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.