Environmental Exposure and Genetic Predisposition as Risk Factors for Asthma in China.

Asthma is the most common chronic pulmonary disease worldwide and places a considerable economic burden on society. China is the world's largest developing country and has the largest population. China has undergone dramatic changes in the past few decades. The traditional lifestyle and living environment have changed in ways that directly affect the prevalence of asthma. The prevalence of asthma is lower in Chinese children and adults than in developed countries, but the prevalence has been on the rise during the past 30 years. The prevalence significantly varies among different parts of China. Polymorphisms of multiple genes, outdoor air pollution caused by PM2.5, PM10, SO₂, NO₂, environmental tobacco smoke, and coal, indoor pollution, and inhaled allergens, such as house dust mites, pollen, and cockroach particles, are risk factors for asthma.

INTRODUCTION

Asthma is one of the most common chronic lung diseases all over the world. It affects people of all genders, races, and ages. The cost of treatment has consumed an enormous amount of health resources in all affected nations. These issues pose severe social and economic problems. Approximately 3 billion patients have been diagnosed with asthma. The total cost of asthma to society is about 1% of global disability-adjusted life years (DALYs), being comparable to that of diabetes mellitus.1

In the past few decades, China has undergone huge social changes. Traditional lifestyle and environment have been challenged by industrialization, urbanism, and the accompanying environmental pollution and changes in the weather and ecological environment. According to the China guideline for management of asthma,2 the criteria for diagnosis of asthma includes: (1) symptoms, such as episodic breathlessness, wheezing, cough, and chest tightness after an incidental allergen exposure, seasonal variability, exposure to physical and chemical stimulants, upper airway viral infection, and exercise; (2) bilateral and scattered or diffuse expiratory wheezing on auscultation, with expiratory phase extension; (3) the above symptoms and signs that can be relieved automatically or after treatments; (4) symptoms of episodic breathlessness, wheezing, cough, and chest tightness not being caused by other diseases; and (5) reversibility of pulmonary function, such as improvement in forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) measurements after inhalation of a short-acting bronchodilator or more sustained improvement over days or weeks after the introduction of effective controller treatment, such as inhalant glucocorticosteroids. The prevalence of asthma has also changed. Most of the Western countries have followed a similar pattern: the prevalence of asthma first increased and then stabilized or decreased.3 In contrast, several epidemiological studies have shown the prevalence of asthma to be lower in China than in developed Western countries, but available data suggested a more rapid rising trend.3 However, the population of China is 1.3 billion and continues to grow. Even small increases in prevalence bring huge increases in the number of patients and place a great burden on families and society. Recent national epidemiological surveys in China have estimated the prevalence and evaluated possible risk factors of asthma, thereby facilitating evidence-based asthma prevention. This review sought to use the data from these surveys to establish the trends and to determine of the prevalence of asthma in China and to identify the environmental and genetic factors associated with asthma.

Regional difference in the prevalence of asthma

The epidemiologic questionnaire surveys conducted after 2000 are shown in Table 1.4567891011121314 Results showed asthma in China to have the highest prevalence in children in Hong Kong at 10.2%5 and the lowest in Lhasa at 1.1%.6 Among inner city environment, the highest prevalence was detected in Chongqing at 7.45%,8 and the lowest in Shijiazhuang at 1.2%.11 Another study conducted in 8 inner city settings showed the prevalence of "current asthma" (asthma in the past 12 months) in children at ages 6-7 ranged from 0.9% in Hohhot and 1.1% in Xi'an to 7% in Shanghai.15

Table 1

Lifetime prevalence of asthma* as indicated by international questionnaires and surveys

Author (yr)	Region	Study year	Questionnaire category	Simple size	Age group (yr)	Prevalence (%)
Lee SL, 20044	Hong Kong	2001	ISAAC	4,448	6-7	7.9
Wong GW, 20045	Hong Kong	2002	ISAAC	3,321	13-14	10.2
Droma Y, 20076	Lhasa	2001	ISAAC	3,196	13-14	1.1
Ma Y, 20097	Beijing	2003-2004	ISAAC	3,531	13-14	6.3
Zhao J, 20118	Beijing	2008-2009	ISAAC	10,372	≤14	3.15
	Chongqing			9,874		7.45
	Guangzhou			4,072		2.09
Wang HY, 20069	Guangzhou	2001	ISAAC	3,516	13-14	4.6
Li J, 201310	Guangzhou	2009-2010	ISAAC	6,928	13-14	6.9
Song N, 201411	Shijiazhuang	2011	ISAAC	10,338	3-18	1.2
Dong GH, 201112	Liaoning	2009	ATS	30,139	3-12	6.6
Wilson, 200813	Liaoning	2002	ATS	31,704	≥14	1.0
Shi Z, 201214	Jiangsu	2007	CNNH	1,486	≥20	1.4

*Asthma: defined as participants self-reported or parents reported "ever had asthma" by questionnaire.

ISAAC, The international study of asthma and allergies in childhood; ATS, The American Thoracic Society questionnaire; CNNH, The Chinese National Nutrition and Health Survey.

Table 2 lists the epidemiologic studies of asthma based on physician diagnosis.1617181920212223242526272829 The investigations were performed through screening by questionnaires, followed by medical history taking, physical examination, pulmonary function testing, and airway reversibility tests for suspected patients, and ultimately the diagnosis of asthma was made according to the Chinese asthma diagnosis guideline. In the 3 nationwide epidemiological surveys of childhood asthma, the lowest overall prevalence was found in Lhasa (0.09% in 1990, 0.48% in 2010) and in xining (0.12% in 2000). The highest rates were detected in Chongqing (2.9% in 1990), in Shanghai and Chongqing together (3.34% in 2000), and in Shanghai (7.57% in 2010). In other similar surveys conducted in 10 inner cities, the prevalence ranged from 1.34% in Dalian to 4.56% in Shaoxing.30313233343536373839 The prevalence was higher in children than in adults in all the locations tested except Hainan.22 The prevalence among individuals older than 14 ranged from 0.31% in Qinghai to 3.6% in Hainan.2223

Table 2

Lifetime prevalence of asthma* by Chinese physician diagnosed surveys

Author (yr)	Region	Study year	Age group (yr)	Sample size	Prevalence (%)
Chen YZ, 200416	27 cities	1990	≤14	399,193	0.09-2.60
Chen YZ, 200317	43 cities	2000	≤14	432,500	0.12-3.34
Chen YZ, 201318	43 cities	2009-2010	≤14	463,982	0.48-7.57
FenXK, 201419	Beijing	2010	>14	57,647	1.19
	Shanghai			17,805	1.14
	Guangdong			14,465	1.13
	Liaoning			18,648	1.69
	Jiangsu			14,069	0.86
	Sichuan			9,030	2.30
	Henan			17,017	0.87
	Shaanxi			15,534	1.21
Wang GB, 200220	Henan	2000	≤14	16,997	1.71
			>14	48,036	0.82
Zhang SZ, 200521	Zaozhuang	2003	≤14	2,923	2.02
			>14	7,687	0.90
Ding YP, 201222	Hainan	2003-2007	≤14	1,352	1.48
			>14	11,698	3.6
Gao F, 201123	Qinghai	2006-2007	≤14	3,510	0.85
			>14	24,341	0.31
Wang, 201324	Jinan	2009	≤14	1,355	0.81
			>14	12,013	0.62
Yang Y, 201225	Qiannan	2010-2011	1-14	2,802	9.28
			>14	18,765	2.73
Qian JJ, 201126	Shanghai	2010-2011	4-14	257	3.89
			>14	4,699	1.81
Cai WS, 201327	Jinzhou	2010-2011	≥4	4,000	1.2
Hwang, 201028	Taiwan	2000-2007	All age	997,729	2.9
Lei M, 200529	Xianing	2002	All age	14,216	0.96

*Asthma is defined as physician diagnosed base on the Chinese diagnostic criteria. Participants screened by questionnaires, and suspected cases were diagnosed by case history, clinical signs, and lung function tests.

A preliminary map was created to show geographical differences in the prevalence of asthma (Fig. 1). Overall asthma prevalence was higher in plains areas than in plateau areas, in southern cities than in northern cities, and in eastern China than in further western China. The highest prevalence of childhood asthma in China, as assessed by questionnaires and physician diagnosis, were 10.2% and 7.57%, respectively, far below Australia's 32%, the United States's 24.4%, England's 14.9%, and Singapore's 27.4%.40414243 For adults, the prevalence of asthma varies by age and urban or rural area. The highest prevalence in China, as assessed by questionnaires and physician evaluations, were 5.1% and 3.58%, respectively, being both lower than in Western countries, such as the United States's 8.4% or Canada's 13.5%.4445

Fig. 1

Geographic differences in the prevalence of asthma in (A) children and (B) adults. Childhood asthma prevalence was retrieved from the 2010 nationwide data. Adult asthma prevalence was determined using data from local area studies.

Trends in the epidemiology of asthma

In Hong Kong, the incidence of asthma in children of two age groups showed no change between phases I and III of the International Study of Asthma and Allergies in Childhood (ISAAC) surveys (7.8% and 7.9% at ages 6-7, 11.2% and 10.2% at ages 13-14).45 Furthermore, the prevalences of current wheeze and other asthmatic symptoms in children at ages 13-14 all showed decreased trends in the 2 surveys.5 As shown in national epidemiological studies of children with asthma in inner cities conducted in 1990, 2000, and 2010, the incidence in most cities increased significantly (Fig. 2).161718 The incidences in some large cities that had shown a higher incidence in the past continued to rise. For instance, in these 3 epidemiological studies,1618 the incidence in Beijing was 0.77%, 2.05%, and 2.55%, respectively, and the incidence in Shanghai was 1.50%, 3.34%, and 5.73%, respectively. In Suzhou, the incidence was lower in 2010 than in 2000 (3.22% vs 3.74%) but higher than in 1990 (1.85%). Guangzhou is the only one city that showed no change across these 3 epidemiological studies. However, from the results of the ISAAC study, the prevalence of children aged 13-14 years in Guangzhou increased significantly, from 3.9% in 1996 and 4.6% in 2002 to 6.9% in 2010.10 In these 3 epidemiological studies of children with asthma,1618 the prevalence in children at ages 0-14 increased from 0.91% in 1990 and 1.97% in 2000 to 3.02% in 2010, increases of 64.84% and 52.8%, respectively. The 2-year cumulative incidence increased from 1.54% in 2000 to 2.32% in 2010, by 50.6%.

Fig. 2

The Prevalence and trend of asthma among children in the last 3 decades.

*no significant difference between 2000 and 2010 surveys; †no significant difference between 1990 and 2000 surveys.

The incidence of asthma in other age groups showed a similar upward trend. In 2010, the incidences in individuals over 14 years in Guangdong, Liaoning, and Henan Provinces were 1.13%, 1.69%, and 0.87%, respectively.19 These rates represented 14.14%, 21.58%, and 6.1% increases, when compared with their respective prevalences. They were only 0.99% in 1999 for Guangdong,46 1.39% in 1999 for Liaoning,47 and 0.82% in 2000 for Henan.20 Jinzhou showed a significant increase from 0.71% in 1999 to 1.2% in 2010 in a survey of individuals above 4 years old.27

Genetics and asthma

The study of Wang et al.48 indicated that ethnicity is a risk factor among urban Chinese children at ages between 6 and 14 (OR=1.61, 95% CI: 1.26-2.06). A series of studies have given considerable attention to the idea that genetic polymorphism might contribute to the development of asthma and may possibly be one of the reasons for these difference.495051 Liu found that the genotype and allele frequencies of the 2 SNPs Rs2289276 and Rs2289278 in the TSLP were significantly different between Chinese Han asthma patients and the healthy controls. The C allele of rs2289278 showed a close association with the decrease in FEV1:FVC.52 Chen et al.53 found that IL-17 G-152A polymorphism (rs2275913) is a risk factor for allergic asthma of children in southwestern China and the AA genotype presents an association with an increase in IgE serum levels of asthmatic children and abnormal pulmonary function. The distribution frequency of the ADAM33 and CD14 gene polymorphisms differed between the Uighur people of the Turpan region, Chinese Han individuals, and Caucasian individuals. The Hap3 (CAC) and Hap4 (CAG) haplotypes are risk factors for asthma, whereas the Hap2 (TGC) haplotype may be a protective factor against the disease among Uighur individuals.54 The interaction of coal combustion type of air pollution (PM4, SO2, CO) with the Gly/Gly genotype of β2-AR 16 loci and the DD genotype of the ACE gene might increase the risk of childhood asthma.55 The polymorphism of 17q21 may be related to adult-onset asthma in China.56 Leung et al.57 compares more than 20 SNPs from asthma candidate genes between southern Han Chinese subjects in Hong Kong and other populations, including other Han Chinese subjects in the rest of China, Japanese subjects, European white subjects, Yoruba African subjects, and American Puerto Rican subjects. Substantial interethnic differences in the genetic epidemiology of many SNPs were found.

Prevalence of asthma in urban and rural areas

Some epidemiological surveys compared the prevalence of asthma in urban and rural areas (Fig. 3). Almost all the surveys showed remarkable differences between urban and rural areas. The prevalence of asthma in children in rural parts of Lhasa was 2.5%. It was only 1.1% in urban areas.658 The prevalence of asthma in individuals older than 14 years was higher in rural parts of Hainan and Henan than in cities in those provinces.2022 In areas other than the ones listed above, the prevalence of asthma was higher in urban areas than in rural areas. Children at ages 13-14 showed a much higher prevalence in urban areas in Beijing (6.3%) than in rural areas (1.1%).7 The prevalence of children aged 13-14 with asthma and recent wheezing in urban parts of Guangzhou were 6.9% and 6.1%, respectively. These values were higher than the 3.4% and 1.6% in rural areas.1059 Among the children at ages 0-14, those in urban parts of Chengdu and other cities showed significantly higher prevalences of asthma than in rural parts.32366061 Similar results were observed in surveys of adults and children in Jinan and Xianning.2429 Gao et al.23 showed that urban parts of Qinghai Province had a higher prevalence of asthma than rural areas (0.27% vs 0.64%), but the pastoral and half-farming/half-herding areas had an even lower prevalence (0.04% and 0.15%). A comparative study between urban and rural areas in Guangzhou revealed that the concentration and load of endotoxin were higher in rural areas than in urban areas. Endotoxin levels have been shown to be correlated with PD20-FEV1, but negatively with allergic skin tests against house dirt mites and dust mites. This might be a possible reason for the lower prevalence of asthma in rural areas.62

Fig. 3

The difference in asthma prevalence (%) between urban and rural areas.

*data from surveys in children

Air pollution and asthma

Air pollution is one of the major contributors to airway disease. Air pollution can induce and aggravate asthma symptoms.63 The frequencies of emergency department visits and hospitalizations in asthmatic patients increase with the levels of specific air pollutants, such as O3, PM10, PM2.5, NO2, and SO2.646566 The investigation of over 30,000 adults in Liaoning Province, a northern China's great industrial province, indicated that the prevalences of persistent cough, persistent sputum production, and wheezing were increased progressively with proximity of housing to major traffic roads, factories, and large smokestacks (persistent cough χ2=24.58, P<0.001; persistent sputum production χ2=16.47, P<0.00l; wheezing χ2=8.49, P<0.05).13 Another investigation of children in the same province showed that the prevalence of asthma increased 1.34-fold, 1.23-fold, and 1.31-fold for each additional 31 m µg/m3 of PM10, 21 m µg/m3 of SO2, 10 m µg/m3 of NO2, and 23 m µg/m3 of O3.67 The improved air quality during Beijing Olympics was associated with a significant reduction in the frequency of outpatient visits by asthmatics. This provides further evidence that outdoor air pollution is related to asthma attacks.68

Indoor air quality has similar effects on asthma. Rural areas showed a higher prevalence of asthma than urban areas in Hainan Provinc. The pattern may be related to the habit of using biomass, heavy smoke air pollution, and airway injury caused by long-term inhalation of those gases. This is consistent with previous findings reported by Smith.69 Based on a study of ISAAC, the use of open fire as a cooking method was associated with the increased risk of asthma symptoms.70 Another study among 4 cities in China, children exposed to heating coal smoke more easily presented with wheezing and sputum production. Children exposed to environmental tobacco smoke (ETS) present with chronic coughing with sputum. However, increased indoor air ventilation was associated with a lower frequency of these symptoms.71

In the absence of a birth cohort study, it is difficult to confirm whether air pollution is related directly to the development of asthma. Average air quality index data in 2004-2010 were collected from National Bureau of Statistics of China for correlation analysis that measures the change rate of children asthma prevalence in 2000-2010.72 No correlation was found between asthma prevalence and PM10, SO2, or NO2 (Fig. 4). Zhang et al.73 conducted a study of 10 cities, including Beijing, and found no correlation between the PM10 level and the prevalence of childhood asthma at ages between 3 and 6 years. Another paradox is that the air pollution index is 3-to 4-fold higher in China than in Western countries, but the prevalence of asthma is much lower in China. Air pollution is more likely to cause exacerbations in those with pre-existing asthma and may not play an important role in the inception of asthma.

Fig. 4

Bland-Altman plots showing the average air-pollution index vs the mean change in prevalence of asthma from 2004 to 2010.

Environmental allergen and asthma

Allergens are important influential factors for asthma. The most common inhaled allergen in China is the house dust mites (HDMs). A recent study showed that 59.0%, 57.6%, and 40.7% of patients with allergic diseases were allergic to Dermatophagoides (D.) farinae, D. pteronyssinus and Blomia tropicalis respectively.74 HDMs multiply easily in warm, humid indoor environment found in southern China. Dust samples were collected from 107 participating households in Guangzhou. Dust mite allergens were detected in 99% of the dust samples. The level of HDM allergens in 88% of the bedding samples was above 10 µg/g.75 Another study in Guangzhou showed the prevalence of wheezing symptoms in children with sensitization to D. farinae increased from 14.4% in 2001 to 30.9% in 2009. The prevalence of wheezing symptoms in children with sensitization to D. pteronyssinus also increased from 15.3% in 2001 to 33.1% in 2009.

The prevalence of wheezing was higher in children with sensitization to HDMs than in those without sensitization to HDMs (33.1% vs 6.8% for positive and negative reaction to D. pteronyssinus, and 30.9% vs 9.5% for positive and negative reaction to D. farinae). It has been demonstrated that sensitization against HDMs is an important risk factor for the increasing prevalence of childhood asthma.10

In the dry climate of northern China, the concentration of HDMs is very low. A previous study on families with asthmatic children in Beijing reported that the average concentrations of D. pteronyssinus and D. farinae were 0.02 µg/g and 0.13 µg/g, respectively.76 Another important inhalant allergen in northern area is pollen. Artemisia and Humulus (including Cannabis Sativa L) are the main airborne pollen in autumn in Beijing, accounting for 31% and 51%, respectively. The daily average concentrations of Artemisia and Humulus pollen allergens are 71 g/m3 and 672 g/m3 with an average of 124 g/m3 during Artemisia pollen season from August to October, respectively. In summer and autumn, 88.5% of out-patients with hay fever, asthma, or both were positive for Artemisia pollen, and 28.2% were positive for Humulus pollen.77 An other study of asthmatic patients allergic to Artemisia and Humulus showed significant correlations between asthmatic symptoms, PEF values and pollen concentrations. The higher the pollen concentration, the lower the patient's PEF value, the higher the asthma symptom score and PEF daily variation. Pollen is found to play a critical role in allergic asthma during summer and autumn in northern China.78

Other common inhaled allergens include cockroach, cat fur, and dog fur. Cockroach exposure is a major risk factor for the development of asthma79 and common in southern China, especially in rural areas.6280 A multicenter study on sensitizations in patients with rhinitis and/or asthma in China showed that the rate of sensitization to Periplaneta americana and Blattella germanica were 26.34% and 19.37%, respectively. Although skin reaction against cockroach was mild in our patients, there was a significant relationship between cockroach sensitization and prevalence of asthma.81 In the past few decades, more and more Chinese families started keeping pets. The presence of cats in households is strongly associated with the detection of cat allergen Fel d1.82 Most investigations have suggested a strong association between the positive IgE antibody or positive skin test reaction against Fel d1 or cat and asthma. Nevertheless, some studies have shown a lower asthma prevalence to be associated with a high level of Fel d 1 IgG but not IgE indicated that children were highly exposed to cat.83 Birth cohort studies showed that the first year after birth is a critical period for inducing tolerance to cat allergen. Among children who came into contact with cats in the first year of life, sensitivity to cats at age of 18 years decreased by more than half.84

CONCLUSIONS

The prevalence of asthma is lower in Chinese children and adults than in those of developed countries but has rapidly risen during the past 30 years. The prevalence significantly varies among different parts of China. The polymorphism of multiple genes, outdoor air pollution caused by PM2.5, PM10, SO2, NO2, ETS, and coal, indoor pollution, and inhaled allergens, such as HDMs, pollen, and cockroach particles, are risk factors for asthma. In-depth studies of both genetic factors and their interaction with different environmental factors are crucial for our understanding of true causes of asthma.