African ancestry, lung function and the effect of genetics

Introduction

African-Americans have shown consistently smaller lung function compared with European-Americans [1–9]. In addition, forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) in African-Americans differed from those in Caucasians by the same percentage, signifying that, for the same age and height, lung dimensions differed proportionately [6]; it should be mentioned that the information about race and ethnicity in most of the literature has been self-reported. However, according to Kumar et al. [3], in the absence of genetic typing, predicted values in self-reported African-Americans may be biased by up to 200 mL. It should be emphasised that most of the literature does not define race at all [9].

Commonly reported ethnic and racial differences in pulmonary function have been attributed to differences in body build, such as chest size relative to height (approached by the Cormic index: sitting to standing height ratio). Lung function in general is proportional to body size as indicated by standing height. However, ethnic groups with smaller lung function also have historically lower socioeconomic status (determining bodily development in early life and leading to trends in body size and pulmonary function that continue into adulthood) and possibly other environmental factors [10–19], which are important determinants of lung growth and development.

A recent systematic review about race and/or ethnicity and lung function showed that researchers have failed to explore this association in a proper way, and an appeal was made to the scientific community to clarify this relationship [9]. Of the 226 eligible papers published between 1922 and 2008, in 83.6% of the articles it was reported that “other racial and ethnic groups” had a smaller lung volume compared with “white” groups, and 94% failed to examine socioeconomic status; in those papers that reported smaller lung function in “other racial and ethnic groups”, 21.8 and 29.4% of explanations cited inherent factors and anthropometric differences, respectively, whereas 23.1% cited environmental and social factors [9].

The debate on this association has been ongoing for decades and in recent years it has been emphasised due to different interpretations of the available data [5, 7]. The present study addresses whether lung function varies according to the proportion of African genomic ancestry (based on DNA) and how this interacts with anthropometric measurements, socioeconomic status, smoking, comorbidities and birth weight.

Results

In the 2012–2013 follow-up (participants aged 30 years old), 3701 subjects were interviewed, which added to the 366 subjects who were known to have died represents a 68.8% follow-up rate. The present analysis took into account only those individuals who had information on ancestry (from follow-up at 22–23 years of age) and on lung function (obtained at the 2012–2013 visit) (n=2869).

Table 1 shows the percentage of subjects with spirometric and ancestry data and the total number of individuals evaluated at 2012–2013 follow-up visit. More than 75% of individuals evaluated in the last follow-up visit were included in the present analysis. For those with the highest family income at birth and those born to mothers who had ≥12 years of schooling the percentage participating in the last follow-up visit was lower compared with those individuals with less favourable socioeconomic variables.

Table 2 shows that those who had more than one quarter African ancestry had lower birth weight, as well as income and maternal schooling at birth. By the same token, socioeconomic indicators at 30 years were unfavourable for those with higher proportion of African ancestry. Current anthropometric variables were inversely associated with African ancestry, except mean chest circumference (table 2).

Table 3 shows the crude and adjusted association between African ancestry with FEV₁ and FVC stratified by sex. We opted for using the denominator of 927 for males and 943 for females due to missing information for some covariables. For males, those with more than 25.9% African ancestry had a smaller FEV₁ (crude analysis β= −0.31 L, 95% CI −0.43 – −0.20 L; and full adjusted β (model 4)= −0.13 L; 95% CI −0.23 – −0.03 L) and FVC (crude analysis β= −0.46 L; 95% CI −0.59 – −0.32 L; and fully adjusted β (model 4)= −0.21 L; 95% CI −0.32 – −0.09 L) compared with those with <5% African ancestry. For females, the results were similar, but the strength of the association was lower compared with males.

The linear regression coefficients (height and sitting/standing height ratio in cm) and the adjusted-R² values according to African ancestry are shown in table 4. African ancestry explains less of the variability for height than for the sitting/standing height ratio, especially in males; the R² for the crude model was 2% for height and around 6% for the sitting/standing height ratio.

Discussion

Our results show smaller lung function volumes among those subjects with increased African ancestry after adjustment for anthropometrics and several other variables. We have shown that the sitting to standing height ratio is related to African ancestry having taken into account socioeconomic confounders, whereas overall height is not affected by African ancestry per se (table 4). This confirms the work of others showing that height, sitting/standing height ratio and thoracic circumference are linked to the association between African ancestry and lung function [2, 6, 7, 13, 28, 29]. We did not include sitting height on its own in our analysis due to its colinearity with other variables.

Having taken into account height and the sitting to standing height ratio African ancestry was still associated with significantly lower FEV₁ (−150 mL in men and −200 mL in women) and FVC (−240  and −190 mL, respectively). After then accounting for all the additional confounders in table 2 these estimates were only changed by 10–30 mL. We accept that residual confounding may still be an issue and that 18% of the variance in height in our subjects was related to our measured confounders. However, the effect of African ancestry, height and sitting to standing height ratio on determining FEV₁ and FVC are much larger than that of the confounders we have measured.

Socioeconomic status may affect health in a variety of ways [30], including adverse environmental exposures, and it is unlikely that specific indicators, or even a combination of indicators, can take into account all of its impact. In addition, socioeconomic status has impacts throughout life, even before birth, and current status may differ from that present at key stages of growth and development. In fact, separating genetic African ancestry from socioeconomic status may be unfeasible for some time as both have been deeply linked for centuries and it will require a considerable population of individuals with high African ancestry living their whole life in adequate socioeconomic status. A key strength of our study was the availability of socioeconomic status at more than one time point.

Although several researchers have carried out genomic ancestry analysis it should be mentioned that this method has some limitations; in the present study inferred ancestry was performed through a larger set of SNPs from different datasets and not only from Pelotas. We believe we have adjusted for a variety of indicators of ancestral history that contribute to current Latin-American populations, and therefore have partially reduced the problem of studying an unusually varied population.

The additional analysis carried out to identify whether height was more determined by genetics or by the environment shows that the inclusion of African ancestry resulted in minor increases in the R² and adjusted-R² values for both sexes. There was no convincing evidence supporting that the genetic differences among ethnic groups in our sample played an important role in explaining the differences in height.

The complex relationship between lung function and race and/or ethnicity [5, 7] has been addressed in several studies; a key issue in this discussion is to disentangle the contribution of “genetics” and “other variables” which is very difficult or impossible to achieve at present time. To the best of our knowledge this is the first study in a middle-income country assessing the independent role of genomic ancestry on lung function and several anthropometric measures, indicators of socioeconomic status at birth and later in life, morbidities, smoking, and birth weight in a longitudinal cohort.

Brazil is a huge country and it is common to use three skin colour categories to assess race: white, brown or “mixed”, and black [31]. In the city of Pelotas, site of the present study, 80% of the population classify themselves as white [32]; however, the population is highly admixed [33, 34]. It has been shown that those subjects who self-reported their skin colour as black had lower lung function parameters compared with those who self-reported white skin colour (table S1). Previous data from the genome-wide study in Brazil showed that self-reported skin colour has a good correlation with genomic ancestry (data not shown).

Categorising subjects into racial/ethnical groups is done on the assumption that race/ethnicity is a proxy for genetic relatedness, but this can misrepresent genetic variation and leads to confounding [8]. Yaeger et al. [35], comparing genetic ancestry and self-described race, found that self-reported race generally agreed well with the inferred genetic population cluster, but did not reveal the extent of admixture; other researchers have found a good correlation between self-defined race with inferred genetic clusters [36, 37]. However, the opposite has also been found: a poor correlation between self-reported race and genetic typing [38], with practical consequences such as lung function underestimation using predictive equations based on self-reported race alone [3].