Biochemical liver tests reflect the genetic risk for fatty liver with increasing body weight but not with alcohol consumption

Background and Aims:

Liver tests are commonly used as surrogates for liver health. We aimed to examine whether liver biochemistries are related to the genetic risk for fatty liver, conferred by PNPLA3 and TM6SF2 risk alleles, in groups stratified by weight and alcohol consumption on the population level.

Method:

PNPLA3 and TM6SF2 genotypes were determined in 1809 Caucasian subjects from a colonoscopy screening program. Clinical and biochemical data were obtained by standard methods. Subjects were grouped according to BMI, alcohol consumption and genotypes.

Results:

Carriers of the PNPLA3 risk variant (OR 1.260, 1.047 – 1.518, p = 0.015) or the TM6SF2 risk variant (OR 1.531, 1.186 – 1.977, p = 0.001) had a higher risk for fatty liver compared to wild type carriers. Carriage of the PNPLA3 risk variant augmented the effects of BMI on serum GGT and ALT levels. Similarly, but to a lesser degree, carriage of the TM6SF2 risk variant increased the effects of BMI on ALT levels. Biochemical liver tests were not related to the genetic risk for fatty liver in groups stratified by alcohol consumption. Body weight and HOMA-IR are the key determinants of GGT and ALT independent of the underlying genetic risk.

Conclusion:

This study confirmed that carriers of the PNPLA3 variant and the TM6SF2 variant exhibit an increased risk for developing fatty liver. The commonly used liver biochemistries are related to the underlying genetic risk for hepatic steatosis in the obese study cohort. However, liver biochemistries do neither reflect the genetic risk in the lean nor overweight group, nor with alcohol consumption. BMI and HOMA-IR are the determinants of liver tests, however, this relationship is independent from the underlying genetic risk.