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Background   PNPLA3 I148M  variant and  TM6SF2 E167K  variant are recognized as the major genetic modifiers of nonalcoholic fatty liver disease (NAFLD). The present study sought to evaluate the potential additive effect of the two variants on the risk of NAFLD in Qingdao Han Population, China.    Methods  We genotyped  PNPLA3 I148M  variant and  TM6SF2 E167K  variant in a cohort of 512 unrelated NAFLD patients and 451 healthy controls by sequencing and polymerase chain reaction analysis. In addition, serum lipid profiles and liver enzymes were determined by standard clinical laboratory methods.    Results  The minor allele frequencies were 45.48% for  PNPLA3 148  locus G allele and 6.69% for  TM6SF2 167  locus T allele .  The  PNPLA3 I148M  variant was significantly associated with the risk of NAFLD in an additive model (CG, OR = 2.092, 95% CI: 1.551–2.820,  P  = 0.000; GG, OR = 4.566, 95% CI: 3.141–6.638,  P  = 0.000, respectively). And, our data suggested a strong link between the  TM6SF2 E167K  variant and the risk of NAFLD in a dominant model (CT + TT, OR = 2.327, 95% CI: 1.542–3.513,  P  = 0.000). In addition, the increasing of the number of risk alleles were associated with the risk of NAFLD (1 risk allele, OR = 1.687,  P  = 0.001; 2 risk alleles, OR = 4.326,  P  = 0.000; 3 risk alleles, OR = 6.018,  P  = 0.027, respectively).    Conclusions  Combining the  I148M  and  E167K  variants in a manner of an additive effect could improve risk prediction for NAFLD in a Qingdao Han Population cohort.    Trial registration  Chinese Clinical Trial  Register.gov : ChiCTR1800015426.

Combining I148M and E167K variants to improve risk prediction for nonalcoholic fatty liver disease in Qingdao Han population, China