. As such, evaluating the potential causal relation of FBN1 gene—plasma asprosin levels with risks of T2D and cardiovascular diseases (CVD) in a large prospective cohort such as the Women's Health Initiative (WHI) would have strong clinical and public health implications.
We therefore propose to conduct a case-cohort study to investigate the relation between FBN1 genotypes, plasma levels of Asprosin phenotype and incidence of T2D and CVD among ethnically diverse, postmenopausal women aged 50-79 years participating in the WHI-observational cohort (OS).
The Specific Aims of this study are:
Aim 1. To evaluate associations between asprosin and T2D risk in women and men.
Hypothesis 1. Higher plasma levels of asprosin are associated with a higher risk of developing T2D in the WHI and HPFS. This hypothesis will be examined in WHI and HPFS, respectively (Nwhi= 8,362 from 4,181 case-control pairs in the WHI and NHPFS=1,200 from 600 case-control pairs in the HPFS).
Aim 2. To examine associations between asprosin and long-term weight change and the risk of obesity in women and men.
Hypothesis 2.1. Higher plasma levels of asprosin are associated with long-term weight changes and risk of obesity among free-living women and men during 20 years of follow-up. This hypothesis will be examined among women controls (n0= 4,181) in WHI and men controls (n0=600) in HPFS.
Hypothesis 2.2. Body weight changes partially mediate the positive associations between asprosin levels and T2D risk.
Aim 3. To investigate the potential causal and mediating effects of asprosin on T2D risk.
Hypothesis 3.1. SNPs in FBN1 region are associated with plasma levels of asprosin. We will examine this hypothesis using existing genome-wide association study (GWAS) data among controls in both WHI and HPFS. We will perform both a GWAS and candidate-gene analysis to explore other genetic predictors of asprosin.
Hypothesis 3.2. If the levels of asprosin accounted for by genetic factors are associated with a higher risk of T2D, we will use the Mendelian randomization approach to establish a causal relation between asprosin levels and T2D risk. The genetic predictors of asprosin levels and T2D risk found in Aim 3.1 will be used as instrumental variables.