Comparing rare variants versus common in the pathogenesis of nonalcoholic fatty liver disease: a whole exome...

Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis.

This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven nonalcoholic steatohepatitis and persistently elevated liver enzymes were included. Controls were with normal CT/MR fat fraction. DNA was isolated from whole blood, amplified (SureSelect^XT Human All Exon V5 + UTR kit) and sequenced (Illumina). Data were filtered for quality, aligned (hg19), and annotated (OpenCRAVAT). Pathogenic (Polyphen-2/SIFT/ClinVar) variants and variants reported to be associated with NAFLD based on published literature were extracted from our data and compared between patients and controls.

The mean age of controls (N = 17) and patients (N = 37) was 46.88 ± 6.94 and 37.46 ± 13.34 years, respectively. A total of 251 missense variants out of 89 286 were classified as pathogenic. Of these, 106 (42.23%) were unique to the patients and remaining (n = 145; 57.77%) were found in both patients and controls. Majority (25/37; 67.57%) patients had a minimum of one or more rare pathogenic variant(s) related to liver pathology that was not seen in the controls.

Elucidating the contribution of rare pathogenic variants would enhance our understanding of the pathogenesis. Including the rarer genes in the polygenic risk scores would enhance prediction power.