Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Krawczyk, Marcin; Rau, Monika; Schattenberg, Jörn M.; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Böettler, Tobias; Lammert, Frank; Geier, Andreas

doi:10.1194/jlr.p067454

Cited by 182 publications

(193 citation statements)

References 25 publications

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“…33 Thus, lifestyle interventions for patients with the inherently increased risk of a poorer prognosis would be advantageous. 36 34, 35 We did not find differences in CAP values based on the TM6SF2 and MBOAT7 genotypes; however, a trend for higher CAP was observed based on the presence of risk alleles.…”

Section: Discussioncontrasting

confidence: 57%

Hepatic steatosis in patients with acromegaly

Koutsou‐Tassopoulou

Papapostoli‐Sklavounou

Krawczyk

et al. 2019

Endocrino Diabet & Metabol

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Objective Comorbid NAFLD is increasingly being diagnosed in patients with diabetes and nondiabetic endocrinopathies. The aim of this study was to assess hepatic steatosis noninvasively by transient elastography in patients with acromegaly. Design A cross‐sectional study including 22 patients with acromegaly. Methods Hepatic steatosis was quantified using controlled attenuation parameter (CAP) during elastography. Anthropometric measurements were obtained, serum liver function tests and lipid and hormone profiles were measured, and prosteatogenic gene variants were genotyped using standard assays. Results In total, 41% of patients were women (mean age 60 ± 14.7 years, mean BMI 31.2 ± 4.6 kg/m2). Hepatic steatosis, as defined by CAP > 248 dB/m, was present in 66% of patients. Five (45%) of the patients with hepatic steatosis also had fibrosis, and one presented with cirrhosis. Nine patients were carriers of the PNPLA3 p.I148M prosteatogenic [M] risk allele, eight of whom were heterozygotes. CAP values were significantly (P = .045) higher in these patients and corresponded to advanced steatosis, as compared to patients with the wild‐type genotype, who demonstrated CAP values consistent with mild steatosis (311 ± 33 dB/m. vs 254 ± 62 dB/m). CAP values did not differ significantly in carriers of distinct TM6SF2 and MBOAT7 genotypes; however, carriers of the risk alleles displayed higher CAP as compared to wild‐type patients. Conclusions This study shows that in patients with acromegaly, carriers of the PNPLA3 susceptibility allele are at risk of developing hepatic steatosis, as assessed by CAP. Comorbid NAFLD might compound prognosis in such patients; thus, further research into the pathomechanisms and treatment of NAFLD in acromegaly is warranted.

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Section: Discussioncontrasting

confidence: 57%

Hepatic steatosis in patients with acromegaly

Koutsou‐Tassopoulou

Papapostoli‐Sklavounou

Krawczyk

et al. 2019

Endocrino Diabet & Metabol

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“…Recently, Krawczyk et al . reported the combined effects of both variants on liver enzymes, but not the histological severity, in biopsy‐confirmed NAFLD subjects …”

Section: Discussionmentioning

confidence: 98%

Additive effects of PNPLA3 and TM6SF2 on the histological severity of non‐alcoholic fatty liver disease

Koo

Joo

Kim

et al. 2018

J of Gastro and Hepatol

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“…Studies of genetic regions like PNPLA3 , SAMM50 and PARVB support this idea, since variants in these genes have been associated with NAFLD and elevated ALT and AST levels (Flores et al, 2016; Kitamoto et al, 2013; Ravi Kanth et al, 2014). Krawczyk et al found that the combined effect of several SNPs was linked to the presence of elevated ALT levels, as well as NAFLD severity (Krawczyk et al, 2017). The SNPs included in the PRS we created are likely associated with higher levels of ALT/AST and fatty liver through different mechanisms, which account for the complexity of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in COL13A1, ADIPOQ and SAMM50 , in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population

Larrieta‐Carrasco

Flores

Macías-Kauffer

et al. 2018

Experimental and Molecular Pathology

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Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥40 IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9–12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1–4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis.

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Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Cited by 182 publications

References 25 publications

Hepatic steatosis in patients with acromegaly

Hepatic steatosis in patients with acromegaly

Additive effects of PNPLA3 and TM6SF2 on the histological severity of non‐alcoholic fatty liver disease

Genetic variants in COL13A1, ADIPOQ and SAMM50 , in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population

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