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The development of fibrosis in nonalcoholic fatty liver disease (NAFLD) is influenced by genetics, sex, and menopausal status, but whether genetic susceptibility to fibrosis is influenced by sex and reproductive status is unclear. Our aim was to identify metabolism‐related single nucleotide polymorphisms (SNPs), whose effect on NAFLD fibrosis is significantly modified by sex and menopausal status. We performed a cross‐sectional, proof‐of‐concept study of 616 patients in the Duke NAFLD Clinical Database and Biorepository. The primary outcome was nonalcoholic steatohepatitis–Clinical Research Network (NASH–CRN) fibrosis stage. Menopause status was self‐reported; age 51 years was used as a surrogate for menopause in patients with missing menopause data. The Metabochip was used to obtain 98,359 SNP genotypes in known metabolic pathway genes for each patient. We used additive genetic models to characterize sex and menopause‐specific effects of SNP genotypes on NAFLD fibrosis stage. In the main effects analysis, none of the SNPs were associated with fibrosis at  P  < 0.05 after correcting for multiple comparisons. Twenty‐five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction  P  < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes:  KCNIP4  (potassium voltage‐gated channel interacting protein 4),  PSORS1C1  (psoriasis susceptibility 1 candidate 1),  KLHL8  (Kelch‐like family member 8),  GLRA1  (glycine receptor alpha 1),  NOTCH2  (notch receptor 2), and  PRKCH  (protein kinase C eta), and four SNPs were intergenic. In stratified models, four SNPs were significant in premenopausal and postmenopausal women, three only in postmenopausal women, two in men and postmenopausal women, and one only in premenopausal women.  Conclusion:  We identified 10 loci with a significant sex/menopause interaction with respect to fibrosis. None of these SNPs were significant in all sex/menopause groups, suggesting modulation of genetic susceptibility to fibrosis by sex and menopause status. Future studies of genetic predictors of NAFLD progression should account for sex and menopause.

Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD