Genetic Loci in Phospholipase C-Like 1 (PLCL1) are Protective Factors for Allergic Rhinitis in Han Population of Northern Shaanxi, China

Figures & data

Table 1 Characteristics of Patients with AR and Healthy Individuals

Characteristics		Cases	Control	p
		n = 978	n = 997
Age (years)	Mean ± SD	42.60 ± 10.38	43.80 ± 8.19	0.004^a
	≤43	491 (50.2%)	424 (42.5%)
	>43	487 (49.8%)	573 (57.5%)
Gender	Male	377 (38.5%)	345 (34.6%)	0.076^b
	Female	601 (61.5%)	652 (65.4%)
BMI (kg/m^2)	Mean ± SD	24.80 ± 3.62	24.88 ± 3.65	0.631^a
	≤24	483 (49.4%)	470 (47.1%)
	>24	495 (50.6%)	527 (52.9%)
Area	Blown-sand region	270 (27.1%)	254 (26.0%)	0.610^b
	Hilly loess	727 (72.9%)	724 (74.0%)

Note: ^aRepresents the p value calculated by the t-test; ^brepresents the p value calculated by the chi-square test.

Abbreviation: AR, allergic rhinitis.

Table 2 The Basic Information and HWE About the Candidate SNPs of PLCL1

SNP ID	Function	Chr: Position	Alleles (A/B)	MAF		HWE (P value)	Haploreg 4.1
				Cases	Controls
rs2139049	Intronic	2: 198022936	A/G	0.21	0.24	0.100	Motifs changed; Selected eQTL hits
rs6738825	Intronic	2: 198032171	G/A	0.21	0.24	0.084	Enhancer histone marks; Motifs changed; NHGRI/EBI GWAS hits; Selected eQTL hits
rs2164068	Intronic	2: 198079128	A/T	0.22	0.25	0.050	Motifs changed; GRASP QTL Hits; Selected eQTL hits
rs2228135	Synonymous	2: 198085305	G/A	0.34	0.32	0.380	SiPhy cons; GRASP QTL Hits; Selected eQTL hits

Note: P > 0.05 indicates that the genotypes were in Hard–Weinberg Equilibrium; “-” indicates data missing.

Abbreviations: A, minor allele; B, wild-type allele; HWE, Hardy–Weinberg equilibrium; SNP, Single nucleotide polymorphisms; MAF, minor allele frequency.

Table 3 Genetic Variants in PLCL1 Associated with Susceptibility of AR

SNP ID	Model	Genotype	Control	Case	OR (95% CI)	p
rs2139049	Allele	G	1513 (75.9%)	1539 (78.8%)	1
		A	481 (24.1%)	415 (21.2%)	0.85 (0.73–0.98)	0.031
	Codominant	GG	564 (56.6%)	584 (59.8%)	1
		AG	385 (38.6%)	371 (38%)	0.93 (0.77–1.11)	0.413
		AA	48 (4.8%)	22 (2.2%)	0.44 (0.26–0.74)	0.002
	Dominant	GG	564 (56.6%)	584 (59.8%)	1	0.140
		AG-AA	433 (43.4%)	393 (40.2%)	0.87 (0.73–1.04)
	Recessive	GG-AG	949 (95.2%)	955 (97.8%)	1	0.002
		AA	48 (4.8%)	22 (2.2%)	0.46 (0.27–0.76)
	Overdominant	GG-AA	612 (61.4%)	606 (62%)	1	0.730
		AG	385 (38.6%)	371 (38%)	0.97 (0.81–1.16)
	Log-additive	—	—	—	0.83 (0.71–0.97)	0.021
rs6738825	Allele	A	1501 (75.7%)	1535 (78.6%)	1
		G	481 (24.3%)	417 (21.4%)	0.84 (0.73–0.98)	0.022
	Codominant	AA	558 (56.3%)	581 (59.5%)	1
		GA	385 (38.9%)	373 (38.2%)	0.93 (0.77–1.12)	0.428
		GG	48 (4.8%)	22 (2.2%)	0.44 (0.26–0.74)	0.002
	Dominant	AA	558 (56.3%)	581 (59.5%)	1	0.140
		GA-GG	433 (43.7%)	395 (40.5%)	0.87 (0.73–1.05)
	Recessive	AA-GA	943 (95.2%)	954 (97.8%)	1	0.002
		GG	48 (4.8%)	22 (2.2%)	0.46 (0.27–0.76)
	Overdominant	AA-GG	606 (61.1%)	603 (61.8%)	1	0.750
		GA	385 (38.9%)	373 (38.2%)	0.97 (0.81–1.17)
	Log-additive	—	—	—	0.83 (0.71–0.97)	0.023
rs2164068	Allele	T	1499 (75.3%)	1529 (78.3%)	1
		A	493 (24.7%)	423 (21.7%)	0.85 (0.73–0.98)	0.030
	Codominant	TT	552 (55.4%)	577 (59.1%)	1
		TA	395 (39.7%)	375 (38.4%)	0.91 (0.75–1.09)	0.292
		AA	49 (4.9%)	24 (2.5%)	0.46 (0.28–0.77)	0.003
	Dominant	TT	552 (55.4%)	577 (59.1%)	1	0.092
		TA-AA	444 (44.6%)	399 (40.9%)	0.86 (0.72–1.03)
	Recessive	TT-TA	947 (95.1%)	952 (97.5%)	1	0.003
		AA	49 (4.9%)	24 (2.5%)	0.48 (0.29–0.80)
	Overdominant	TT-AA	601 (60.3%)	601 (61.6%)	1	0.560
		TA	395 (39.7%)	375 (38.4%)	0.95 (0.79–1.14)
	Log-additive	—	—	—	0.82 (0.70–0.96)	0.015
rs2228135	Allele	A	1356 68.2(%)	1281 (65.6%)	1
		G	632 (31.8%)	671 (34.4%)	1.12 (0.98–1.28)	0.085
	Codominant	AA	456 (45.9%)	414 (42.4%)	1
		GA	444 (44.7%)	453 (46.4%)	1.12 (0.93–1.36)	0.221
		GG	94 (9.5%)	109 (11.2%)	1.27 (0.93–1.73)	0.126
	Dominant	AA	456 (45.9%)	414 (42.4%)	1	0.130
		GA-GG	538 (54.1%)	562 (57.6%)	1.15 (0.96–1.37)
	Recessive	AA-GA	900 (90.5%)	867 (88.8%)	1	0.230
		GG	94 (9.5%)	109 (11.2%)	1.20 (0.89–1.60)
	Overdominant	AA-GG	550 (55.3%)	523 (53.6%)	1	0.430
		GA	444 (44.7%)	453 (46.4%)	1.07 (0.90–1.28)
	Log-additive	—	—	—	1.13 (0.98–1.29)	0.085

Notes: “-” indicates Log-additive model. “p < 0.05” and bold text represent statistical significance.

Abbreviations: AR, allergic rhinitis; SNP, single-nucleotide polymorphisms; OR, odds ratio; CI, confidence interval.

Table 4 Genetic Variants in PLCL1 Associated with Susceptibility of AR in the Subgroup Analysis (Age and Gender)

SNP ID	Model	GenoType	≤43 Years Old		>43 Years Old		Female		Male
			OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
rs2139049	Allele	G	1		1		1		1
		A	0.98 (0.79–1.22)	0.868	0.74 (0.61–0.92)	0.005	0.86 (0.72–1.04)	0.118	0.83 (0.65–1.07)	0.152
	Codominant	GG	1		1		1		1
		AG	1.03 (0.78–1.36)	0.825	0.87 (0.67–1.12)	0.277	0.87 (0.69–1.10)	0.254	1.02 (0.76–1.39)	0.881
		AA	0.74 (0.36–1.51)	0.403	0.21 (0.08–0.52)	0.001	0.66 (0.37–1.15)	0.141	/	/
	Dominant	GG	1	0.990	1	0.065	1	0.160	1	0.580
		AG-AA	1.00 (0.76–1.31)		0.79 (0.61–1.01)		0.85 (0.68–1.07)		0.92 (0.68–1.24)
	Recessive	GG-AG	1	0.380	1	0.0002	1	0.190	1	/
		AA	0.73 (0.36–1.48)		0.22 (0.09–0.54)		0.70 (0.40–1.21)		/
	Overdominant	GG-AA	1	0.730	1	0.590	1	0.380	1	0.530
		AG	1.05 (0.80–1.38)		0.93 (0.72–1.20)		0.90 (0.72–1.13)		1.10 (0.81–1.49)
	Log-additive	—	0.97 (0.76–1.22)	0.780	0.73 (0.58–0.91)	0.005	0.85 (0.70–1.03)	0.099	0.80 (0.61–1.05)	0.110
rs6738825	Allele	A	1		1		1		1
		G	0.97 (0.78–1.21)	0.767	0.76 (0.62–0.93)	0.008	0.88 (0.73–1.05)	0.160	0.81 (0.63–1.04)	0.102
	Codominant	AA	1		1		1		1
		GA	1.03 (0.78–1.36)	0.838	0.87 (0.67–1.13)	0.295	0.89 (0.71–1.13)	0.347	0.99 (0.73–1.34)	0.949
		GG	0.68 (0.33–1.41)	0.299	0.25 (0.11–0.59)	0.002	0.67 (0.38–1.17)	0.156	/	/
	Dominant	AA	1	0.960	1	0.081	1	0.230	1	0.440
		GA-GG	0.99 (0.76–1.30)		0.80 (0.62–1.03)		0.87 (0.70–1.09)		0.89 (0.66–1.20)
	Recessive	AA-GA	1	0.280	1	0.001	1	0.200	1	/
		GG	0.67 (0.33–1.38)		0.27 (0.11–0.62)		0.70 (0.40–1.21)		/
	Overdominant	AA-GG	1	0.720	1	0.590	1	0.500	1	0.670
		GA	1.05 (0.80–1.39)		0.93 (0.72–1.21)		0.92 (0.73–1.16)		1.07 (0.79–1.44)
	Log-additive	—	0.95 (0.75–1.21)	0.690	0.74 (0.59–0.93)	0.009	0.87 (0.71–1.05)	0.140	0.78 (0.59–1.02)	0.071
rs2164068	Allele	T	1		1		1		1
		A	0.96 (0.77–1.19)	0.715	0.74 (0.60–0.91)	0.004	0.84 (0.70–1.01)	0.068	0.85 (0.66–1.09)	0.199
	Codominant	TT	1		1		1	0.150	1
		TA	1.01 (0.76–1.33)	0.951	0.84 (0.65–1.09)	0.179	0.83 (0.66–1.05)		1.05 (0.78–1.43)	0.739
		AA	0.70 (0.35–1.4)	0.310	0.25 (0.11–0.59)	0.002	0.66 (0.38–1.16)		0.11 (0.02–0.46)	0.003
	Dominant	TT	1	0.850	1	0.044	1	0.075	1	0.690
		TA-AA	0.97 (0.74–1.28)		0.77 (0.60–0.99)		0.82 (0.65–1.02)		0.94 (0.70–1.27)
	Recessive	TT-TA	1	0.300	1	0.001	1	0.230	1	0.0001
		AA	0.70 (0.35–1.38)		0.27 (0.12–0.63)		0.71 (0.41–1.24)		0.10 (0.02–0.46)
	Overdominant	TT-AA	1	0.820	1	0.400	1	0.190	1	0.420
		TA	1.03 (0.78–1.36)		0.90 (0.69–1.16)		0.86 (0.68–1.08)		1.13 (0.84–1.53)
	Log-additive	—	0.94 (0.74–1.19)	0.600	0.73 (0.58–0.91)	0.005	0.83 (0.68–1.00)	0.051	0.82 (0.63–1.08)	0.150
rs2228135	Allele	A	1		1		1		1
		G	1.01 (0.83–1.23)	0.890	1.22 (1.02–1.47)	0.031	1.08 (0.92–1.28)	0.348	1.2 (0.96–1.50)	0.105
	Codominant	AA	1		1		1		1
		GA	1.00 (0.75–1.32)	0.981	1.29 (0.99–1.68)	0.055	0.83 (0.66–1.05)	0.118	1.41 (1.03–1.92)	0.031
		GG	1.11 (0.71–1.73)	0.659	1.43 (0.92–2.23)	0.114	0.66 (0.37–1.16)	0.148	1.20 (0.72–2.00)	0.479
	Dominant	AA	1	0.900	1	0.032	1	0.730	1	0.035
		GA-GG	1.02 (0.78–1.33)		1.32 (1.02–1.69)		1.04 (0.83–1.30)		1.37 (1.02–1.85)
	Recessive	AA-GA	1	0.630	1	0.290	1	0.140	1	0.930
		GG	1.11 (0.73–1.69)		1.25 (0.82–1.91)		1.32 (0.92–1.90)		1.02 (0.63–1.66)
	Overdominant	AA-GG	1	0.860	1	0.130	1		1	0.040
		GA	0.98 (0.75–1.28)		1.21 (0.94–1.56)		0.99 (0.78–1.25)	0.922	1.36 (1.01–1.83)
	Log-additive	—	1.03 (0.85–1.26)	0.750	1.23 (1.02–1.49)	0.034	1.31 (0.89–1.93)	0.167	1.21 (0.96–1.51)	0.100

Notes: “-” indicates Log-additive model; “/” indicates that the data are missing. “p < 0.05” and bold text represent statistical significance.

Abbreviations: AR, allergic rhinitis; SNP, single-nucleotide polymorphisms; OR, odds ratio; CI, confidence interval.

Table 5 Genetic Variants in PLCL1 Associated with Susceptibility of AR in the Subgroup Analysis (BMI and Region)

SNP ID	Model	Genotype	BMI ≤24 kg/m^2		BMI >24 kg/m^2		Blown-Sand Region		Hilly Loess
			OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
rs2139049	Allele	G	1		1		1		1
		A	0.76 (0.61–0.94)	0.012	0.94 (0.76–1.16)	0.552	0.65 (0.48–0.86)	0.003	0.94 (0.79–1.12)	0.471
	Codominant	GG	1		1		1		1
		AG	0.82 (0.63–1.07)	0.140	1.03 (0.80–1.34)	0.801	0.74 (0.52–1.06)	0.098	1.00 (0.80–1.24)	0.991
		AA	0.39 (0.19–0.80)	0.010	0.5 (0.23–1.08)	0.078	0.06 (0.01–0.43)	0.006	0.63 (0.36–1.11)	0.112
	Dominant	GG	1	0.043	1	0.880	1	0.019	1	0.740
		AG-AA	0.77 (0.59–0.99)		0.98 (0.76–1.26)		0.66 (0.46–0.93)		0.96 (0.78–1.19)
	Recessive	GG-AG	1	0.013	1	0.061	1	0.0001	1	0.110
		AA	0.43 (0.21–0.86)		0.49 (0.23–1.06)		0.06 (0.01–0.49)		0.63 (0.36–1.11)
	Overdominant	GG-AA	1	0.290	1	0.610	1	0.270	1	0.780
		AG	0.87 (0.67–1.13)		1.07 (0.83–1.38)		0.82 (0.57–1.17)		1.03 (0.83–1.28)
	Log-additive	—	0.75 (0.60–0.93)	0.010	0.92 (0.74–1.15)	0.480	0.60 (0.43–0.82)	0.001	0.93 (0.77–1.11)	0.410
rs6738825	Allele	A	1		1		1		1
		G	0.75 (0.61–0.93)	0.010	0.95 (0.77–1.16)	0.597	0.67 (0.50–0.90)	0.007	0.92 (0.78–1.1)	0.373
	Codominant	AA	1		1		1		1
		GA	0.82 (0.63–1.07)	0.152	1.03 (0.80–1.33)	0.811	0.80 (0.56–1.14)	0.217	0.98 (0.79–1.21)	0.842
		GG	0.36 (0.17–0.74)	0.006	0.55 (0.26–1.17)	0.119	0.06 (0.01–0.45)	0.006	0.62 (0.35–1.10)	0.102
	Dominant	AA	1	0.043	1	0.910	1	0.053	1	0.600
		GA-GG	0.77 (0.59–0.99)		0.99 (0.77–1.27)		0.71 (0.50–1.01)		0.95 (0.77–1.17)
	Recessive	AA-GA	1	0.007	1	0.100	1	0.0001	1	0.110
		GG	0.39 (0.19–0.79)		0.55 (0.26–1.14)		0.06 (0.01–0.49)		0.63 (0.36–1.11)
	Overdominant	AA-GG	1	0.320	1	0.640	1	0.490	1	0.920
		GA	0.88 (0.67–1.14)		1.06 (0.82–1.37)		0.88 (0.62–1.26)		1.01 (0.82–1.25)
	Log-additive	—	0.74 (0.59–0.92)	0.008	0.93 (0.75–1.16)	0.540	0.64 (0.46–0.87)	0.005	0.91 (0.76–1.10)	0.320
rs2164068	Allele	T	1		1		1		1
		A	0.76 (0.61–0.94)	0.011	0.93 (0.76–1.14)	0.475	0.65 (0.48–0.87)	0.003	0.92 (0.78–1.10)	0.355
	Codominant	TT	1		1		1		1
		TA	0.85 (0.65–1.11)	0.231	0.96 (0.74–1.23)	0.733	0.76 (0.53–1.08)	0.128	0.96 (0.78–1.19)	0.726
		AA	0.34 (0.16–0.69)	0.003	0.65 (0.32–1.33)	0.242	/	/	0.67 (0.39–1.15)	0.145
	Dominant	TT	1	0.061	1	0.570	1	0.026	1	0.520
		TA-AA	0.78 (0.60–1.01)		0.93 (0.72–1.19)		0.67 (0.47–0.95)		0.93 (0.76–1.15)
	Recessive	TT-TA	1	0.003	1	0.250	1	/	1	0.160
		AA	0.36 (0.18–0.73)		0.67 (0.33–1.35)		/		0.68 (0.40–1.16)
	Overdominant	TT-AA	1	0.480	1	0.870	1	0.320	1	0.940
		TA	0.91 (0.70–1.18)		0.98 (0.76–1.26)		0.84 (0.59–1.19)		0.99 (0.80–1.23)
	Log-additive	—	0.74 (0.59–0.93)	0.009	0.91 (0.73–1.13)	0.380	0.60 (0.43–0.83)	0.002	0.91 (0.76–1.09)	0.300
rs2228135	Allele	A	1		1		1		1
		G	1.10 (0.91–1.33)	0.323	1.14 (0.95–1.38)	0.162	1.15 (0.89–1.48)	0.294	1.12 (0.96–1.31)	0.156
	Codominant	AA	1		1		1		1
		GA	1.05 (0.80–1.37)	0.753	1.20 (0.92–1.55)	0.177	1.07 (0.74–1.56)	0.726	1.16 (0.93–1.44)	0.187
		GG	1.27 (0.82–1.96)	0.278	1.26 (0.81–1.96)	0.298	1.44 (0.82–2.54)	0.207	1.22 (0.85–1.77)	0.285
	Dominant	AA	1	0.540	1	0.140	1	0.480	1	0.140
		GA-GG	1.08 (0.84–1.40)		1.21 (0.94–1.55)		1.14 (0.80–1.62)		1.17 (0.95–1.44)
	Recessive	AA-GA	1	0.300	1	0.500	1	0.220	1	0.470
		GG	1.24 (0.82–1.87)		1.15 (0.76–1.76)		1.39 (0.82–2.36)		1.14 (0.80–1.62)
	Overdominant	AA-GG	1	0.970	1	0.270	1	0.910	1	0.290
		GA	0.99 (0.77–1.29)		1.15 (0.90–1.47)		0.98 (0.69–1.39)		1.12 (0.91–1.38)
	Log-additive	—	1.10 (0.91–1.33)	0.340	1.15 (0.95–1.39)	0.150	1.16 (0.89–1.51)	0.260	1.13 (0.96–1.32)	0.140

Notes: “-” indicates Log-additive model; “/” indicates that the data are missing. “p < 0.05” and bold text represent statistical significance.

Abbreviations: AR, allergic rhinitis; SNP, single-nucleotide polymorphisms; OR, odds ratio; CI, confidence interval.

Table 6 PLCL1 SNP-SNP Interaction Models Analyzed by the MDR Method

Model	Training Bal. Acc	Testing Bal. Acc	OR (95% CI)	p-value	CVC
rs2228135	0.521	0.505	1.18 (0.98–1.41)	0.0759	6/10
rs2164068, rs2228135	0.526	0.506	1.31 (1.07–1.61)	0.0092	6/10
rs2139049, rs2164068, rs2228135	0.531	0.528	1.37 (1.12–1.67)	0.0022	10/10
rs2139049, rs6738825, rs2164068, rs2228135	0.532	0.521	1.39 (1.14–1.70)	0.0013	10/10

Note: p values were calculated using χ² tests; “p-value < 0.05” and bold text represent statistical significance.

Abbreviations: MDR, multifactor dimensionality reduction; Bal. Acc., balanced accuracy; CVC, cross-validation consistency; OR, odds ratio; 95% CI, 95% confidence interval.

Figure 1 Multifactor dimensionality reduction (MDR) analysis of interaction between the candidate genetic loci of PLCL1 (rs2139049, rs6738825, rs2164068, and rs2228135). The color represents the degree of redundancy or synergy between SNP-SNP; the closer the color is to red, the more synergy, and the closer to blue, the more redundancy.

Table 7 Haplotype Analysis of Candidate PLCL1 Genetic Polymorphisms with AR Risk

SNP	Haplotype	Freq (Case)	Freq (Control)	Crude Analysis		Adjusted by Gender, Age, BMI
				OR (95% CI)	p	OR (95% CI)	p
rs2139049|rs6738825|rs2164068|rs2228135	GATA	0.436	0.428	1		1
rs2139049|rs6738825|rs2164068|rs2228135	GATG	0.341	0.313	1.08 (0.93–1.25)	0.320	1.07 (0.93–1.24)	0.340
rs2139049|rs6738825|rs2164068|rs2228135	AGAA	0.207	0.230	0.86 (0.73–1.02)	0.092	0.86 (0.72–1.02)	0.088
rs2139049|rs6738825|rs2164068|rs2228135	GAAA	0.007	0.014	0.51 (0.27–0.96)	0.037	0.50 (0.27–0.95)	0.033
Rare	****	0.015	0.010	0.68 (0.31–1.47)	0.330	0.67 (0.31–1.47)	0.320

Note: “p < 0.05” and bold text represent statistical significance.

Abbreviations: AR, allergic rhinitis; SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Figure 2 Haplotype block map for the PLCL1 genetic loci (rs2139049, rs6738825, rs2164068, and rs2228135). (A) The numbers inside the diamonds indicate the D’ for pairwise analyses. (B) The numbers inside the diamonds indicate the r² for pairwise analyses. The colors represent the degree of linkage disequilibrium: the redder the color, the stronger the linkage disequilibrium.