Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

doi:10.4254/wjh.v16.i3.366

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World J Hepatol. Mar 27, 2024; 16(3): 366-378
Published online Mar 27, 2024. doi: 10.4254/wjh.v16.i3.366

Table 1 Baseline characteristics of metabolic-associated fatty liver disease patients and controls

Characteristics	PLWH and MAFLD (n = 83)	PLWH and non-MAFLD (n = 94)	P value	MAFLD (n = 145)	P value	Chinese Dai (n = 93)	P value
Age (yr)	51.99 ± 7.65	49.55 ± 8.27	0.044^a	65.00	< 0.001^b	N/A	N/A
Gender
Male	54 (65.10)	48 (51.10%)	0.060	68 (46.90%)	0.008^b	44 (47.30%)	0.950
Female	48 (34.90%)	46 (48.90%)		77 (53.10%)		49 (52.70%)
BMI (kg/m²)	25.42	21.79	< 0.001^a	27.67	< 0.001^b	N/A	-
CD4 (cells/mm³)	619.00	570.50	0.033^a	N/A	-	N/A	-
%CD 4	26.10 ± 0.83	25.76 ± 0.81	0.853	N/A	-	N/A	-
Hb (g/dL)	14.36 1.62	13.84 1.90	0.015^a	N/A		N/A
Platelets (-/mm³)	259063 77332	261694 66966	0.744	N/A		N/A
AP (U/L)	85.00	86.00	0.821	72.00	0.001^b	N/A	-
AST (U/L)	33.00	28.00	< 0.001^a	38.00	0.015^b	N/A	-
ALT (U/L)	38.00	25.00	< 0.001^a	50.00	0.004^b	N/A	-
GGT (U/L)	47.00	35.50	< 0.001^a	51.50	0.853	N/A	-
Total protein (g/L)	79.60 ± 0.56	78.28 ± 0.47	0.071	75.96 ± 0.42	< 0.001^b	N/A	-
Albumin (g/L)	40.80	38.35	< 0.001^a	40.65	0.255	N/A	-
Total bilirubin (mg/dL)	0.60	0.50	0.759	0.70	0.10	N/A	-
Direct bilirubin (mg/dL)	0.20	0.20	0.862	0.30	0.007^b	N/A	-
HbA1C (mmol/L)	5.68	5.38	< 0.001^a	6.36	< 0.001^b	N/A	-
Fasting plasma Glucose (mg/dL)	98	93	0.026	108	< 0.001^b	N/A	-
Triglyceride (mg/dL)	169	109	< 0.001^a	123	< 0.0001^b	N/A	-
Total Cholesterol (mg/dL)	206.78 ± 5.57	199.10 ± 3.57	0.212	183	0.428	N/A	-
HDL (mg/dL)	44	49	0.004^a	49	0.10	N/A	-
LDL (mg/dL)	130.67 ± 4.27	122.46 ± 2.98	0.086	114.94 ± 2.83	0.001^b	N/A	-
Drug-regimen, n (%)
NRTI+NNRTI	62 (74.7)	71 (75.5)	0.573	N/A	-	N/A	-
NRTI+PI	19 (22.9)	18 (19.1)		N/A	-	N/A	-
Alternative	2 (2.4)	5 (5.3)		N/A	-	N/A	-
Co-morbidities
Dyslipidemia	30 (36.1)	15 (16.0)	0.002^a	82 (56.9)	0.002^b	N/A	-
Hypertension	21 (25.3)	6 (6.4)	0.001^a	64 (44.1)	0.003^b	N/A	-
Diabetes mellitus	16 (19.3)	5 (5.3)	0.005^a	63 (43.4)	< 0.001^b	N/A	-

^aP value < 0.05 compared between people living with human immunodeficiency virus (PLWH) and metabolic-associated fatty liver disease (MAFLD) vs PLWH and non-MAFLD.

^bP value < 0.05 compared between PLWH and MAFLD vs MAFLD.

Data represent as mode, mean ± standard deviation or n (%), differences between groups were tested by Chi-square test or one-way ANOVA as appropriate. AP: Alkaline phosphatase; AST: Aspartate aminotransaminase; ALT: Alanine aminotransaminase; ALP: Alkaline phosphatase; Hb: Henoglobin; TB: Total bilirubin; MAFLD: Metabolic-associated fatty liver disease; N/A: Not available; PLWH: People living with human immunodeficiency virus; GGT: Gamma-glutamyl transferase; HbA1C: Hemoglobin A1C; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; NRTI: Nucleoside reverse transcriptase inhibitor; NNRTI: Non-nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor.

Table 2 Genotype distributions and Minor allele frequency of candidates single-nucleotide polymorphisms

Polymorphism	PLWH and MAFLD (n = 83)	PLWH and non-MAFLD (n = 94)	P value	MAFLD (n = 145)	Chinese Dai (n = 94)	P value
PNPLA3 rs738409
MAF = G	57 (34.33)	56 (29.78)	0.413	92 (31.73)	43 (23.12)	0.035^a
APOC3 rs2854116
MAF=T	81 (47.09)	87(46.28)	0.691	128 (44.14)	88 (47.31)	< 0.001^b
LEP rs7799039
MAF=G	57 (33.14)	57 (30.32)	0.738	85 (29.31)	48 (25.81)	0.674
GHRL rs27647
MAF = C	13 (7.56)	25 (13.30)	0.055	28 (9.66)	18 (9.68)	0.702
LIPC rs1800588
MAF = T	70 (42.17)	70 (37.33)	0.421	101 (34.83)	67 (36.02)	0.872
APOB rs10495712
MAF = A	15 (8.06)	14 (7.45)	0.853	22 (7.59)	8 (4.30)	0.339
APOA5 rs662799
MAF = G	41 (22.04)	51 (27.13)	0.766	75 (25.86)	52 (27.96)	0.834

^aP value < 0.05 compared between people living with human immunodeficiency virus (PLWH) and metabolic-associated fatty liver disease (MAFLD) vs PLWH and non-MAFLD.

^bP value < 0.05 compared between PLWH and MAFLD vs MAFLD MAF minor allele frequency, Chinese Dai was represented as general population. Data represented as n (%), PLWH and MAFLD vs other groups, differences between groups were tested by Chi-square test. MAFLD: Metabolic-associated fatty liver disease; PLWH: People living with human immunodeficiency virus; MAF: Metabolic-associated fatty.

Table 3 Genotype and allele frequencies of the single-nucleotide polymorphisms in the people living with human immunodeficiency virus and metabolic-associated fatty liver disease compared with people living with human immunodeficiency virus and non-metabolic-associated fatty liver disease group

Gene	SNP	B allele	Dominant model				Recessive model
			PLWH and MAFLD vs PLWH and non-MAFLD		PLWH and MAFLD vs Chinese Dai		PLWH and MAFLD vs PLWH and non-MAFLD		PLWH and MAFLD vs Chinese Dai
			OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
PNPLA3	rs738409	G	1.476 (0.809-2.694)	0.204	2.539 (1.382-4.665)	0.002^b	0.94 (0.276-3.202)	0.921	0.929 (0.273-3.166)	0.907
APOC3	rs2854116	C	1.117 (0.543-2.297)	0.764	1.203 (0.588-2.462)	0.613	0.798 (0.411-1.550)	0.506	0.828 (0.425-1.614)	0.579
LEP	rs7799039	G	0.704 (0.287-1.727)	0.422	0.408 (0.146-1.142)	0.080	0.886 (0.491-1.601)	0.689	0.730 (0.403-1.322)	0.298
GHRL	rs27647	G	0.466 (0.217-1.001)	0.047^a	0.704 (0.317-1.566)	0.388	2.146 (1.832-2.514)	0.469	2.134 (1.823-2.499)	0.472
LIPC	rs1800588	T	1.506 (0.806-2.815)	0.198	1.676 (0.898-3.128)	0.104	1.053 0.452-2.456)	0.905	1.040 (0.446-2.427)	0.928
APOB	rs10495712	A	1.264 (0.557-2.871)	0.575	2.156 (0.855-5.436)	0.098	1.134 (0.070-18.422)	1.000	2.134 (1.823-2.499)	0.472
APOA5	rs662799	G	0.914 (0.505-1.654)	0.766	0.960 (0.330-2.790)	0.940	0.629 (0.177-2.231)	0.470	0.734 (0.200-2.697)	0.751

Data expressed as OR odds ratio, CI confidence interval.

^aP value < 0.05 compared between people living with human immunodeficiency virus (PLWH) and metabolic-associated fatty liver disease (MAFLD) vs PLWH and non-MAFLD.

^bP value < 0.05 compared between PLWH and MAFLD vs Chinese Dai was represented as general population, B-allele expressed risk allele. MAFLD: Metabolic-associated fatty liver disease; PLWH: People living with human immunodeficiency virus; SNP: Single-nucleotide polymorphism.

Table 4 Genotype and allele frequencies of the single-nucleotide polymorphisms in the metabolic-associated fatty liver disease compared with Chinese Dai

Gene	SNP	B allele	Dominate model		Recessive model
Gene	SNP	B allele	OR (95%CI)	P value	OR (95%CI)	P value
PNPLA3	rs738409	G	1.970 (1.160-3.345)	0.012^a	1.074 (0.377-3.061)	0.894
APOC3	rs2854116	C	6.109 (2.490-14.986)	< 0.001^a	0.485 (0.259-0.907)	0.022^b
LEP	rs7799039	G	0.840 (0.300-2.355)	0.740	0.790 (0.469-1.332)	0.376
GHRL	rs27647	G	0.953 (0.491-1.850)	0.888	1.646 (1.486-1.823)	1.000
LIPC	rs1800588	T	0.889 (0.525-1.504)	0.661	1.042 (0.494-2.199)	0.914
APOB	rs10495712	A	1.799 (0.762-4.251)	0.176	1.642 (1.486-1.823)	1.000
APOA5	rs662799	G	0.854 (0.507-1.438)	0.552	0.960 (0.330-2.790)	0.940

^aP value < 0.05 compared between metabolic-associated fatty liver disease (MAFLD) vs Chinese Dai in dominant model.

^bP value < 0.05 compared between MAFLD vs Chinese Dai in recessive model, B-allele expressed risk allele. Data expressed as n (%). MAFLD: Metabolic-associated fatty liver disease; PLWH: People living with human immunodeficiency virus; SNP: Single-nucleotide polymorphism; OR: Odds ratio.

Table 5 Association between genetic polymorphism and Lipid profile

Genetic polymorphisms	Lipid parameters
Genetic polymorphisms	Triglyceride (mg/dL), (n = 177)		Total cholesterol (mg/dL), (n = 177)		LDL-cholesterol (mg/dL), (n = 177)		HDL-cholesterol (mg/dL), (n = 66)	HDL-cholesterol (mg/dL), (n = 111)
	< 150	≥ 150	< 200	≥ 200	< 130	≥ 130	Men ≥ 40 mg/dL, women ≥ 50 mg/dL	Men < 40 mg/dL, women < 50 mg/dL
PNPLA3 rs738409 CC vs CG+GG
OR (95%CI)	0.699 (0.383-1.277)		1.053 (0.580-1.912)		1.088 (0.597-1.981)		0.9967 (0.538 -1.846)
P value	0.243		0.865		0.784		0.992
APOC3 rs2854116 TT vs CT+CC
OR (95%CI)	0.796 (0.387-1.635)		1.611 (0.780-3.328)		1.173 (0.568-2.423)		0.4696 (0.253-0.873)
P value	0.534		0.195		0.666		0.017^a
APOA5 rs662799 AA vs AG+GG
OR (95%CI)	1.021 (0.562-1.855)		0.543 (0.299-0.989)		0.595 (0.326-1.084)		0.739 (0.374-1.461)
P value	0.946		0.045^a		0.089		0.385
APOB rs10495712 (GG vs AG+AA)
OR (95%CI)	0.749 (0.322-1.743)		0.719 (0.315-1.639)		0.807 (0.351-1.855)		0.816 (0.343-1.938)
P value	0.501		0.431		0.613		0.645
LIPC rs1800588 CC vs CT+TT
OR (95%CI)	0.870 (0.467-1.621)		0.732 (0.393-1.363)		0.607 (0.326-1.132)		0.911 (0.482-1.722)
P value	0.661		0.325		0.115		0.774
LEP rs7799039 GG vs AG+AA
OR (95%CI)	9.316 (2.064-40.428)		1.623 (0.655-4.017)		1.518 (0.602-3.825)		1.317 (0.507-3.419)
P value	0.001^a		0.292		0.374		0.572
GHRL rs27647 (AA vs AG+GG)
OR (95%CI)	0.570 (0.265-1.224)		0.997 (0.483-2.058)		0.905 (0.436-1.878)		0.889 (0.417-1.895)
P value	0.147		0.993		0.788		0.761

^aP < 0.05 compare between normal level vs abnormal level. OR: Odds ratio; HDL: High-density lipoprotein; LDL: Low-density lipoprotein.

Table 6 Association between genetic polymorphism and metabolic traits

Genetic polymorphisms	Metabolic traits
Genetic polymorphisms	FPG (mg/dL), n = 175		HbA1C (mmol/L), n = 159		AST (U/L), n = 175		ALT (U/L), n = 177
	< 100	≥ 100	< 6.5	≥ 6.5	< 34	≥ 34	< 40	≥ 40
PNPLA3 rs738409 (CC vs CG+GG)
OR (95%CI)	0.354 (0.063-1.984)		1.055 (0.437-2.543)		2.568 (1.243-5.305)		1.679 (0.713-3.953)
P value	0.219		0.906		0.010^a		0.232
APOC3 rs2854116 (TT vs CT+CC)
OR (95%CI)	0.956 (0.923-0.991)		1.553 (0.495-4.897)		0.735 (0.335-1.614)		0.630 (0.253-1.570)
P value	0.342		0.448		0.442		0.318
APOA5 rs662799 (AA + AG+GG)
OR (95%CI)	1.167 (0.229-5.946)		1.213 (0.509-2.893)		0.823 (0.421-1.611)		0.730 (0.320-1.664)
P value	1.000		0.663		0.570		0.453
APOB rs10495712 (GG vs AG+AA)
OR (95%CI)	1.100 (0.123-9.802)		1.150 (0.356-3.720)		2.063 (0.879-4.840)		1.255 (0.431-3.651)
P value	0.923		0.815		0.092		0.774
LIPC rs1800588 (CC vs CT+TT)
OR (95%CI)	0.947 (0.907-0.989)		1.709 (0.636-4.592)		1.476 (0.719-3.027)		2.208 (0.844-5.776)
P value	0.093		0.284		0.287		0.100
LEP rs7799039 (GG vs AG+AA)
OR (95%CI)	0.268 (0.046-1.561)		1.008 (0.272-3.746)		1.329 (0.462-3.827)		2.016 (0.444-9.155)
P value	0.166		1.000		0.579		0.535
GHRL rs27647 (AA vs AG+GG)
OR (95%CI)	1.045 (1.009-1.083)		0.700 (0.222-2.206)		0.676 (0.285-1.605)		0.795 (0.280-2.256)
P value	0.345		0.541		0.373		0.666

^aP value < 0.05. AST: Aspartate aminotransaminase; ALT Alanine aminotransaminase; OR: Odds ratio; FPG: Fasting plasma glucose; HbA1C: Hemoglobin A1C.

Table 7 Logistic regression analysis of factors associated with metabolic-associated fatty liver disease (people living with human immunodeficiency virus and metabolic-associated fatty liver disease vs people living with human immunodeficiency virus and non-metabolic-associated fatty liver disease)

Factor	Exp(B)	95%CI	P value
AST	4.615	1.081-19.709	0.039^a
Fasting Plasma glucose	21.5	5.327-86.767	< 0.001^a
Triglyceride	6.747	1.747-26.047	0.006^a
Total cholesterol	0.125	0.019-0.819	0.030^a
LDL	12.97	1.983-84.827	0.007^a
APOB rs10495712	4.195	1.304-18.532	0.019^a
APOA5 rs662799	0.012	0.002-0.770	< 0.001^a
LEP rs7799039	0.321	0.070-1.469	0.143^a

^aP value < 0.2. AST: Aspartate aminotransaminase; LDL: Low-density lipoprotein.

Citation: Choochuay K, Kunhapan P, Puangpetch A, Tongsima S, Srisawasdi P, Sobhonslidsuk A, Sungkanuparph S, Biswas M, Sukasem C. Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus. World J Hepatol 2024; 16(3): 366-378
URL: https://www.wjgnet.com/1948-5182/full/v16/i3/366.htm
DOI: https://dx.doi.org/10.4254/wjh.v16.i3.366