Discussion
To the best of our knowledge, the present study is the first
population-scale study to investigate relationships between HGS and
C-section. We performed observational analysis and GWEIS using over
160,000 participants from the UK Biobank. We showed significant
associations between HGS and C-section and proved several Gene×C-section
interactions effecting on HGS.
Our observational analysis proved a significant association between
C-section and HGS in offspring. Based on previous studies, we
hypothesized that this association might be related to the changes
caused by C-section in intestinal flora 24 and immune
responses in offspring 25. These changes might act as
prenatal environmental factors that have long-term or permanent effects
on skeletal muscle growth and decline in offspring 26.
Previous studies have observed the cross talk between gut microbiota and
skeletal muscle in pathological conditions27 and
proposed that intestinal flora regulates skeletal muscle function
through skeletal muscle-gut axis 27, 28. Lahiri et al.29 observed that the mice lacked gut microbiota had
skeletal muscle atrophy, decreased expression of insulin-like growth
factor 1, and reduced transcription of genes associated with skeletal
muscle growth and mitochondrial function. These phenomena could be
improved by transplanting intestinal flora from pathogen-free mice into
germ-free mice 29. A population-based study found that
C-section lead to a decrease in the abundance of Bifidobacteriumin the intestines of infants 30.Bifidobacterium may influence gut-muscle communication and
regulate muscle size 31. Data showed that treatment
which could increase the abundance of Bifidobacterium in older
individuals may prophylactically moderate aging muscle loss31. In addition, immune responses also might be
implicated in the mechanism of this association between C-section and
HGS. Lipopolysaccharide (LPS), sitting at the neonatal immune system
priming, was significantly under-represented in C-section neonates32, which may result in persistent effects on human
physiology in later life 33. Immune responses and
related factors play a role in skeletal muscle formation. For example,
the TGF-β family members are implicated in the regulation of myogenic
differentiation and have been shown to be potent inhibitors of myoblasts
differentiation 34. These results suggested a role for
the gut microbiota and immune system in regulating skeletal muscle mass
and function.
ADGRV1 gene showed a significant G×E interaction effect on left grip
strength. ADGRV1 encodes a member of the G-protein coupled receptor
superfamily and act as an important regulator of bone homeostasis and
muscle function directly or indirectly. Mutations in this gene
contribute to epilepsy with myoclonic seizures 35.
Mouse models and qRT-PCR analysis demonstrated that ADGRV1-deficient
osteoblasts have increased RANKL expression, which result in low BMD36. RANKL as a member of the TNF receptor superfamily
is essential for osteoclastogenesis, and its activation induces
high-turnover osteoporosis37. In addition, RANKL is
also expressed in skeletal muscle and activates the NF-κB pathway, which
inhibits myogenic differentiation and leads to skeletal muscle
dysfunction and loss38. Inhibition of RANKL expression
could improve muscle strength in osteoporotic mice and
humans39. Previous studies have reported muscle-bone
interactions and possible bone-to-muscle communication40. Our result supported previous findings and
suggested that the effects of C-section on hand grip might be related to
muscle-bone interactions.
POLR3G gene and WASL gene showed significant G×E interaction effects on
left grip strength while CRPPA gene and APBB2 gene showed significant
G×E interaction effects on right grip strength. POLR3G participants in
the transcription of RNA polymerase III (Pol III) and express in the
skeletal muscle cell lineage, which results in a significant reduction
in the activation of muscle genes 41. In addition, the
POLR3G overexpression had some ability to reverse differentiation41. WASL gene encodes a member of the Wiskott-Aldrich
syndrome (WAS) protein family named N-WASP, which is expressed
ubiquitously42. WASL could promote actin
polymerization and the formation of branched actin polymers which plays
an important role in the differentiation of myoblast to myotubes43. Cai et al. suggested that N-WASP is a key
intermediate in the regulation of myofibroblast differentiation and
maturation 44. CRPPA gene, locating at chromosome
7p21, is a frequent cause of Walker–Warburg syndrome45. Although the functional role of human CRPPA
remains unknown, Riemersma et al. 46 suggested that
CRPPA deficiency contribute to tertiary dystroglycanopathies, which is
strongly associated with congenita muscular dystrophy (CMD)45. APBB2 gene encodes a kind of cytoplasmic adaptor
protein which mediates the assembly of multimolecular complexes47. APBB2 knockout (KO) mice showed several phenotypes
in muscle that are comparable to the clinical features of CMD in humans,
including motor impairments and neuromuscular junction (NMJ)
abnormalities 47 48.
Interestingly, gene set enrichment analyses results suggested a role of
immune system involved in the association between C-section and HGS. The
relationship between C-section and immunity has been discussed above. In
addition, the relationship between immunity and HGS has been observed in
a monozygotic-twins epigenome-wide study 49. CLEC16A
gene was reported as a candidate gene associated with both left and
right HGS in present study. CLEC16A gene encodes a member of the C-type
lectin domain containing family and has been showed to be associated
with susceptibility for various autoimmune diseases, such as rheumatoid
arthritis and systemic lupus erythematous (SLE) 50.
One of the possible potential functional links between CLEC16A and
autoimmunity is autophagy 51, which has been showed to
have crosstalks with signaling cascades in both innate and adaptive
immune responses 52. According to a quantitative
proteomics analysis, Tam et al. 51 identified that
CLEC16A may enhance mTORC1 activity and act as a negative regulator
through mTOR pathway in autophagy. The mTOR is a serine/threonine kinase
capable of integrating several stimuli from the medium and growing
evidence suggests that mTOR signaling pathway plays an important role in
maintaining muscle fiber size in healthy muscle 53.
For example, mTORC1 could mediate the signaling of substrates and
control the initiation of translation by which consequently promote the
synthesis of muscle protein 54.
What’s more, the results of gene set enrichment analysis suggested the
role of central nervous system (CNS) in the relationship between
C-section and HGS. Besides the muscle structure, the ability of muscle
to produce force is also associated with neuromotor control. Evidence
showed that the primary motor cortex (M1) contributes to the control of
a power grip of finger muscles during a variety of grasping behaviors55. Kara et al. demonstrated that neuromotor control
dysfunction contributes to the deterioration of the force generating
capacity of skeletal muscles 56. More research is
needed to verify this hypothesis.
One of the innovations of this study is to consider the G×E interaction
effects on hand grip strength, which has been demonstrated to contribute
to the etiology of complex traits. The GWEIS analyses complement the
genetic relationships between C-section and HGS and provide several
novel loci contributing to the variation of HGS. In addition, the large
samples of HGS in UK biobank increased the accuracy and effectiveness of
our analyses. Previous studies focused on the effect of C-section on
child health, less study have assessed its effect on the overall health
status of offspring. Our study demonstrated the interaction association
between C-section and the HGS for offspring. As far as we known, this is
the first systemic study exploring the effect of C-section as
environmental factor on HGS for offspring. Our study holds great
potential for clarifying the functional relevance of C-section with HGS.
Admittedly, there are still limitations in present study. First, because
of the sample population, our results cannot be generalized across
ethnic groups. Secondly, although several genes have been reported to
have interaction effects with C-section, the specific biological
functions and mechanisms of action need further experimental studies.
In summary, we performed an observational analysis and a genome-wide
interaction analysis of C-section and HGS. We reported significant
interactions whether from phenotypic or genetic perspective. Our study
reported several novel candidate loci and indicated the role of
C-section in HGS.