Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function

Abstract

Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.

Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.

Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.

Measurements and main results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)).

Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

Figure 1.

Study design. Single-nucleotide polymorphisms (SNPs) genotyped at each of the loci listed were rs2571445 (TNS1), rs10516526 (GSTCD), rs12504628 (near HHIP), rs3995090 (HTR4), rs2070600 (AGER), and rs12899618 (THSD4). Study 1 included all participating studies. Study 2 included the subset of studies that were genotyped for all six SNPs and that were not included in the discovery set of genome-wide association study (GWAS) data that led to the discovery of our five loci (9). Individuals excluded from study 2 chronic obstructive pulmonary disease (COPD) analyses were as follows: (1) individuals under the age of 40 years, (2) individuals with stage 1 COPD (FEV₁/FVC < 0.7 and percent predicted FEV₁ > 80%), and (3) individuals with FEV₁/FVC greater than 0.7 but percent predicted FEV₁ less than 80%. Study abbreviations are as follows: EPIC obese case subjects (European Prospective Investigation into Cancer and Nutrition-obese case subjects) and EPIC population-based (European Prospective Investigation into Cancer and Nutrition cohort), GS:SFHS (Generation Scotland: Scottish Family Health Study), KORA F4 (Cooperative Health Research in the Region of Augsburg), ADONIX (Adult-onset Asthma and Nitric Oxide), BHS (Busselton Health Study), BRHS (British Regional Heart Study), BWHHS (British Women's Heart and Health Study), Gedling (Gedling Study), HCS (Hertfordshire Cohort Study), Health 2000 (Finnish Health 2000 Survey), Nottingham Smokers (Nottingham Smokers Study), and NSHD (Medical Research Council National Survey of Health and Development, also known as the British 1946 Birth Cohort).

Figure 2.

Association of sentinel single-nucleotide polymorphisms (SNPs) at five novel lung function loci and a previously reported HHIP SNP with chronic obstructive pulmonary disease (COPD), and comparison with reported associations with FEV₁ and FEV₁/FVC. Shown are the results for COPD after testing for association in 3,284 COPD case subjects and 17,538 control subjects, and a comparison with the associations with FEV₁ and FEV₁/FVC in the combined discovery and follow-up data reported by Repapi and colleagues (9). Boxes indicate the point estimates of the effect sizes and whiskers the 95% confidence intervals.

Figure 3.

Forest plots of the meta-analysis of association tests with chronic obstructive pulmonary disease (COPD) for the six loci (TNS1, GSTCD, HHIP, HTR4, AGER, and THSD4). *rs12504628 (HHIP) data were not available in GS:SFHS or KORA F4. ^†KORA F4 failed to genotype rs3995090 (HTR4). ADONIX = Adult-onset Asthma and Nitric Oxide Study; BHS = Busselton Health Study; BRHS = British Regional Heart Study; BWHHS = British Women's Heart and Health Study; COPD = chronic obstructive pulmonary disease; EPIC = European Prospective Investigation into Cancer and Nutrition; GS:SFHS = Generation Scotland: Scottish Family Health Study; HCS = Hertfordshire Cohort Study; KORA F4 = Cooperative Health Research in the Region of Augsburg; NSHD = Medical Research Council National Survey of Health and Development.

Figure 4.

Association of risk scores with lung function and chronic obstructive pulmonary disease (COPD). The risk score theoretically ranges from 0 to 12 across the six loci (TNS1, GSTCD, HHIP, HTR4, AGER, and THSD4). The risk allele category was in each case compared with a baseline of seven risk alleles. Boxes indicate the point estimates of the effect sizes and whiskers the 95% confidence intervals. ^‖To facilitate the plotting of the effect size estimates for FEV₁ and FEV₁/FVC on the same axes, effect sizes are given in terms of the proportion of a standard deviation of FEV₁ and FEV₁/FVC; we used a standard deviation of 752 ml for FEV₁ and 9.45% for FEV₁/FVC (obtained as weighted averages across studies). **Proportion of individuals within each risk score category.