Abstract P008: Plasma Levels of Fetuin-a and Other Hepatic Enzymes as Predictors of Coronary Heart Disease Risk in US Women
Authors: Sun Qi , Jimenez Monik , Rimm Eric B , Manson JoAnn E , Albert Christine M , Rexrode Kathryn M 
Published: July 2021

Background:
Several liver-derived proteins, such as fetuin-A, alanine transaminase (ALT), and γ-glutamyltranspeptidase (GGT), have been linked to fatty liver disease, insulin resistance, dyslipidemia, and inflammation. Some studies have suggested an association with increased risk of coronary heart disease (CHD); but data thus far have been limited and inconsistent.

Methods and Results:
During 16 years of follow-up (1990-2006), we prospectively identified and confirmed 520 incident fatal or non-fatal CHD events and matched 976 controls to them in the Nurses’ Health Study. Plasma levels of fetuin-A, ALT, and GGT were measured and examined in relation to CHD risk using conditional logistic regression. Of the three markers, higher GGT levels were most strongly correlated with higher levels of blood lipids, C-reactive protein, and hemoglobin-A1c and lower levels of adiponectin. After multivariate adjustment for lifestyle and dietary risk factors for CHD, higher GGT levels, but not fetuin-A or ALT levels, were associated with increased risk of CHD (Table 1). However, further adjustment for history of chronic diseases attenuated the association of GGT with CHD: odds ratio (OR) (95% confidence interval [CI]) comparing extreme quintiles of GGT was 1.35 (0.91, 2.01; P for trend = 0.18). Corresponding ORs (95% CI) were 0.89 (0.51, 1.54; P for trend = 0.99) for fetuin-A and 0.89 (0.59, 1.35; P for trend = 0.96) for ALT. The association of GGT with CHD was abolished after further adjustment for biomarkers of dyslipidemia, inflammation, and insulin resistance that may affect GGT levels: the OR (95% CI) comparing extreme quintiles was 1.01 (0.62, 1.64; P for trend = 0.64).

Conclusion:
In this cohort of women, higher circulating GGT levels were associated with multiple cardiovascular risk factors, but GGT, ALT, and fetuin-A levels were not associated with subsequent risk of CHD after accounting for standard risk factors.

Table 1.

Relative risk (95% CI) of coronary heart disease (CHD) associated with the levels fetuin-A, ALT, and GGT, the Nurses’ Health Study

Quintiles of biomarker levels
P for trend

1 (lowest)
3
5 (highest)

Fetuin-A (μ g/mL)

Model 1
*

1.0
0.75 (0.46, 1.24)
1.07 (0.64, 1.78)
0.58

Model 2
†

1.0
0.69 (0.40, 1.17)
0.89 (0.51, 1.54)
0.99

Model 3
‡

1.0
0.60 (0.32, 1.15)
0.62 (0.31, 1.24)
0.36

ALT (IU/L)

Model 1
*

1.0
0.86 (0.57, 1.28)
0.98 (0.66, 1.44)
0.46

Model 2
†

1.0
0.87 (0.57, 1.32)
0.89 (0.59, 1.35)
0.96

Model 3
‡

1.0
0.82 (0.48, 1.39)
0.80 (0.48, 1.32)
0.49

GGT (IU/L)

Model 1
*

1.0
1.34 (0.92, 1.96)
1.65 (1.14, 2.40)
0.009

Model 2
†

1.0
1.35 (0.91, 2.01)
1.35 (0.91, 2.01)
0.18

Model 3
‡

1.0
0.84 (0.52, 1.37)
1.01 (0.62, 1.64)
0.64

*

Model 1 was adjusted for the matching factors (age, smoking status, fasting status, and time of blood drawing), body mass index, postmenopausal status, hormone use, physical activity, alcohol use, parental history of MI before age 65 years, use of aspirin, and Alternative Healthy Eating Index score.

†

Based on model 1, model 2 was further adjusted for history of hypercholesterolemia, hypertension, or diabetes.

‡

Based on model 2, model 3 was further adjusted for levels of total cholesterol, triacylglycerol, C-reactive protein, hemoglobin-A1c, and total adiponectin.