Study aims

This project contained three aims, the first of which characterized growth trajectories in the SLS sample and estimated their association with sociodemographic predictors. The second part contained the central premise of the dissertation: to estimate the association between infant growth as an exposure and lipid levels during adolescence as an outcome. The last aim estimated effect modification of the exposure-outcome association between genetic variants linked and lipid traits. The overarching goal uniting these aims is to better understand the role of infant growth patterns as a factor influencing dyslipidemia in adolescence.

To summarize, the three aims are as follows:

• Aim 1: Characterize individual infant growth trajectories and identify sociodemo- graphic predictors of such growth in a Chilean infancy cohort.

– Aim 1.1: Characterize infant growth trajectories with nonlinear mixed effects models (Cole, Donaldson, and Ben-Shlomo 2010), which measure individual shifts relative to the population average curve in: (a) size (above or below on the outcome scale), (b) tempo (to the right or left on the age scale), and (c) velocity (steep or shallow slope). Assess the association between postnatal growth characteristics and sociodemographic predictors of these postnatal growth characteristics including a socioeconomic index and maternal education.

– Aim 1.2: Determine presence of child growth trajectory latent classes with latent growth mixture models (LGMM).

• Aim 2: Examine the association between infant growth trajectory characteristics and lipid levels at 17 years of age.

• Aim 3: Assess gene-environment interaction between growth trajectory characteristics and genetic variants underlying lipid metabolism at 17 years of age.

Several points regarding lipids support investigation of these three proposed aims. First, current estimates put the prevalence of dyslipidemia in children age 6 to 19 years at around one in five children. This high level of a well established modifiable risk factor for ASCVD alongside the known properties of dyslipidemia tracking into adulthood makes for a prime interventional target. Second, race/ethnic groups show substantial heterogeneity in prevalence levels with certain groups such as HL groups experiencing higher levels of dyslipidemia than others putting this group at higher risk for later disease. Third, there are polygenic factors at play as well. These polygenic factors include over 150 variants and can explain over twenty percent of lipid trait variability making them viable variables to consider in the context of GXE analyses.

Examining lipid outcomes following infant growth, results are inconsistent from obser- vational human studies. However, the majority of studies underscore faster than average growth being associated with adverse lipid outcomes such as higher TC and TG following faster than average growth. These associations also found in animal studies operating under a more controlled environment, which reinforces the idea that adverse levels of ASCVD risk factors in later life may follow earlier abnormal growth patterns.

Molecular processes form one biologically plausible explanation linking postnatal growth with lipid outcomes. Some of these domains relate to liver function, gene expression timing

subsequent growth manipulation. Thus far the most convincing evidence arises from animal models, and these reflect a growing body of literature that demonstrate a programming effect of postnatal growth on lipid metabolism later in life span.

In sum, these aims can 1) provide a detailed characterization of infant growth and its association with lipids, 2) assess postnatal growth as an effect modifier, and 3) describe these relationships in a HL sample – the combination of which is previously lacking in prior research on these topics. These three areas can provide information that is needed to clarify the role of infant growth as a factor influencing adverse lipid levels and metabolism in diverse populations.

7.1.2 Results

In assessing the relationship between early infancy anthropometric growth and sociode- mographic position in manuscript 1 (Chapter 4), we observed that slower linear (length) growth was associated with lower socioeconomic position. Previous studies have reported a similar association between linear growth and maternal education. Furthermore, lower SEP was also associated with a later WFL growth timing. We restricted our investigation down to a narrower window of time, and this association matches those found in larger spans of time of the first year of life or beyond.

In the second manuscript (Chapter 5), we examined both latent and observed early infancy growth constructs and their association with lipid levels in adolescence. Both of these approaches supported an association between faster growth and favorable lipid levels. In the SITAR model we found a positive association between linear (length) growth from birth to five months and HDL-C levels at 17 years. In the latent growth mixture model models the strongest associations were between slower weight and WFL growth and higher LDL-C values. In either situation faster growth appears to act as a protective role instead of the

deleterious one as hypothesized.

Lastly, in the third manuscript (Chapter 6) we estimated SNP-lipid associations across different latent infant growth groups as a way to assess gene-environment interaction. We found one SNP, rs11076175 (CETP), in which the faster growth group demonstrated a favorable association between the coded G allele and the LDL-C trait. We found only one significant gene-environment interaction that supports a hypothesis of growth during early infancy influencing lipid metabolism at a molecular level. Notably, lipid-specific risk scores were one measure we expected to be adequately powered to find effect modifications. However, we did not detect significant terms, perhaps due to the heterogeneity in the direction of interaction terms for the SNPs forming the risk scores. This finding is interesting and a reminder of the diverse genetic pathways to lipid metabolism changes.

The hypotheses in this research project pivoted around the idea that faster growth during early infancy would be an unfavorable exposure. However, the findings from these last two aims offer support that faster growth during early infancy, i.e. prior to six months, may be protective. The fact that this period has been understudied, partly due to the dearth of high quality data available for analysis, may explain the novelty of these findings. If true, and future studies are able to confirm these findings, it underscores the need to collect more data during this period, which may offer a great potential for public health returns on intervention.

7.2

Strengths and Limitations