DISCUSSION
We found that, a family history of asthma could increase the childhood asthma risk and the magnitude of ORs increased by the number of affected family members. Independent of having a parent with asthma, a paternal grandparent or a maternal grandparent with asthma could increase the risk for children to develop asthma. Children with father and parental grandfather affected by asthma (OR=11.11) had less asthma risk than those with parents affected (OR=15.92), but they had higher risk than those with two other family members affected by asthma. In addition, we also identified parents partially mediated the associations between grandparental asthma and childhood asthma.
By combining family history of parents and grandparents affected by asthma, we observed that the magnitude of ORs for childhood asthma increased by the number of affected family members and the trend was statistically significant, suggesting that a combined family history could be used as a tool to predict the potential risk for a child to develop asthma. A family history of parent affected by asthma has been widely reported to increase asthma risk. A review of 33 studies found that the ORs of asthma for children with the father affected by asthma ranged from 1.5 to 7.2, and for those with mother affected ORs ranged from 1.5 to 9.7.10 In our study, the ORs for a family history of father and mother were 4.89 and 3.94, which fell within the range.
It remains controversial whether paternal or maternal asthma have more impact on the development of childhood asthma. In our study, we observed children who had father affected by asthma were at greater risk than those with mother affected. We also observed although the ORs of asthma for those having a father and paternal grandfather with asthma were less than those having parents with asthma (OR=11.11 vs OR=15.92), they were much higher than those who had two other family members with asthma, suggesting that inheritance of asthma tend to be paternal link. The underlying biological mechanism is poorly understood. However, studies have identified that a family history of paternal asthma was associated with airway hyperresponsiveness (AHR) in children with asthma, whereas a family history of maternal asthma was not.17,18 Since AHR is a major character of asthma, it is speculated that genetic risk factors for AHR that passed down from father’s side might contribute to childhood asthma.18
A family history of second-degree relatives has been proved to be a risk factor for many diseases19,20, but studies investigating the impact of second-degree relatives on the development of childhood asthma are limited. A study on Utah population found that a family history of second-degree relatives who died of asthma could increase the risk of asthma mortality by 34% (95%CI: 9-62%).21 A previous study reported that, among 823 children diagnosed with asthma, 69.8% had a family history of asthma, of which 14.2% had an affected grandmother, 6.5% had an affected grandfather and 3.3% had both affected grandparents.22 Valerio et al, who investigated the intergenerational asthma, found that a family history of grandparental asthma was associated with childhood asthma (OR=1.52) and children with a parent and grandparent affected by asthma were over four times more at risk of developing asthma compared to those with no parent and grandparent affected (OR=4.27).23 These studies did not consider lineage (paternal grandparents or maternal grandparents) which have different influence on certain diseases.24,25 In our study, based on the sufficiently large sample, we were able to distinguish grandparents between paternal and maternal lineage. Our results showed that a family history on either a paternal grandparent or a maternal grandparent with asthma was associated with an increased risk of childhood asthma, independent of parental asthma, although the impact on the asthma risk was less than a family history of a parent. This suggested that shared asthma susceptibility genes play a small role in transgenerational inheritance. Furthermore, our results of mediation analysis, which showed the small proportion of mediation effect of parental asthma, supported this evidence. Asthma is a complex disease, and the interaction of gene-gene and gene-environment which influences the asthma susceptibility may lead to the transgenerational inheritance of asthma from grandparents to grandchildren with parents skipping over.
In our study, we recruited a large number of participants, which allowed us to differentiate paternal and maternal grandparents and investigate the associations between the family history of a grandparent with asthma and asthma risk in grandchildren. Environmental factors are confounders for family history used to predict the hereditary patterns of a disease7. In this study we controlled a series of environmental factors associated with asthma, especially PM2.5, a major ambient air pollution in recent years in China. Our study, however, has several limitations. The information of both childhood asthma and their family history of asthma was from self-reported questionnaires, but not from the hospital discharge registries, which may cause the recall bias and misclassification of a family history. Since the one child-policy in China, the family history of sibling, which is an important genetic risk factor for hereditary disease, were unable to evaluated.