<i>APOE</i> and <i>KLF14</i> genetic variants are sex-specific for low high-density lipoprotein cholesterol identified by a genome-wide association study

Lee, Ying-Hui; Chang, Ya-Sian; Hsieh, Chih-Chang; Wang, Rong-Tsorng; Chang, Jan-Gowth; Chen, Chung-Jen; Chang, Shun-Jen

doi:10.1590/1678-4685-GMB-2021-0280

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Human and Medical Genetics • Genet. Mol. Biol. 45 (1) • 2022 • https://doi.org/10.1590/1678-4685-GMB-2021-0280 copy

APOE and KLF14 genetic variants are sex-specific for low high-density lipoprotein cholesterol identified by a genome-wide association study

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

To demonstrate the loci that relate to high-density lipoprotein cholesterol (HDL-C) levels and genetic sex heterogeneity, we enrolled 41,526 participants aged between 30 and 70 years old from the Taiwan Biobank in a genome-wide association study. We applied the Manhattan plot to display the p-values estimated for the relationships between loci and low HDL-C. A total of 160 variants were significantly associated with low HDL-C. The genotype TT of rs1364422 located in the KLF14 gene has 1.30 (95% CI=1.20 - 1.42) times the risk for low-HDL compared to genotype CC in females (log(-p) =8.98). Moreover, the genes APOC1, APOE, PVRL2, and TOMM40 were associated significantly with low-HDL-C in males only. Excluding the variants with high linkage disequilibrium, we revealed the rs429358 located in APOE as the major genetic variant for lowering HDL-C, in which genotype CT has 1.24 (95% CI= 1.16 - 1.32) times the risk. In addition, we also examine 12 genes related to HDL-C in both sexes, including LPL, ABCA1, APOA5, BUD13, ZPR1, ALDH1A2, LIPC, CETP, HERPUD1, LIPG, ANGPTL8, and DOCK6. In conclusion, low-HDL-C is a genetic and sex-specific phenotype, and we discovered that the APOE and KLF14 are specific to low-HDL-C for men and women, respectively.

Keywords:
Genome-wide association study; High-density lipoprotein cholesterol; sex-specific; KLF14 ; APOE

	Males (n=20,763)			Females (n=20,763)
	HDL-C Lower	HDL-C normal	p-values	HDL-C Lower	HDL-C normal	p-values
Age (mean ±SD))	50.7±11.1	50.8±11.3	0.804	51.2±11.2	50.6±11.3	0.0001
BMI (mean ±SD)	26.8±3.6	24.8±3.3	<0.001	25.2±3.9	22.9±3.4	<0.001
WC (mean ±SD)	91.9±9.3	86.7±9.0	<0.001	84.9±9.7	79.1±9.2	<0.001
SBP (mean ±SD)	128.9±17.3	126.9±17.5	<0.001	121.2±18.9	116.7±18.7	<0.001
DBP (mean ±SD)	80.1±11.1	78.5±10.9	<0.001	73.0±10.5	70.5±10.5	<0.001
Fasting glucose (mean ±SD)	103.3±29.2	98.2±21.5	<0.001	98.4±25.0	92.3±15.7	<0.001
Triglycerides (mean ±SD)	207.0±195.5	115.6±77.4	<0.001	145.7±96.6	84.1±43.5	<0.001

SNP	Chr.	Position	Gene	Alt.	Males (n=20763)			Females (n=20763)
SNP	Chr.	Position	Gene	Alt.	Case (%)	OR (95% CI)	-log (p-value)	Case (%)	OR (95% CI)	-log (p-value)
rs1364422	7	130761222	KLF14	T
		TT			973 (25.79)	0.94(0.86-1.03)	0.81	1282 (34.52)	1.30(1.20-1.42)	8.98
		CT			2755 (27.39)	1.02(0.95-1.09)	0.20	3153 (31.27)	1.13(1.05-1.20)	3.27
		CC			1867 (27.06)	1.0		1996 (28.79)	1.0
rs429358	19	44908684	APOE	C
		CC			42 (34.15)	1.32(0.96-1.76)	1.11	47 (38.84)	1.28(0.94-1.68)	1.02
		CT			1032 (32.14)	1.24(1.16-1.32)	9.22	1109 (34.39)	1.13(1.06-1.20)	3.62
		TT			4453 (25.95)	1.0		5103 (30.45)	1.0
rs4420638	19	44919689	APOC1	G
		GG			69 (33.82)	1.26(0.99-1.58)	1.30	69 (34.33)	1.13(0.88-1.42)	0.49
		GA			1159 (30.86)	1.18(1.11-1.26)	6.42	1274 (33.56)	1.10(1.04-1.17)	2.74
		AA			4374 (26.04)	1.0		5102 (30.44)	1.0
rs34342646	19	44884873	PVRL2	A
		AA			49 (36.03)	1.38(1.03-1.80)	1.59	47 (36.15)	1.18(0.87-1.56)	0.60
		GA			964 (31.27)	1.20(1.11-1.28)	6.32	1048 (33.44)	1.09(1.02-1.17)	2.09
		GG			4589 (26.16)	1.0		5348 (30.58)	1.0
rs34404554	19	44891079	TOMM40	G
		GG			50 (35.71)	1.37(1.02-1.78)	1.54	47 (35.07)	1.15(0.85-1.51)	0.46
		CG			965 (31.19)	1.19(1.11-1.28)	6.16	1054 (33.47)	1.09(1.02-1.17)	2.14
		CC			4584 (26.16)	1.0		5341 (30.57)	1.0

SNP	Genotypes	Males (n=20763)			Females (n=20763)
SNP	Genotypes	No.	mean ±SD (mg/dl)	-log(p) post hoc	No.	mean ±SD (mg/dl)	-log(p) post hoc
rs1364422
	TT^a	3773	48.04 ±11.22	0.526	3714	57.11 ±13.25	4.76 a<c, b<c
	CT^b	10059	47.76 ±11.09		10082	57.94 ±13.26
	CC^c	6900	47.71 ±11.09		6933	58.37 ±12.97
rs429358
	CC^a	123	46.43 ±10.98	10.89 b<c	121	55.15 ±13.25	9.63 b/c, a<c
	CT^b	3211	46.55 ±11.03		3225	56.60 ±13.06
	TT^c	17158	48.04 ±11.12		16761	58.19 ±13.20
rs4420638
	GG^a	204	46.22 ±11.29	9.80 b<c	201	56.39 ±12.51	7.38 b<c
	GA^b	3756	46.76 ±10.87		3796	56.87 ±13.03
	AA^c	16795	48.04 ±11.15		16761	58.19 ±13.20
rs34342646
	AA^a	136	45.76 ±11.17	7.89 b<c	130	55.59 ±13.01	6.31 b<c
	GA^b	3083	46.77 ±11.03		3134	56.86 ±12.94
	GG^c	17543	47.99 ±11.12		17491	58.14 ±13.20
rs34404554
	GG^a	140	45.79 ±11.06	7.74 b<c	134	55.87 ±13.04	6.36 b<c
	CG^b	3094	46.78 ±11.04		3149	56.84 ±12.92
	CC^c	17521	47.99 ±11.12		17469	58.14 ±13.21

Variants	Chr.	Position	Gene	Alt.	Males (n=20763)			Females (n=20763)
Variants	Chr.	Position	Gene	Alt.	Case (%)	OR (95% CI)	-log (p-value)	Case (%)	OR (95% CI)	-log (p-value)
rs17482753	8	199751350	LPL	T
		TT			35 (18.13)	0.64(0.45-0.88)	2.03	47 (21.08)	0.65(0.48-0.86)	2.47
		GT			822 (22.03)	0.78(0.72-0.84)	10.23	995 (25.80)	0.80(0.74-0.85)	10.35
		GG			4740 (28.20)	1.0		5396 (32.39)	1.0
Affx4282911	11	116790676	APOA5	A
		AA			71 (66.98)	2.65(2.07-3.32)	15.38	64 (66.67)	2.28(1.76-2.89)	10.24
		CA			952 (37.06)	1.46(1.36-1.57)	25.96	1087 (42.21)	1.44(1.35-1.54)	27.45
		CC			4575 (25.32)	1.0		5290 (29.26)	1.0
rs7350481	11	116715567	BUD13	C
		CC			457 (38.12)	1.55(1.41-1.71)	17.78	496 (40.82)	1.42(1.29-1.56)	12.59
		TC			2185 (29.20)	1.19(1.13-1.26)	9.22	2481 (33.20)	1.16(1.10-1.22)	7.40
		TT			2958 (24.52)	1.0		3469 (28.74)	1.0
rs2160669	11	116776891	ZPR1	T
		TT			354 (38.23)	1.52(1.36-1.70)	13.32	341 (39.84)	1.34(1.20-1.49)	6.62
		CT			1952 (29.20)	1.16(1.10-1.23)	6.98	2184 (32.43)	1.09(1.03-1.15)	2.89
		CC			3285 (25.08)	1.0		3905 (29.76)	1.0
rs261291	15	58387979	ALDH1A2	C
		CC			759 (21.56)	0.66(0.60-0.72)	17.56	926 (26.75)	0.72(0.66-0.79)	11.67
		TC			2731 (27.10)	0.89(0.83-0.95)	3.32	3125 (30.77)	0.88(0.83-0.94)	3.82
		TT			2104 (37.61)	1.0		2375 (33.50)	1.0
rs2070895	15	58431740	LIPC	A
		AA			700 (23.33)	0.71(0.64-0.78)	11.51	831 (26.76)	0.72(0.66-0.79)	11.34
		GA			2518 (25.64)	0.80(0.75-0.86)	10.17	2937 (30.33)	0.86(0.81-0.92)	5.38
		GG			2374 (30.05)	1.0		2663 (33.58)	1.0
rs17231506	16	56960616	CETP	T
		TT			71 (12.46)	0.41(0.32-0.51)	13.06	93 (15.71)	0.46(0.37-0.56)	12.85
		CT			1128 (19.80)	0.65(0.61-0.70)	37.04	1419 (24.97)	0.73(0.69-0.78)	24.17
		CC			4391 (30.40)	1.0		4923 (34.06)	1.0
rs247616	16	56955678	HERPUD1	T
		TT			67 (11.92)	0.39(0.31-0.50)	13.47	92 (15.54)	0.46(0.37-0.56)	13.00
		CT			1129 (19.92)	0.66(0.62-0.70)	35.58	1418 (25.08)	0.74(0.70-0.78)	23.22
		CC			4402 (30.31)	1.0		4930 (34.00)	1.0
rs9958734	18	49592028	LIPG	C
		CC			792 (23.12)	0.72(0.65-0.79)	11.43	911 (27.02)	0.73(0.67-0.80)	10.79
		TC			2634 (26.44)	0.86(0.80-0.92)	5.18	3066 (30.56)	0.87(0.82-0.93)	4.47
		TT			2163 (29.55)	1.0		2451 (33.53)	1.05
rs2278426	19	11239812	ANGPTL8	T
		TT			438 (32.74)	1.29(1.17-1.43)	6.27	557 (39.70)	1.37(1.25-1.50)	11.11
		CT			2257 (28.35)	1.12(1.06-1.18)	4.25	2580 (32.36)	1.12(1.06-1.17)	4.48
		CC			2887 (25.32)	1.0		3285 (29.02)	1.0
rs3760782	19	11235874	DOCK6	T
		TT			451 (32.87)	1.30(1.17-1.43)	6.50	562 (39.03)	1.35(1.23-1.47)	10.17
		CT			2254 (28.28)	1.11(1.05-1.18)	3.95	2586 (32.54)	1.12(1.07-1.18)	5.00
		CC			2889 (25.37)	1.0		3287 (28.97)	1.0

SNP	Males (n=20763)		Females (n=20763)
SNP	aOR (95% CI)	-log(p-value)	aOR (95% CI)	-log(p-value)
Tobacco smoking
Yes	1.87 (1.74-2.01)	65.61	1.43 (1.21-1.70)	-log(p-value)	4.40
No	1.0		1.0
Alcohol consumption
Yes	0.70 (0.64-0.77)	12.19	0.51 (0.39-0.67)	5.98
No	1.0		1.0
rs1364422
TT	0.94(0.86-1.03)	0.74	1.31(1.21-1.43)	9.35
CT	1.02(0.95-1.10)	0.28	1.13(1.05-1.21)	3.33
CC	1.0		1.0
rs429358
GG	1.50(1.03-2.19)	1.46	1.45(1.01-2.10)	1.33
GA	1.36(1.26-1.48)	12.93	1.20(1.11-1.30)	5.07
AA	1.0		1.0

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[1] Send correspondence to
Shun-Jen Chang. National University of Kaohsiung, Department of Kinesiology, Health and Leisure Studies, No. 700, Nanzih District, 81148, Kaohsiung, Taiwan. Email: changsj1104@gmail.com.