The HSD17B13:TA (rs72613567) splice variant protects against severity of non-alcoholic fatty liver disease but not fibrosis

Background and Aims:

Recently, the splice variant rs72613567:TA in the 17β-hydroxysteroid dehydrogenase 13(HSD17B13) gene has been shown to be associated with a reduced risk for alcoholic liver disease, non-alcoholic liver disease (NAFLD)and of progression from steatosis to steatohepatitis. Aim of our study was to investigate the effects of rs72613567:TA carriage in a well-defined group of patients with biopsy-proven NAFLD.

Methods:

Patients with NAFLD in a prospective registry study who underwent liver biopsy were genotyped for the HSD17B13-(minor allele: TA) and the PNPLA3-gene (minor allele: G). Furthermore, standard laboratory tests were measured. The NAFLD-activity score (NAS)was used to grade all liver biopsy samples.

Results:

239 patients with biopsy proven NAFLD were included in the study: Age 49 ± 13, 143 male (59.8%), BMI 33 (Median; range 28 – 41), NAS: ≤4: 124 (51.9%); 5 – 8: 115 (48.1%); fibrosis: F0 – 2: 180 (75.3%); F3 – 4: 59 (24.7%). 78 (32.6%) patients underwent bariatric surgery. 81 (33.9%) patients were rs72613567:TA heterozygotes and 17 (7.1%)homozygotes (overall allele frequency: 24.1%). NAS scores ≥5 in TA-allele carriers were less frequent than in T/T carriers (T/T: 77 [54.6%] vs. all TA carriers: 38 [38.8%], p = 0.016; vs. TA/T: 32 [39.5%] or TA/TA 6 [35.3%], p = 0.039). In PNPLA3 G-allele carriers NAS scores ≥5 were significantly more frequent than in C/C carriers (C/C 42 [36.8%] vs. C/G 47 [54.7%] vs. G/G 26 [66.7%], p = 0.002]. The protective effect of the TA-allele was only observed in PNPLA3 C/C homozygotes (NAS≥5: TA-carriers 11 [23.4%] vs. T/T 31 [46.3%], p = 0.013) but not G-allele carriers (NAS≥5: TA-carriers 27 [52.9%] vs. T/T 46 [62.2%], p = 0.304). rs72613567 was not associated with more advanced fibrosis (F≥3/4: TA-carriers 23 [23.7%] vs. T/T 36 [25.5%], p = 0.749). In a multivariate regression analysis (Table 1) harboring at least one TA-allele was associated with a reduced risk for NAS≥5 independent of PNPLA3 G-allele carriage, serum triglyceride-levels and fibrosis-stage. Diabetes mellitus and older age were independent markers of advanced fibrosis (F3/4).

Table 1:

Uni-and multivariate binary regression analysis of factors associated with NAS ≥5.

	Univariate			Multivariate
	HR	95%CI	p-value	HR	95%CI	p-value
Age	0.992	0.97 – 1.01	0.397
Sex	0.822	0.49 – 1.38	0.459
BMI	0.983	0.95 – 1.01	0.280
HSD17B13 T/T vs. TA	0.526	0.31 – 0.89	0.016	0.43	0.24 – 0.76	0.004
PNPLA3 C/C vs. C/G G/G	2.06 3.43	1.17 – 3.65 1.59 – 7.38	0.013 0.002	2.23 4.13	1.20 – 4.15 1.78 – 9.58	0.011 0.001
Fibrosis. Per Grade (0 – 4)	1.39	1.11 – 1.74	0.004	1.35	1.06 – 1.71	0.015
Diabetes	1.34	0.76 – 2.36	0.302
Arterial Hypertension	1.53	0.89 – 2.62	0.127
Total Cholesterol	0.999	0.993 – 1.004	0.640
Triglycerides	1.004	1.001 – 1.007	0.011	1.006	1.002 – 1.009	0.001

Conclusion:

In biopsy proven NAFLD patients the loss-of-function rs72613567 T>TA variant in the HSD17B13-gene is associated with significantly less severe fatty liver disease, irrespective of PNPLA3 genotype and metabolic risk factors.