Key result
PNPLA3 rs738409 variant linked to ~3-fold greater NAFLD risk versus non-carriers.
Why the study?
Do genetic variants in candidate genes predict the presence and severity of NAFLD in adults?
Case-Control (n=445)
No
Do genetic variants in candidate genes predict the presence and severity of NAFLD in adults?
Odds Ratio: 3.12 (95% CI 1.8–5.5)
p-value: p=<0.001
A polygenic risk score incorporating variants in TM6SF2, GCKR, PNPLA3, and MBOAT7 is highly predictive of NAFLD susceptibility.
May inform genetic risk assessment in NAFLD; extends candidate gene studies but leaves prospective validation open.
NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001). A 4-SNPs weighted genetic risk score value >0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity.
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Costanzo et al. (2018) conducted a case-control in Non-Alcoholic Fatty Liver Disease (NAFLD) (n=445). PNPLA3 rs738409 variant vs. Non-carriers was evaluated on Presence of NAFLD (OR 3.12, 95% CI 1.8-5.5, p=<0.001). The PNPLA3 rs738409 variant was the strongest genetic predictor of NAFLD, associated with a 3.12-fold increased risk compared to non-carriers.
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