Exploring Factors Underlying Poorly-Controlled Asthma in Adults by Integrating Phenotypes and Genotypes Associated with Obesity and Asthma: A Case-Control Study

Figures & data

Figure 1 Flow chart of the enrollment of study participants.

Table 1 Baseline Characteristics of Included Participants

Characteristic	Total (n = 1360)	Poorly- Controlled (n = 340)	Well-Controlled (n = 1020)	p-value
Demography
Age (year)				0.969
30–39	216 (15.9)	55 (16.2)	161 (15.8)
40–49	279 (20.5)	69 (20.3)	210 (20.6)
50–59	348 (25.6)	84 (24.7)	264 (25.9)
60–70	517 (38.0)	132 (38.8)	385 (37.8)
Female	739 (54.3)	181 (53.2)	558 (54.7)	0.637
Education				0.625
Primary and below	136 (10.0)	37 (10.9)	99 (9.71)
Junior/ senior high school	535 (39.3)	138 (40.6)	397 (38.9)
College and above	689 (50.7)	165 (48.5)	524 (51.4)
Family history
One of the parents has asthma	145 (10.7)	51 (15.0)	94 (9.22)	0.003
Disease history
COPD	430 (31.6)	124 (36.5)	306 (30.0)	0.026
GERD	125 (9.19)	47 (13.8)	78 (7.65)	<0.001
Medication history
Metformin	29 (2.13)	9 (2.65)	20 (1.96)	0.448
Stain	22(1.62)	2 (0.59)	20(1.96)	0.082
Aspirin	152 (11.2)	39 (11.5)	113 (11.1)	0.843
Beta-blockers	146 (10.7)	36 (10.6)	110 (10.8)	0.919
Steroid	981 (72.1)	275 (80.9)	706 (69.2)	<0.001
Steroid for Asthma
Oral	759 (55.8)	272 (80.0)	487 (47.8)	<0.001
Injection	117 (8.60)	66 (19.4)	51 (5.00)	<0.001
Anthropometry
BMI (kg/m^2)	24.8±3.84	25.3±3.83	24.6±3.83	0.002
Underweight (<18.5)	31 (2.28)	5 (1.47)	26 (2.55)	0.032
Normal (18.5–23.9)	581 (42.7)	132 (38.8)	449 (44.0)
Overweight (24.0–26.9)	423 (31.1)	103 (30.3)	320 (31.4)
Obesity (≥27.0)	325 (23.9)	100 (29.4)	225 (22.1)
WHtR	0.53±0.06	0.54±0.06	0.53±0.06	<0.001
Obesity	901 (66.3)	251 (73.8)	650 (63.7)	<0.001
Non-obesity	459 (33.8)	89 (26.2)	370 (36.3)
Health behaviors
Physical activity				0.252
Light-intensity (<3METs)	1041 (76.5)	268 (78.8)	773 (75.8)
High-intensity (≥3METs)	319 (23.5)	72 (21.2)	247 (24.2)
Smoking
Never	941 (69.2)	236 (69.4)	705 (69.1)	0.301
Former	314 (23.1)	72 (21.2)	242 (23.7)
Current use	105 (7.72)	32 (9.41)	73 (7.16)
Secondhand smoke	119 (8.75)	34 (10.0)	85 (8.33)	0.346
PM2.5(μg/m^3)	23.2±10.5	23.9±11.3	23.0±10.2	0.176
Medical service utilization^a
Total OPD visits	16.0 (2.00, 51.5)	20.0 (3.0, 60.0)	14.0 (1.50, 48.0)	<0.001
Asthma OPD visits	0.00 (0.00, 8.00)	1.00 (0.00, 14.5)	0.00 (0.00, 4.00)	<0.001
Total ER visits	13.0 (2.00, 48.5)	18.0 (4.00, 57.5)	12.0 (1.00, 46.0)	<0.001
Asthma ER visits	0.00 (0.00, 4.00)	1.00 (0.00, 8.00)	0.00 (0.00, 2.00)	<0.001
Total hospitalization visits	0.00 (0.00, 1.00)	0.00 (0.00, 2.00)	0.00 (0.00, 1.00)	<0.001
Asthma hospitalization visits	0.00 (0.00, 0.00)	0.00 (0.00, 1.00)	0.00 (0.00, 0.00)	<0.001

Notes: Continuous variables are presented as mean ± SD, and categorical variables are expressed as n (%). ^aindicates that descriptive statistics for variables are presented as medians (P5, P95).

Abbreviations: COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; BMI, body mass index; WHtR, waist-to-height ratio; OPD, outpatient department; ER, emergency department.

Table 2 Combination Effect of Central Obesity and General Obesity, Stratified by WHtR and BMI on Poorly-Controlled Asthma

	BMI (kg/m^2)
	Underweight (<18.5)	Normal (18.5–23.9)	Overweight (24.0–26.9)	Obesity (≥27.0)
	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
Non-central obesity (WHtR < 0.5)	0.58 (0.20, 1.73)	Ref	0.51 (0.21, 1.24)	-
Central obesity (WHtR ≥0.5)	-	1.41 (<1.00, 2.15) ^†	1.34 (0.94, 1.90)	1.66 (1.17, 2.35)*

Notes: Adjusted for one of the parents has asthma. *p< 0.05, ^†0.05≤ p <0.1.

Abbreviations: BMI, body mass index; WHtR, waist-to-height ratio; OR, odds ratio; CI, confidence interval.

Table 3 Genetic Model of Obese-Associated SNPs and Poorly-Controlled Asthma (Only Show Results with p-values <0.05)

SNPs	Chr: Position	A1/ A2	Nearby Gene(s)	Regulated Gene(s)^a (p <10^−4)	Poor Asthma Control
					BMI-Associated		WHtR-Associated
					AM	DM	AM	DM	RM
					OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
Risk SNPs
rs720631	2: 208693307	C/ T	PLEKHM3	FZD5		1.46 (1.09, 1.95)
rs11735097	4: 174559666	G/ T	RANP6	RP11-475B2.1				1.34 (1.04, 1.73)
rs26956	5: 59790985	A/ C	PART1 PDE4D	ELOVL7 DEPDC1B ERCC8			1.21 (1.01, 1.45)		1.49 (1.09, 2.04)
rs12153582	5: 89008780	C/ T	LINC02161	-			1.28 (1.03, 1.59)		2.16 (1.13, 4.12)
rs2151317	6: 64468738	C/ T	PHF3 EYS	LGSN					5.07 (1.40, 18.3)
rs4873644	8: 53379300	C/ T	Intergenic	ALKAL1				1.32 (1.02, 1.72)
rs16936559	11: 42379607	A/ C	Intergenic	-			1.36 (1.00, 1.84)	1.40 (1.01, 1.73)
rs7323765	13: 20807243	C/ G	GJB6	GJB6		1.32 (1.02, 1.71)
rs117777319	14: 59363486	C/ T	LINC01500	-	1.64 (1.15, 2.35)	1.76 (1.17, 2.63)
rs6020323	20: 48785923	G/ A	RP11-112L6.2 RP11-112L6.3 RP11-112L6.4	LINC01273 TMEM189 RP11-112L6.3 CEBPB-AS1 UBE2V1			1.45 (1.19, 1.77)	1.49 (1.16, 1.90)	2.06 (1.24, 3.41)
Protective SNPs
rs318773	3: 64778758	G/ A	ADAMTS9-AS2	-	0.80 (0.65, 0.98)	0.73 (0.57, 0.93)
rs17531088	3: 174893775	C/ T	NAALADL2	-	0.78 (0.65, 0.93)	0.69 (0.53, 0.89)
rs6533014	4: 103349740	G/ A	SLC39A8	SLC39A8			0.80 (0.66, 0.95)		0.64 (0.45, 0.9)
rs2075050	4: 13526386	G/ A	Intergenic	-		0.76 (0.59, 0.99)
rs72971630	6: 136115951	A/ G	Intergenic	-	0.77 (0.61, 0.96)	0.76 (0.59, 0.99)
rs75080842	18: 74270848	C/ T	LINC00908	-			0.63 (0.40, 0.97)	0.63 (0.41, 0.99)

Notes: Adjusted for obesity phenotype and one of the parents has asthma. SNPs information were obtained from the SNP database (dbSNP, GRCH 37.p13: https://www.ncbi.nlm.nih.gov/snp) of the National Center for Biotechnology Information (NCBI) and the Taiwan Biobank v3 (https://taiwanview.twbiobank.org.tw/index). “a” means the gene expression is regulated by the SNPs, and the information of SNPs was obtained from GTEx portal (https://www.gtexportal.org/home/).

Abbreviations: AM, additive model; DM, dominant model; RM, recessive model; BMI, body mass index; WHtR, waist-to-height ratio; OR, odd ratio; CI, confidence interval.

Table 4 Effects of Asthma-Associated SNPs on Poorly-Controlled Asthma Under Three Genetic Model (Only Show Results with p-values <0.05)

SNPs	Chr: Position	A1/ A2	Nearby Gene(s)	Regulated Gene(s) ^a (p <10^−4)	Poor Asthma Control
					BMI			WHtR
					AM	DM	RM	AM	DM	RM
					OR (95%CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
Risk SNPs
rs4688261	3: 61620775	A/ G	PTPRG	–	1.21 (1.01, 1.44)			1.20 (1.01, 1.44)
rs3800570	7: 138411332	G/ C	ATP6V0A4	–	1.31 (1.04, 1.66)		2.97 (1.44, 6.13)	1.35 (1.07, 1.72)		3.14 (1.51, 6.52)
rs4497664	15: 89261134	C/ T	Intergenic	ISG20 ACAN	1.27 (1.03, 1.57)		2.27 (1.30, 3.98)	1.28 (1.03, 1.58)		2.36 (1.34, 4.15)
rs437587	2: 79272737	T/ C	Intergenic	REG3G	1.24 (1.02, 1.52)		2.02 (1.25, 3.27)	1.23 (1.01, 1.51)		1.97 (1.21, 3.18)
rs1926075	20: 54880817	C/ A	Intergenic	–	1.24 (1.03, 1.49)		1.43 (1.01, 2.03)	1.22 (1.01, 1.46)
Protective SNPs
rs4663568	2: 236207394	G/ C	Intergenic	–	0.79 (0.65, 0.97)			0.78 (0.63, 0.95)	0.77 (0.60, 0.99)
rs210774	4: 27428596	C/ A	Intergenic	–	0.67 (0.52, 0.85)	0.60 (0.45, 0.79)		0.67 (0.53, 0.86)	0.60 (0.45, 0.80)
rs981710	4: 27658939	C/ T	Intergenic	–	0.77 (0.64, 0.92)	0.76 (0.58, 0.99)	0.64 (0.46, 0.89)	0.76 (0.63, 0.91)	0.75 (0.57, 0.98)	0.64 (0.46, 0.88)
rs10143946	14: 39040391	G/ T	Intergenic	–	0.81 (0.67, 0.98)	0.67 (0.52, 0.86)		0.82 (0.68, 0.99)	0.68 (0.53, 0.87)

Notes: Adjusted for obesity phenotype and one of the parents has asthma. SNPs information were obtained from the SNP database (dbSNP, GRCH 37.p13: https://www.ncbi.nlm.nih.gov/snp) of the National Center for Biotechnology Information (NCBI) and the Taiwan Biobank v3 (https://taiwanview.twbiobank.org.tw/index). “a” means the gene expression is regulated by the SNPs, and the information of SNPs was obtained from GTEx portal (https://www.gtexportal.org/home/).

Abbreviations: AM, additive model; DM, dominant model; RM, recessive model; BMI, body mass index; WHtR, waist-to-height ratio; OR, odd ratio; CI, confidence interval.

Figure 2 Covariate-adjusted ROC curve of combination effect of WHtR and BMI. (A) The effect of BMI and WHtR traits on poorly-controlled asthma. Model 1: BMI (CONT.) + WHtR (CONT). Model 2: BMI (BIN.) + WHtR (BIN). Model 3: Model 1+ asthma genetic score+ one of the parents has asthma. Model 4: Model 2+ asthma genetic score+ one of the parents has asthma. (B) The effect of BMI- and WHtR - related genetic score on poorly-controlled asthma. Model 1: BMI-related GRS+ WHtR-related GRS. Model 2: Model 1+ asthma genetic score+ one of the parents has asthma. Model 3: BMI-related GPS+ WHtR-related GPS. Model 4: Model 3+ asthma genetic score+ one of the parents has asthma. Model 5: Model 1+ Model 3. Model 6: Model 5+ asthma genetic score+ one of the parents has asthma. (C) The effect of BMI, WHtR and genetic score on poorly-controlled asthma. Model 1: BMI (CONT.)+ WHtR (CONT.)+ BMI-related GRS+ WHtR-related GRS. Model 2: Model 1+ asthma genetic score+ one of the parents has asthma. Model 3: BMI (CONT.)+ WHtR (CONT.)+BMI-related GPS + WHtR-related GPS. Model 4: Model 3+ asthma genetic score+ one of the parents has asthma. Model 5: Model 1+ Model 3. Model 6: Model 5+ asthma genetic score+ one of the parents has asthma. (D) The effect of obesity phenotype and genetic score on poorly-controlled asthma. Model 1: BMI (BIN.)+ WHtR (BIN.)+ BMI-related GRS+ WHtR-related GRS. Model 2: Model 1+ asthma genetic score+ one of the parents has asthma. Model 3: BMI (BIN.)+ WHtR (BIN.)+BMI-related GPS + WHtR-related GPS. Model 4: Model 3+ asthma genetic score+ one of the parents has asthma. Model 5: Model 1+ Model 3. Model 6: Model 5+ asthma genetic score+ one of the parents has asthma. The asthma genetic score was established using asthma-associated SNPs from Table 4.

Abbreviations: BMI, body mass index; WHtR, waist-to-height ratio; CONT, continuous; BIN, binary; GRS, genetic risk score; GPS, genetic protective score.