Abstract

Background: Genetic factors contribute to the risk and severity of NAFLD and fibrosis, however, the utility of genetic testing to stratify the risk for advanced fibrosis and cirrhosis among patients with type 2 diabetes mellitus (T2DM) remains poorly characterized.

Methods: This prospective study enrolled adults age ≥ 50 years with T2DM recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with fasting labs and detailed assessment for other causes of liver disease. Polygenic risk score (PRS) was the sum of established risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13 and dichotomized into low and high risk according to the median. Magnetic resonance elastography (MRE), vibration controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) were performed. Advanced fibrosis was defined as MRE ≥ 3.63 kPa, or VCTE ≥ 8.8 kPa if MRE was not available. Cirrhosis was defined as MRE ≥ 4.67 kPa or VCTE ≥ 15 kPa if MRE was not available.

Results: Of 382 included patients the mean age and BMI were 64.8 (± 8.4) years and 31.7 (± 6.2) kg/m², respectively. The cohort was 61.5% female, and 40.9% Hispanic. The prevalence advanced fibrosis and cirrhosis was 12.3% and 5.24%, respectively and higher PRS was associated with higher risk of cirrhosis (2.7% vs. 7.5%, P=0.037) (Fig. 1a). Evaluating PNPLA3 alone revealed that patients with CG or GG vs. CC were associated with higher risk of both advanced fibrosis (15.2% vs. 8.2%, P=0.042) and cirrhosis (7.1% vs. 2.5%, P=0.046) (Fig. 1b). The prevalence of advanced fibrosis and cirrhosis by PRS was further stratified by the Fibrosis-4 (FIB-4) index categories; < 1.3, 1.3-2.67 and > 2.67. High PRS was associated with an increased risk of advanced fibrosis among those with low FIB-4 index (FIB-4 < 1.3) (9.6% vs 2.3%, P=0.036) but was not significantly different in other FIB-4 categories.

Conclusion: Utilizing a well-phenotyped, prospective cohort of adults with T2DM we found that genetic risk amplifies the prevalence of advanced fibrosis and cirrhosis, and evaluating PNPLA3 alone stratifies patients well. Adding an assessment of genetic risk to recent recommendations to screen at risk populations, including T2DM, may add precision to identifying patients at the greatest risk of liver related morbidity and mortality and identify patients with low FIB-4 who are still at risk for liver related morbidity and mortality.