Genetic ancestry is associated with asthma, and this could be modified by environmental factors. A systematic review

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Genetic ancestry is associated with asthma, and this could be modified by environmental factors. A systematic review
To the editor, Certain ethnic populations have a higher prevalence of asthma, a phenomenon which can be independent of socio-economic status. 1 Ethnicity is a product of genetic and cultural and behavioural factors. Using identified alleles in reference to genetic repositories, 'genetic ancestry' is a way of quantifying an individual's genetic composition inherited from ancestors of a particular geographic origin. Kumar et al. demonstrated that increased African genetic ancestry is independently associated with lower lung function. 2 Genetic ancestry can lead to disease via epigenetic mechanisms.
Evidence suggests DNA methylation can significantly differ between ethnic groups and this is induced by genetic ancestry and also environmental factors, such as tobacco smoke, air pollution and airborne pathogens. 3 We systematically reviewed the evidence on associations between specific genetic ancestries and asthma, and environmental factors that could mediate or modify these associations. The study protocol was prospectively registered with PROSPERO (CRD42021222527). We searched MEDLINE, EMBASE and EBSCO Global Health for published studies that examined the association between genetic ancestry and asthma, to December 2022.
We searched full-text peer-reviewed articles using a pre-specified search strategy (exp asthma/OR asthma*.tw.) AND (exp ethnic groups/ OR ethnic*.tw. OR racial*tw. OR race.tw) AND (ancestr*. tw.). To be included, manuscripts defined asthma by physician diagnosis, ≥2 episodes of childhood wheeze, or using validated questionnaires, and quantified genetic ancestry on a continuous scale. We excluded manuscripts in which asthma severity or phenotypes were the outcome, rather than asthma risk. We included manuscripts that estimated the proportion of genetic ancestry using admixture mapping of participants' genome-wide data. Genetic ancestry can be determined by quantifying the number of previously identified alleles in reference populations that strongly correlate with ancestral origins of a specific geographic origin (e.g., Europe, Africa, etc.)-known as ancestry informative markers (AIMs). Analysis of an individual's genetic data allows quantification of AIMs and, therefore, estimation of proportions of genetic ancestry.
Screening, data extraction and assessment of bias were con- Genetic ancestry was associated with asthma in high, rather than low, socio-economic strata. One possible explanation is that high socio-economic status may lead to increased hygiene and reduced levels of protective microbiologic exposure in early life. This has been described among the Hutterites with decreased childhood exposure to airborne animal endotoxins and higher levels of asthma compared to the genetically similar Amish population. 6 Our systematic review has identified certain populations vulnerable to asthma, owing to a combination of genetic and sociodemographic factors, likely to induce gene-environment interactions between genetic ancestry, country of residence, cultural affiliation and socio-economic status. These findings could help inform future case findings and public health interventions by identifying high-risk sociodemographic profiles, supported by genetic ancestry data. In addition, further genetic analysis within such high-risk profiles could yield future genetic targets for personalized medicine. For instance, recent data among Hispanic Americans demonstrate that Native American genetic ancestry at chromosomal region 18q21 (upstream of the SMAD2 gene) is associated with excess asthma risk. 7 Given that SMAD2 has also been implicated in transforming growth factor beta (TGFβ) signal transduction in asthma, 8 it is possible that Hispanic Americans bearing this genotype may respond to therapies targeting TGFβ.
One major limitation of this review is the paucity of genetic cohorts available, small sample sizes and heterogeneity of findings.
Rapid advances in genome-wide genotyping methods have improved the understanding of complex trait illnesses such as asthma. However, the majority of genetic cohort studies are from European ancestry populations, representing a significant knowledge gap. 9 Empirically applying disease-predictive algorithms to ethnic populations is not only inappropriate but has also been shown to give rise to spurious results. 9 Heterogeneity of effect estimates in our review could be explained by differences in sampled sub-ethnic subpopulations and/ or genetic reference measurements. For instance, Hispanic American subpopulations differed between studies, such as Puerto Rican versus Mexican American, who could exhibit different environmental exposures. Furthermore, genetic ancestry measurement was not standardized across studies which could impact comparability. For example, African genetic ancestry was drawn from different populations, such as the Yoruba in West Africa (Nigeria) and Luhya in East Africa (Kenya).
In summary, genetic ancestry is associated with asthma and this could be modified by cultural affiliation, country of residence and socioeconomics. Our findings identify socio-demographic profiles which, supported by genetic ancestry data, could be targeted for additional public health intervention and case finding. Further research to identify genetic targets for therapeutic intervention, catering for at-risk genetic profiles, may alleviate asthma inequality across ethnic populations.

Key messages
• While Native American genetic ancestry appears protective against asthma, African ancestry increases risk.
• There is indirect evidence that the latter is modified by self-identified ethnicity, socio-economics and country.
• Complex gene-environment interactions contribute to asthma in ethnic populations, highlighting the need for nuanced risk stratification.