PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease

doi:10.3748/wjg.v27.i25.3863

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World J Gastroenterol. Jul 7, 2021; 27(25): 3863-3876
Published online Jul 7, 2021. doi: 10.3748/wjg.v27.i25.3863

Table 1 Clinical characteristics of patients with nonalcoholic fatty liver disease and controls

Variables	NAFLD (n = 59)	Controls (n = 93)	P value
Sex (M/F)	43/16	59/34	0.227
Age (year)	38.20 ± 13.78	42.20 ± 11.05	0.039
BMI (kg/m²)	27.31 ± 3.31	23.06 ± 2.74	< 0.0001
ALT (U/L)	70.56 ± 47.6	24.98 ± 16.07	< 0.0001
GGT (U/L)	72.75 ± 55.22	25.94 ± 18.17	< 0.0001
ALP (U/L)	97.07 ± 44.73	96.50 ± 32.54	0.347
TC (mmol/L)	4.86 ± 0.86	4.39 ± 0.89	0.001
TG (mmol/L)	1.99 ± 1.25	1.14 ± 0.74	< 0.0001
HDL-C (mmol/L)	1.20 ± 0.28	1.23 ± 0.28	0.177
LDL-C (mmol/L)	2.83 ± 0.7	2.24 ± 0.50	< 0.0001
FBG (mmol/L)	5.93 ± 2.62	5.31 ± 0.79	0.941
UA (μmol/L)	361.32 ± 105.78	274.25 ± 76.53	< 0.0001
CAP (dB/m)	313 (277-351)	212 (172-232)	< 0.0001
LSM (kPa)	7.7 (5.6-12)	5.25 (4.1-7.0)	< 0.0001
Hypertension, n (%)	22 (37.29%)	15 (16.13%)	0.003
T2DM, n (%)	7 (11.86%)	1 (1.08%)	0.005
Obesity, n (%)	41 (69.49%)	19 (20.43%)	< 0.0001
Steatosis (S, n)
S1/S2/S3	25/25/9	/	/
Activity (A, n)
A0/A1/A2/A3/A4	1/12/16/22/8	/	/
Fibrosis (F, n)
F0/F1/F2/F3/F4	11/29/8/7/4	/	/

The data are expressed as mean ± SD, or as n (%) for normally distributed variables and as median (interquartile range) when distribution of the variable was skewed. NAFLD: Nonalcoholic fatty liver disease; BMI: Body mass index; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; TC: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; FBG: Fasting blood glucose; UA: Uric acid; LSM: Liver stiffness measurement; CAP: Controlled attenuation parameter; T2DM: Type 2 diabetes mellitus.

Table 2 Clinical characteristics of patients with nonalcoholic steatohepatitis and nonalcoholic fatty liver among patients with nonalcoholic fatty liver disease

Variable	NAFL (n = 22)	NASH (n = 37)	P value
Sex (M/F)	17/5	26/11	0.559
Age (year)	37.23 ± 13.64	38.78 ± 14.01	0.605
BMI (kg/m²)	27.07 ± 3.69	27.38 ± 3.17	0.675
ALP (U/L)	102.96 ± 52.34	93.56 ± 39.91	0.982
GGT (U/L)	38.00 (23.80-69.03)	69.70 (39.00-85.50)	0.023
ALT (U/L)	46.00 (30.33-64.95)	71.40 (46.9-111.70)	0.006
TC (mmol/L)	5.03 ± 1.04	4.76 ± 0.72	0.801
TG (mmol/L)	1.91 ± 0.74	2.04 ± 1.48	0.532
HDL-C (mmol/L)	1.21 ± 0.28	1.19 ± 0.28	0.903
LDL-C (mmol/L)	2.97 ± 0.91	2.72 ± 0.49	0.444
FBG (mmol/L)	6.43 ± 3.59	5.62 ± 1.77	0.318
UA (μmol/L)	360.91 ± 107.80	361.62 ± 106.22	0.482
CAP (dB/m)	295.50 (249.25-345.00)	333.00 (296.25-356.25)	0.038
LSM (kPa)	6.20 (4.55-9.95)	9.60 (6.50-12.85)	0.008
Obesity, n (%)	16 (72.73)	25 (60.97)	0.677
Hypertension, n (%)	8 (36.36)	14 (37.84)	0.910
T2DM, n (%)	3 (13.64)	4 (10.81)	0.746

The data are expressed as mean ± SD, or as n (%) for normally distributed variables and as median (interquartile range) when distribution of the variable was skewed. NAFL: Nonalcoholic fatty liver; NASH: Nonalcoholic steatohepatitis; BMI: Body mass index; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; ALT: Alanine aminotransferase; TC: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; FBG: Fasting blood glucose; UA: Uric acid; LSM: Liver stiffness measurement; CAP: Controlled attenuation parameter; T2DM: Type 2 diabetes mellitus.

Table 3 Genotype distribution of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3 rs738409 in patients with nonalcoholic fatty liver disease and controls

Genotype	NAFLD (n = 59)	Controls (n = 93)	χ²	P value	OR (95%CI)
PPARGC1A rs8192678
GG	14 (23.73%)	39 (41.94%)
GA	37 (62.71%)	37 (39.78%)	7.148	0.008	2.786 (1.300-5.962)
AA	8 (13.56%)	17 (18.28%)	0.262	0.609	1.311 (0.464-3.704)
GA+AA	45 (76.27%)	54 (58.06%)	5.269	0.022	2.321 (1.121-4.806)
PNPLA3 rs738409
CC	12 (20.34%)	35 (37.63%)
CG	27 (45.76%)	43 (46.24%)	2.152	0.142	1.831 (0.812-4.131)
GG	20 (33.90%)	15 (16.13%)	8.423	0.004	3.889 (1.524-9.926)
CG + GG	47 (79.56%)	58 (62.37%)	5.055	0.025	2.364 (1.105-5.055)

OR: Odds ratio; CI: Confidence interval; PNPLA3: Patatin-like phospholipase domain-containing protein 3; NAFLD: Nonalcoholic fatty liver disease.

Table 4 Association tests of PPARGC1A rs8192678 polymorphism between different groups

PPARGC1A rs8192678	Case			Control			Dominant model
PPARGC1A rs8192678	GG	GA	AA	GG	GA	AA	χ²	P value	OR (95%CI)
NAFLD vs Control	14	37	8	39	37	17	5.269	0.022	2.321 (1.121-4.806)
NASH vs Control	5	28	4	39	37	17	9.550	0.002	4.622 (1.653-12.929)
NASH vs NAFL	5	28	4	9	9	4	5.721	0.017	4.431 (1.245-15.763)
Obese vs nonobese participants	17	33	10	36	41	15	1.864	0.172	1.626 (0.807-3.276)
Obese NAFLD vs nonobese NAFLD	9	27	5	5	10	3	0.235	0.628	1.368 (0.384-4.865)
Obese NASH vs nonobese NASH	4	19	2	1	9	2	0.408	0.348	0.477 (0.047-4.806)
Obese NAFL vs nonobese NAFL	5	8	3	4	1	1	2.264	0.132	4.400 (0.596-32.501)
Obese NASH vs obese NAFL	4	19	2	5	8	3	1.324	0.250	2.386 (0.531-10.734)
Nonobese NASH vs nonobese NAFL	1	9	2	4	1	1	6.785	0.021	22.000 (1.540-314.292)

NAFL: Nonalcoholic fatty liver; NASH: Nonalcoholic steatohepatitis; NAFLD: Nonalcoholic fatty liver disease; OR: Odds ratio; CI: Confidence interval.

Table 5 Multiple logistic regression analysis of predictive factors for nonalcoholic fatty liver disease

Variables	B	S.E.	Wald	OR (95%CI)	P value
Age (year)	-0.031	0.015	4.236	0.970 (0.942-0.999)	0.040
Sex (Male)	-0.233	0.385	0.365	0.793 (0.373-1.686)	0.546
PPARGC1A rs8192678 A allele	0.789	0.388	4.148	2.202 (1.030-4.705)	0.042
PNPLA3 rs738409 G allele	0.857	0.403	4.524	2.356 (1.070-5.191)	0.033

OR: Odds ratio; CI: Confidence interval; PNPLA3: Patatin-like phospholipase domain-containing protein 3.

Table 6 Association of the PPARGC1A genotypes with steatosis, activity, and fibrosis in patients with nonalcoholic fatty liver disease

Histological features		Genotypes		Dominant model		Multivariate analysis¹
Histological features		GG (n = 14)	GA + AA (n = 45)	P value	OR (95%CI)	P value	OR (95%CI)
Steatosis (S)	S1	10 (71.43%)	15 (33.33%)
Steatosis (S)	S2-3	4 (28.57%)	30 (66.67%)	0.012	5.000 (1.343-18.620)	0.011	6.190 (1.508-25.410)
Activity (A)	A < 2	6 (42.86%)	7 (15.56%)
Activity (A)	A ≥ 2	8 (57.14%)	38 (84.44%)	0.031	4.071 (1.076-15.402)	0.040	4.506 (1.070-18.978)
Significant fibrosis	F0-1	12 (85.71%)	28 (62.22%)
Significant fibrosis	F2-4	2 (14.29%)	17 (37.78%)	0.100	3.643 (0.726-18.292)	0.186	3.449 (0.551-21.598)
Advanced fibrosis	F0-2	13 (92.86%)	35 (77.78%)
Advanced fibrosis	F3-4	1 (7.14%)	10 (22.22%)	0.206	3.714 (0.432-31.949)	0.426	2.549 (0.255-25.490)
NASH	NAFL	9 (64.28%)	13 (28.89%)
NASH	NASH	5 (35.71%)	32 (71.11%)	0.017	4.431 (1.245-15.763)	0.035	6.337 (1.135-35.392)

¹Multivariate analysis adjusted for age, sex, body mass index, and patatin-like phospholipase domain-containing protein 3 rs738409 risk G allele. NAFL: Nonalcoholic fatty liver; NASH: Nonalcoholic steatohepatitis; OR: Odds ratio; CI: Confidence interval.

Table 7 Biochemical and genetic characteristics of patients with nonobese nonalcoholic fatty liver disease

Variables	NAFL (n = 6)	NASH (n = 12)	P value
Sex (M/F)	4/2	10/2	0.569
Age (year)	35.33 ± 18.44	39.67 ± 4.80	0.452
BMI (kg/m²)	22.83 ± 1.61	23.69 ± 0.90	0.122
ALP (U/L)	123.32 ± 77.62	84.25 ± 23.28	0.426
GGT (U/L)	28.50 (21.18-85.00)	73.25 (54.75-99.25)	0.068
ALT (U/L)	42.00 (21.78-78.50)	71.15 (41.10-115.25)	0.325
TC (mmol/L)	5.11 ± 0.55	4.96 ± 1.02	0.606
TG (mmol/L)	2.00 ± 0.43	1.77 ± 0.95	0.371
HDL-C (mmol/L)	1.10 ± 0.16	1.24 ± 0.44	0.943
LDL-C (mmol/L)	3.16 ± 0.46	2.82 ± 0.80	0.524
FBG (mmol/L)	5.03 ± 0.94	5.24 ± 0.85	0.587
UA (μmol/L)	360.86 ± 167.34	354.17 ± 67.43	0.684
CAP (dB/m)	257.00 ± 57.03	316.73 ± 43.48	0.056
LSM (kPa)	6.95 ± 4.07	6.79 ± 2.06	0.421
PPARGC1A rs8162678
GG, n (%)	4 (66.67)	1 (8.33)
GA + AA, n (%)	2 (33.33)	11 (91.67)	0.021
PNPLA3 rs738409
CC, n (%)	2 (33.33)	1 (8.33)
CG + GG, n (%)	4 (66.67)	11 (91.67)	0.245

The data are expressed as mean ± SD, or as n (%) for normally distributed variables and as median (interquartile range) when distribution of the variable was skewed. NAFL: Nonalcoholic fatty liver; NASH: Nonalcoholic steatohepatitis; BMI: Body mass index; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; TC: Total cholesterol; TG: Total triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; FBG: Fasting blood glucose; UA: Uric acid; LSM: Liver stiffness measurement; CAP: Controlled attenuation parameter; PNPLA3: Patatin-like phospholipase domain-containing protein 3.

Citation: Zhang RN, Shen F, Pan Q, Cao HX, Chen GY, Fan JG. PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease . World J Gastroenterol 2021; 27(25): 3863-3876
URL: https://www.wjgnet.com/1007-9327/full/v27/i25/3863.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i25.3863