Austin Biomark Diagn. 2015; 2(2): 1020.
Astha Ranjan¹, Gagandeep Kaur Walia² and Vipin Gupta¹*
¹Department of Anthropology, University of Delhi, India
²Public Health Foundation of India, India
*Corresponding author: JVipin Gupta, Department of Anthropology, University of Delhi, Delhi-110007, India
Received: September 08, 2015; Accepted: October 12, 2015; Published: October 17, 2015
Lung function is a gold standard to diagnose Chronic Obstructive Pulmonary Disease (COPD), which is one of the leading causes of mortality in the world. Risk factors for COPD can cause one or more abnormal patterns of lung function, especially, environmental risk factors, like tobacco smoking, air pollutants, biomass fuel among which smoking is the primary risk factor but it is known that only 15-20% smokers develop COPD. With the advent of genomewide association studies, several genetic variants related to lung function like HHIP, HTR4, ADAM19, GPR126, and CHRNA3/5 have been discovered and replicated indicating their potential biological role in determining lung volumes. In this review, we have discussed about the latest developments in genomics of lung function.
Keywords: Lung function; Genomics; Public health; Chronic obstructive pulmonary disease
Lung function reflects the physiological condition of airways and lungs  and acts as an important long term predictor of morbidity and mortality across the globe . Lung volumes reaches its peak in early adulthood, followed by a plateau, and then subsequently declines which is likely to be influenced by genetic and environmental factors . Spirometry is a standard technique used for measuring lung function, identifying respiratory illness (like Chronic Obstructive Pulmonary Disease (COPD)), and for monitoring the progression of lung disease . The primary measures of lung volumes are Forced Vital Capacity (FVC) that approximates vital capacity, and Forced Expiratory Volume in 1st second (FEV1). The ratio of FEV1 to FVC is used to diagnose various respiratory diseases independent of lung size . A reduced FEV1/FVC ratio indicates airflow obstruction. In contrast, a reduced FVC suggests a restrictive ventilator defect, and acts as an independent (of other factors like age and smoking) and reliable predictor of mortality in the human population . Lung function is considered as a complex phenotype influenced by multiple genetic and environmental factors and their interactions . Twins and family based studies have provided consistent evidence of genetic contributions to lung function, with heritability estimates: as 85% for FEV1, 91% for FVC, and 45% for FEV1/FVC .
In GWAS, we test for association between the frequency of each of thousands of common variants and a given phenotype, call significant SNPs (single nucleotide polymorphisms) that exceed a conservative genome-wide threshold for association (usually P <5Ã—10â€“8), and then test these for evidence of replication in independent cohorts . GWAS have identified around 50 loci which have been associated with lung function [1-6,10-16]. Various GWAS studies have been conducted to confirm the association of different loci with lung function. Some of the identified loci have successfully been replicated in independent cohorts or populations. For example, HHIP, FAM13A, DLEU7, CHRNA3/5, HLA-A, ADAM19, RARB, PID1, GPR126, CFDP1, BMP6, EFEMP1, PRDM11, AGER-PPT2, HTR4 INTS12-GSTCD-NPNT were discovered by GWASs in relation to lung function and COPD [1,6,10-14,16]. Only few of them have been reported in more than one study, such as HHIP, HTR4, ADAM19, GPR126, and CHRNA3/5. In most of the studies, replication was not successful as it requires a large sample size [3,6,11-15,17].,
Gene expression studies analyzed 19 transcription sites in whole lung tissue, smooth muscles of airways, peripheral blood mononuclear cells and bronchial epithelial cells [2,3,5,6,13]. Out of 19 transcripts, 5 transcripts (KCNJ2, BMP6, WWOX, PRDM11, and H2D17B12) showed expression in all categories. Further, some of the loci were significantly related to lung function decline along with other variables and diseases, like variants at MFAP2 were associated with decreased FEV1/FVC, increased height as well as lung cancer; KCNE2 was associated with myocardial infarction; NCR3/AIF1 with neonatal lupus and systemic lupus erythematosus; CDC123 with type 2 diabetes, CFPD1 with type 1 diabetes; MECOM with blood pressure; BMP6 and EFEMP1 were also associated with height; an SNP in ADCY2 was associated with increased risk for COPD [1,6,18].
The validation of GWAS results in different human populations is an important task for establishing universal nature of identified genetic variants. For instance, SNPs in IREB2 (rs13180), CHRNA3/5 (rs8034191), ADCY2 (rs11134242) and HHIP (rs13118928) were associated with lung function and COPD in Polish population [18,19]. Genetic variants at or nearby THSD4-UACA-TLE3 and C10 or f11 reached genome-wide significance with FEV1/FVC in the combined (asthmatic and non-asthmatic) sample and in nonasthmatic subset of the Hutterite population (Europeans migrated to United States of America), respectively . Further, carriers of CHRNA3 had a significantly higher annual average decline of pre- FEV1 (used for pre-bronchodilator FEV1) than other genotypes and it was also correlated with COPD progression in a Chinese population . Moreover, there are two casual SNPs (rs1051730 & rs8034191) of CHRNA3 shared by lung cancer and COPD in European populations but were not associated with lung cancer risk in Chinese population . Two genes HTR4 and TNS1 were validated in KARE (Korean Associated Resource) cohort from CHARGE Consortium studies and the SpiroMeta Consortium . There were significant associations of FVC with KCNJ2 in Koreans and with EFEMP1 locus in African- Americans . In India, there are small size validation studies related to COPD where investigators have also investigated association of selected polymorphisms with lung volumes in control samples among male smokers . These observations suggest the relevance of validation of European findings in other human populations.
Unexplained heritability has become a well-known phenomenon in genetic epidemiology and possible explanations include multiple effects of common variants, rare variants, gene-by-environment interactions, gene-gene interactions and epigenetic regulationmechanisms that are not captured by existing GWAS platforms . The interaction effect size for C allele of rs360563 (CRISP2) accelerated decline in FEV1/FVC by 1.1% per Interquartile Range (IQR) change in PM10 (Particulate Matter having diameter 10Î¼m) exposure over 11years. Similarly, G allele of rs2035268 (SNCA) was associated with an accelerated decline by 3.8% per allele and IQR change in exposure, whereas, genotypes of SNCA variant (GT and GG) showed FEV1/FVC decline by 3.9% . Further, influence of interaction of rs9931086 (SLC38A8) with occupational exposure was observed on FEV1 suggesting the mediating pathways due to gene-environment interactions [23,24]. Overall, few number of large studies related to gene-environment interaction on respiratory health have been published  may be due to its requirement of large sample size, robust measurement of exposure and validated genetic variants.
Genome-wide approaches have helped in detecting several genetic variants associated with lung volumes in Western population groups and increased our understanding in their underlying genetic architecture. Gene-environment interaction studies are few in number due to its design related needs but such studies are important for estimating the effect of genetic variants in given environmental context. With very few validation studies in South East Asia, there is a need of research in populations with high diversity such as India, where limited number of genetic studies related to lung volumes are available (that too have used case-control design) rather than required population based studies.
- Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet. 2011; 43: 1082-1090.
- Hancock DB, Artigas MS, Gharib SA, Henry A, Manichaikul A, Ramasamy A, et al. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genet. 2012; 8: e1003098.
- Tang W, Kowgier M, Loth DW, Soler Artigas M, Joubert BR, Hodge E, et al. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. PLoS One. 2014; 9: e100776.
- Ong BA, Li J, McDonough JM, Wei Z, Kim C, Chiavacci R, et al. Gene network analysis in a pediatric cohort identifies novel lung function genes. PLoS One. 2013; 8: e72899.
- Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet. 2010; 42: 36-44.
- Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, et al. Genome-wide association analysis identifies six new loci associated with forced vital capacity. Nat Genet. 2014; 46: 669-677.
- Liao SY, Lin X, Christiani DC. Genome-wide association and network analysis of lung function in the Framingham Heart Study. Genet Epidemiol. 2014; 38: 572-578.
- Yao TC, Du G, Han L, Sun Y, Hu D, Yang JJ, et al. Genome-wide association study of lung function phenotypes in a founder population. J Allergy Clin Immunol. 2014; 133: 248-255.
- Gibson G. Hints of hidden heritability in GWAS. Nat Genet. 2010; 42: 558-560.
- Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT. Framingham Heart Study genome-wide association: results for pulmonary function measures. BMC Med Genet. 2007; 8 Suppl 1: S8.
- Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 2009; 5: e1000429.
- Wilk JB, Shrine NRG, Loehr RL, Zhao JH, Manichaikul A, Lopez LM, et al. Genome-Wide Assocition Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction. Am J Respir Crit Care Med. 2012; 186: 622-632.
- Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet. 2010; 42: 45-52.
- Imboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB, et al. Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clin Immunol. 2012; 129: 1218-1228.
- Hansel NN, Ruczinski I, Rafaels N, Sin DD, Daley D, Malinina A, et al. Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. Hum Genet. 2013; 132: 79-90.
- de Jong K, Boezen HM, Hacken NH, Postma DS, Vonk JM; Lifelines cohort study. GST-omega genes interact with environmental tobacco smoke on adult level of lung function. Respir Res. 2013; 14: 83.
- Hardin M, Zielinski J, Wan ES, Hersh CP, Castaldi PJ, Schwinder E, et al. CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland. Am J Respir Cell Mol Biol. 2012; 47: 203-208.
- Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J, Hawrylkiewicz I, et al. Identification of chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum Mol Genet. 2012; 21: 1325-1335.
- Yang L, Qiu F, Lu X, Huang D, Ma G, Guo Y, et al. Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese. PLoS One. 2012; 7: e46071.
- Lee BY, Cho S, Shin DH, Kim H. Genome-wide association study of copy number variations associated with pulmonary function measures in Korea Associated Resource (KARE) cohorts. Genomics. 2011; 97: 101-105.
- Arja C, Ravuri RR, Pulamaghatta VN, Surapaneni KM, Raya P, Adimoolam C, et al. Genetic determinants of chronic obstructive pulmonary disease in South Indian male smokers. PLoS One. 2014; 9: e89957.
- Curjuric I, Imboden M, Nadif R, Kumar A, Schindler C, Haun M, et al. Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population. PLoS ONE. 2012; 7: e40175.
- Herbert JR, Pednekar MS, Gupta PC. Forced expiratory volume predicts all-cause and cancer morbidity in Mumbai, India: results from a population-based cohort study. International Journal of Epidemiology. 2010; 39: 1619-1627.
- Liao SY, Lin X, Christiani DC. Gene-environment interaction effects on lung function- a genome-wide association study within the Framingham heart study. Environmental Health. 2013; 12: 101.