The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines chronic obstructive pulmonary disease (COPD) as a preventable and treatable condition with extrapulmonary effects that contribute to severity. The pulmonary disease component is characterized by restricted airflow, which is not completely reversible. Airflow obstruction is usually progressive and is associated with an abnormal inflammatory response in the lung, caused by particles or toxic gases. COPD is a disease with several genetic components, of which alpha-1 antitrypsin (AAT) deficiency is the best documented to date.1

AAT is a protein that is mainly synthesized in the liver and secreted into the blood stream, although it is also synthesized to a lesser degree by alveolar macrophages. AAT is an important protease inhibitor, with normal plasma levels ranging from 120 to 220mg/dL, and is also the enzyme responsible for maintaining protease-antiprotease equilibrium in the lung.2 Recent studies have indicated that AAT has anti-inflammatory activity,3 inhibits TNF gene expression,4 and inhibits human monocyte and neutrophil migration when activated by lipopolysaccharide in vitro.5

AAT is encoded by the SERPINA1 gene, which is located in the q32.1 cytogenetic band of chromosome 14. It is transmitted in an autosomal codominant fashion and is characterized by large numbers of polymorphic variants.6,7 The group of AAT variants is referred to as the protease inhibitor (Pi) system. Most of these variants lack any clinical relevance, and only 30 have a defined pathological impact.8 The most common variant is PiM, which is considered a “normal phenotype”, given that 90% of healthy subjects have the homozygous genotype (PiMM). The PiZ (rs28929474) and PiS (rs17580) variants give rise to 90% of AAT deficiency cases. When combined, these variants produce the PiSS, PiSZ and PiZZ phenotypes, the latter two of which are considered severely deficient variants and are associated with low protein concentrations in serum and a high risk of developing COPD at an early age.9,10 Variant Z arises from a G-to-A transition at nucleotide 11940 in exon 5 of the SERPINA1 gene, which results in the substitution of glutamic acid with lysine at position 366 of the AAT and gives rise to a protein with abnormal antiproteolytic function.10,11 Variant S arises from an A-to-T transversion at nucleotide 9628 in exon 3, which leads to the substitution of glutamic acid with valine at position 288 of the protein.11–13

Genotyping the clinically relevant SERPINA1 variants will be beneficial not only for identifying subjects with severe AAT deficiency but also for identifying cases with intermediate deficiency. The latter type of deficiency has also been linked to a decline in lung function.14

In this study, we analyzed the frequency of the genetic polymorphisms PiZ (rs28929474) and PiS (rs17580) associated with AAT deficiency and their association with lung function values in a Mexican mestizo population.

The characteristics of both study groups are briefly summarized in Table 2. A statistically significant difference was found when the age of smokers with COPD was compared to the age of smokers without COPD (P<.05). Gender representation was evenly distributed between groups. When smoking habits between patients with COPD and SWCs were compared, the patients were found to smoke more cigarettes and have decreased lung function in comparison to the control group.

SERPINA1 Variants and Lung Function

The study population (COPD and SWC) was divided according to the genotypes detected, yielding subjects with the common genotype and subjects with the risk genotype for each SNP. The Kruskal–Wallis test was used to compare lung function values. When median FEV1/FVC was compared, the heterozygous genotype for rs17580 (PiS) exhibited a P value of .037 (Fig. 1). The box and whisker plot, which indicates the median for each group and its respective limits, shows that individuals with the heterozygous genotype AT had a lower FEV1/FVC ratio compared to subjects with the homozygous genotype AA, which corresponds to PiM variant in the serum. Furthermore, a bivariate logistical regression revealed a significant association between the FEV1/FVC ratio and the AA genotype for rs17580 (OR=0.982, β coefficient=−0.019, 95% CI=0.966–0.997). These results suggest that genotypes other than AA are risk factors, since the AA genotype encodes normal protein. We found no association with any other lung function measurements.

Fig. 1.

Median FEV1/FVC (%) based on the genotypes obtained for rs17580 (PiS) in the study population. Note: Generated with SPSS 15.0 for Windows using the Kruskal–Wallis test.

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COPD development in an AAT deficiency context is generally variable. Host-specific factors, such as gene modifications, probably interact with environmental factors to contribute to individual disease manifestations. Our study was the first to evaluate the frequency of 2 main risk alleles for AAT (SERPINA1) deficiency, PiS (rs17580) and PiZ (rs28929474), in a Latin American mestizo population with Amerindian and Caucasian genetic contributions. We studied 558 smokers, who were divided according to health status into patients with COPD and disease-free smokers. Our findings indicated that the frequency of the risk genotypes (TT and AA homozygotes) was zero, while the PiS heterozygote (rs17580 AT) genotype was detected at a frequency of up to 10% in patients with COPD and 7.52% in disease-free smokers. In contrast, the PiZ heterozygous genotype (rs28929474 GA) was found in 2.15% of patients but only in 0.35% of control group subjects. The differences in risk genotype frequencies are almost certainly due to the ancestral origin of each genetic variable.

Smoking is the main cause of more than 90% of COPD cases. However, it has been estimated that only 10%–20% of smokers develop this disease, and this could be due to genetic and/or environmental factors that modulate the toxic effect of cigarette smoke.20 The PLATINO study showed that COPD prevalence in Latin America ranges from 5.6% in Mexican women to 27.2% in Uruguayan men, with the lowest prevalence of the disease reported in Mexico. One hypothesis attributes this difference to the altitude above sea level.21,22 However, the population of Mexico City differs from that of other cities mainly due to its ethnic composition, which suggests that genetic factors could play a role in the low COPD prevalence observed among Mexicans. In this regard, AAT deficiency is the genetic factor most clearly associated with COPD and increases the risk of developing pulmonary emphysema for smokers, especially at an early age.20 The guidelines of the World Health Organization (WHO) and the ATS/ERS scientific societies have explicitly indicated that quantification of serum AAT levels should be performed for all COPD patients as part of the standard diagnostic procedure. It is also important to indicate when and how other laboratory diagnostic tests, such as phenotype or genotype assessments, should be performed.23 However, serum AAT quantification requires the absence of temporary inflammatory processes, which could alter the AAT levels.

It is estimated that 100000 individuals are affected by AAT deficiency in the United States, and similar rates have been reported in Europe.24 There are at least 116 million carriers (PiMS and PiMZ) and 3.4 million individuals with a combination of deficiency alleles (PiSS, PiSZ, PiZZ). In addition, it has been reported that AAT deficiency affects individuals of all racial sub-groups worldwide.25 However, there are few data concerning the frequency of these deficiency alleles in a Mexican mestizo population. For historic reasons, this population contains a large, mainly Spanish, Caucasian genetic component.26 In this respect, the use of racial or ethnic classifications in medicine has been the subject of multiple studies.27 Currently, lung function measurements are one of the few clinical applications in which race definition (in terms of ethnicity) is taken into account to establish health condition reference parameters, and ancestry-based lung function prediction models have been shown to fit the data better than standard models.28

Genome mapping studies have suggested that the PiZ allele arose in northern Europe29,30 and it is estimated that this variant has been in existence for 107–135 generations. The PiS allele has been in existence for 279–470 generations, and it is thought to have originated in the European region, given its high incidence in the Iberian Peninsula.30,31

Poorer lung function measurements associated with PiZ homozygotes are well documented. However, the role of the so-called intermediate deficiency genotypes (PiMZ and PiMS) has not been well studied. In our study, we found a lower FEV1/FVC (%) value among AT heterozygote carriers for rs17580 (PiS) compared to AA homozygous subjects. Other studies have shown a similar effect for the PiZ genotype. First in 200131 and subsequently in 2002,32 Morten Dahl et al. studied the effect of the intermediate deficiency genotypes on lung function in a Danish population. By taking spirometric measurements (FEV1 and FVC) and genotyping SERPINA1 alleles, these authors found that PiSZ heterozygotes had lower FEV1/FVC ratios compared to individuals without the risk genotype (PiMM). Although PiZ homozygotes had lower FEV1 percentages and FEV1/FVC ratios than the rest of the genotypes (MS and MZ), stratification of the results by smoking status revealed that the decrease in lung function in SZ and ZZ vs MM individuals was only statistically significant between smokers and ex-smokers. Furthermore, MZ individuals were shown to have decreased lung function compared to MM patients, which suggests that the MZ heterozygous genotype (rs28929474 GA) only acts in certain contexts, which have yet to be determined. These studies show that the MZ genotype, compared to the MM genotype, is associated with decreased lung function in individuals with COPD. Furthermore, the SZ and ZZ genotypes are associated with airway obstruction and decreased lung function, especially in smokers.31

Proper examination of population subgroups is an vital step for identifying important factors related to the prevention and timely treatment of lung diseases associated with total or partial AAT deficiency, primarily COPD.

AAT deficiency risk alleles causing COPD occur at a very low frequency among Mexican mestizo population. Although they are not directly linked in our study population with disease susceptibility, these risk alleles are associated with poorer lung function measurements. It is important to characterize how often these genetic risk variants occur in other Latin American populations.

This study was partially funded by the Consejo Nacional de Ciencia y Tecnología (CONACyT) of Mexico, code FOSIS S0008-87380.

Study design, and technical data by GPR, LOJV, RFV; statistical analysis and drafting of manuscript by GPR, LOJV, ARV, AC, RHS, FFT, JMRH, RFV.

The authors declare no conflict of interests.