Variant PNPLA3 increases the HCC risk: prospective study in patients treated at the Saarland University Medical Center

Sir,

in the last issue of Zeitschrift für Gastroenterologie Dröge et al. presented a comprehensive overview of genetic causes and modifiers of chronic liver diseases in adults [1]. Among the genetic variants, the authors highlight the PNPLA3 (patatin-like phospholipase domain containing 3) non-synonumous polymorphism p.I148 M as a major determinant of chronic liver diseases. Indeed, this variant is associated with increased odds of developing fatty liver [2] and modulates the progression of hepatic fibrosis in chronic liver diseases [3]. As the PNPLA3 risk allele is carried by as many as 50 % of Europeans [4]) it could be demonstrated that it is directly associated with the risk of hospitalization and health-service utilization in Germany [5]. As mentioned by the authors of the review [1] and substantiated by meta-analysis [6], carriers of this variant are also at risk of developing hepatocellular carcinoma (HCC).

To further investigate this association in Germany, we performed an analysis of prospectively recruited patients who were evaluated for resection of HCC between 01/2014 and 01/2016 in our center. Overall we collected samples from 44 patients (age 68 ± 9.7 years; 76 % men; primary liver disease: alcoholic liver disease in 16 cases, chronic hepatitis C in 9 cases, cryptogenic cirrhosis in 9 cases, chronic hepatitis B in 5 cases, NAFLD in 4 cases, autoimmune hepatitis in 1 case; 12 patients without liver cirrhosis; 23 with multifocal HCC; median size of the largest nodule 56 mm with a range from 17 mm to 120 mm). Finally surgical resection was performed in a total of 19 recruited HCC patients. In all patients we genotyped the PNPLA3 p.I148 M variant using Taqman assays with fluorescent detection. The genotype and allele frequencies were compared with frequencies in individuals without any liver diseases who were scheduled for control colonoscopy. The details of the control cohort have been presented previously [7].

[Table 1] summarizes the genotyping results. Overall, we detected a major overrepresentation of the PNPLA3 p.148 M allele among patients with HCC as compared to controls (50 % vs. 22 %, respectively). In [Table 2] the case-control association tests are presented. Notably, homozygous carriers of the risk allele had a 13-times increased risk of developing HCC as compared to patients presenting with the PNPLA3 p.148II wildtype genotype. The presence of the risk allele either in homozygous or heterozygous state was associated with a 3.5-fold increased HCC risk.

Table 1 Distribution of PNPLA3 p.I148 M alleles and genotypes in HCC patients and healthy controls.

	HCC patients (2N = 88)	healthy controls (2N = 348)
counts of alleles/genotypes
[I]	50.0 % (44)	77.6 % (270)
[M]	50 % (44)	22.4 % (78)
[II]	29.5 % (13)	59.8 % (104)
[IM]	41.0 % (18)	35.6 % (62)
[MM]	29.5 % (13)	4.6 % (8)

I = isoleucine; M = methionine; P = p-value; PNPLA3 = patatin-like phospholipase domain containing 3.

Table 2 Case-control association tests in respect to the HCC risk.

	OR (95 % CI)	P
[M] ↔ [I]	3.5 (2.1 – 5.6)	2.6 × 10–7
[MM] ↔ [II]	13.0 (4.5 – 37.2)	4.2 × 10–8
[MM+IM] ↔ [II]	3.5 (1.7 – 7.2)	3.3 × 10–4

I = isoleucine; M = methionine; P = p-value; PNPLA3 = patatin-like phospholipase domain containing 3; OR = odds ratio. The association tests were performed in contingency tables (https://ihg.gsf.de/cgi-bin/hw/hwa1.pl).

Previously, comparable risks of developing HCC among carriers of the PNPLA3 p.148MM genotype were reported by Liu et al. [8] for patients in the UK. Here, we extend this observation to German patients. This ubiquitously increased HCC risk among carriers of the [MM] variant underscores the need for further functional studies that delineate the pathogenesis of HCC in these patients and pave the way for preventive strategies. Finally, given the comparable magnitude of association between HFE and PNPLA3 variants and HCC [9], we advocate inclusion of the p.I148 M polymorphism in the genetic work-up of patients admitted to hepatology departments.

List of abbreviations

HCC: hepatocellular carcinoma

I: isoleucine

M: methionine

OR: odds ratio

P: p-value

PNPLA3: patatin-like phospholipase domain containing 3.

• References

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