Infants and children in Nunavut have high rates of infectious illness, in particular, infant hospitalizations for lower respiratory tract infections (LRTI; 234-306/1000) (1, 2) and otitis media (85% of children <3 years) (3). Nunavut also has an infant mortality rate four times the national average (21.5 vs. 4.5/1,000 livebirths) (4), with sudden unexpected death and respiratory infection comprising the majority of post-neonatal deaths (5). Nunavut is Canada's northernmost territory and largest jurisdictional landmass, which is divided into three regions, Qikiqtani, Kivalliq, and Kitikmeot. The majority of Nunavut residents (referred to as Nunavummiut) identify as Inuit (80% of 40,000 inhabitants) (6, 7), with unique socio-cultural strengths and perspectives. Although social determinants of health and institutional structures that reinforce socioeconomic status influence health outcomes (3, 8, 9), underlying genetic factors may also play a role. Studies have reported that the p.P479L variant of carnitine palmitoyltransferase 1A (CPT1A) may contribute to the high rates of infectious illness and infant death in Northern Indigenous populations (5, 10–12).

Nunavut has a high prevalence of the p.P479L (c.1436C>T, rs80356779) variant of CPT1A, which is prevalent in Indigenous populations of northern Canada, Alaska and Greenland (13–18). The variant has been associated with a number of adverse infant and child health outcomes, including hypoglycemia (10, 19, 20), seizures (21) and sudden unexpected infant death and infant death due to infection (5, 13, 22). Preliminary studies have suggested the variant may be also be associated with infectious illness in early childhood (11, 12). CPT1A is the rate limiting enzyme of long chain fatty acid oxidation in a variety of tissues, including the liver, pancreas and immunocytes (23). Classic CPT1A deficiency (OMIM:255120) is a rare autosomal recessive disease presenting during infancy as hypoketotic hypoglycemia and metabolic decompensation triggered by prolonged fasting and/or vomiting, often precipitated by active infection (24). Unlike variants that cause classic CPT1A deficiency that abolish CPT1A activity, the CPT1A p.P479L variant, also known as the “arctic variant,” is considered a mild variant with reported CPT1A activity of 2–22% of normal (10, 25).

Given the p.P479L variant's high frequency, there has been uncertainty regarding its clinical significance, which has created calls for larger and more comprehensive studies that include other risk factors important in these outcomes (26). We assessed early child health outcomes of 2,225 Inuit children residing in Nunavut to determine whether the CPT1A p.P479L variant is associated with infectious illness in the broader context of other relevant perinatal, postnatal and socioeconomic variables.

Charts for 2,523 Inuit children were reviewed. Charts with only birth data were excluded from analysis (n = 60). CPT1A genotype linkage was successful for 2,225/2,463 records (90.3%). Of those, 68.7% were p.P479L homozygous, 25.6% p.P479L heterozygous and 5.7% non-carrier wildtype (Table 1). The p.P479L allele was in HWE in Kitikmeot and the territorial capital (Iqaluit) but not Kivalliq, Qikiqtaaluk or for the population of Nunavut as a whole. Of the 2,225 children with p.P479L status information, 140 had p.P479L homozygous positive test results documented in the chart.

There were no significant differences in birth related characteristics between CPT1A genotype groups (Table 2). Pairwise correlation analyses showed p.P479L homozygosity was positively correlated with all health outcomes assessed, postnatal maternal smoking and food insecurity and was negatively correlated with CWB and residence in Iqaluit (Supplementary Table 1).

Overall, 607 (27.3%) children were admitted to regional or tertiary hospital for LRTI, including 182 (8.2%) admitted with RSV. The majority of children had one or more episodes of otitis media (86%) and half of all children (50%) had at least one episode of gastroenteritis (Table 3).

Results of univariable and multivariable logistic regression analysis are presented in Table 4. In univariable logistic regression analysis, p.P479L homozygosity was associated with all outcomes and p.P479L heterozygosity was associated with otitis media, dental interventions and gastroenteritis during infancy (Table 4). In multivariable regression analysis adjusting for CWB and residence in Iqaluit (Model 1), p.P479L homozygosity was associated with all outcomes except RSV admission in infancy and p.P479L heterozygosity was associated with otitis media and dental interventions in early childhood but not gastroenteritis during infancy.

Figure 1 shows the effect estimates for p.P479L homozygosity and heterozygosity after further adjustment for postnatal and socioeconomic variables (Model 2). p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64), otitis media (aOR:1.83, 95%CI:1.05–3.21), gastroenteritis (aOR:1.74, 95%CI:1.09–2.77), and dental intervention (aOR:2.11, 95%CI:1.22–3.66) in early childhood and p.P479L heterozygosity was associated with dental interventions (aOR:1.88, 95%CI:1.07–3.32; Figure 1). In infancy (<1 year of age), p.P479L homozygosity was associated with LRTI admission (aOR:2.79, 95%CI:1.29–6.03), otitis media (aOR:1.87, 95%CI:1.18–2.96), and gastroenteritis (aOR:2.32, 95%CI:1.23–4.39) and p.P479L heterozygosity was associated with gastroenteritis (aOR:2.01, 95%CI:1.04–3.87).

The health status of Inuit children in Canada has garnered attention and concern for several decades (1, 28) and Inuit children living in Nunavut have some of the highest reported rates of infectious illness in Canada (1–3). Preliminary studies have implicated the CPT1A p.P479L variant as a possible risk factor for infectious illness in early childhood (11, 12); however, there has been some debate regarding the clinical significance of the variant and calls for larger, population-based comprehensive studies that adjust for known and suspected risk factors for adverse health outcomes (26).

In our comprehensive retrospective study of 2,225 Inuit children, the largest to date, we show that children homozygous for the p.P479L variant had significantly higher rates of infectious illness than non-carriers, which was independent of sex, preterm birth, residence in Iqaluit, breastfeeding for 6 months or longer, postnatal maternal smoking, food insecurity and CWB index (which includes measures of community-level housing, education, and income). Children homozygous for the variant were almost three times as likely to be admitted to hospital for LRTI. We noted that although p.P479L homozygosity was associated with early childhood RSV admission in Model 1 (CWB index and Iqaluit residence) confidence intervals in the full model overlapped one. Since RSV test results were not available for all LRTI admissions, this study may underrepresent the true prevalence of RSV admission, limiting the interpretation of this result.

Children homozygous for the p.P479L variant were also approximately twice as likely to have otitis media and gastroenteritis and require dental interventions than non-carriers in early childhood. Otitis media is associated with impaired hearing at 5 years of age and can have dramatic impacts on speech development and educational attainment (29–31). There are a number of risk factors associated with otitis media; including maternal smoking and preterm birth; however, the association of p.P479L variant with otitis media remained statistically significant after adjustment for many of those factors.

Our results corroborate and are consistent with studies in British Columbia and Alaska reporting association of the p.P479L variant with hospitalization and infectious illness. In 2013, Gessner et al. (11) reported that p.P479L homozygosity was associated with increased risk of otitis media (aOR:3.0, 95%CI:1.8–5.1) and LRTI admission (aOR:2.5, 95%CI:1.6–4.0) and admission for any reason in 427 Alaska Native children (0–2.5 years), adjusting for maternal education, age, prenatal smoking and alcohol use, prenatal care and birth weight. In 2019, Sinclair et al. (12) found that p.P479L homozygosity was associated with admissions for LRTI (OR:6.0, 95%CI:1.6–22.4), otitis media (OR:13.5, 95%CI:1.5–109.4) and dental caries (OR:3.4, 95%CI:1.5–7.8) in 150 children (<7 years) in a British Columbia First Nations community. In our current analysis, we demonstrate that adjustment for SES indicators, including food security and community level measures of education and housing, reduced but did not abolish the association with LRTI admission, otitis media and dental interventions.

Children homozygous for the CPT1A p.P479L variant may experience a more severe illness due to impaired ketogenesis or impaired response of the immune system during infection. As an enzyme critical for long chain fatty acid oxidation, CPT1A is important in a number of tissues, including liver energy homeostasis during fasting, pancreatic glucagon secretion and T cell development and survival (32–34). CD8+ memory T cells (32), especially resident memory T cells (33), and CD4+ Th17 and Treg (34) cells have high demands for fatty acid oxidation and CPT1A activity. Currently, there is no evidence regarding whether the p.P479L variant impairs immune response and/or memory T cell response to repeat infection in humans; however, a recent study of a multiple sclerosis (MS) mouse model (autoimmune encephalomyelitis) found that the CPT1A p.P479L variant may affect the function of cells important in immunity (35). The authors reported that knock-in mice expressing the Cpt1a p.P479L gene variant were resistant to the induction of autoimmune encephalomyelitis, suggesting that the variant conferred protection through blocking the activation of lipid metabolism and/or through impairing the activation of immune system (35). In the context of our study, these results suggest that there should be further studies on the potential effect of altered CPT1A function on immunity to determine if there is evidence of T-cell impact and subsequent impact on vaccine effectiveness for those with the CPT1A p.P479L variant.

The high prevalence of the p.P479L variant in Inuit populations, where the variant flourished to become the major allele (14, 36), suggests an historical advantage compared to non-carriers (18) likely due to synergy with traditional diet practices (10, 15). This speculation is supported by reports of strong signals of positive selection at the site of the nucleotide change (rs80356779) (16–18) and the association of the variant with protection from adverse lipid profiles in adults, including higher HDL-cholesterol and ApoA1 and lower adiposity (15, 36). There is also evidence of an interaction between traditional food intake and the p.P479L variant, supporting the possibility that this interaction may have influenced selection (37). The p.P479L variant is moderately insensitive to malonyl-CoA with fed state residual activity four times control (0.094 vs. 0.023 nmol/min/mg) (25), suggesting a degree of fatty acid metabolism occurs even when carbohydrate is present. Within the harsh arctic environment, this may have conferred advantage for those utilizing a traditional “hunter's diet” rich in omega-3 marine-based fats with little carbohydrate (10, 15).

In our study, p.P479L heterozygosity was associated with dental interventions, gastroenteritis in infancy and with otitis media in Model 1 (adjusting for CWB index and Iqaluit residence), indicating a possible heterozygous effect and could indicate an additive effect for the variant (Tables 3, 4). These results are thought-provoking since classic CPT1A deficiency is considered an autosomal recessive disorder. Other studies have reported intermediate results for p.P479L heterozygotes. In their study of adult Greenlanders, Skotte et al. (16) reported an association between the p.P479L variant and height with an average reduction in height of 2.1 cm per copy of the variant (p = 1.04 × 10⁻⁹), which suggests an additive effect. Furthermore, although the associations were not statistically significant, Sinclair et al. (12) found p.P479L heterozygotes had an intermediate effect (between wildtype and homozygotes) for LRTI admission and dental caries. Rajakumar et al. (36) also found an intermediary heterozygote effect on HDL-cholesterol and associated apoA-I levels. Taken together, these results support a possible additive effect in these outcomes.

Tobacco smoke exposure, household overcrowding and food insecurity are associated with childhood infectious illness (38, 39). In the current cohort, 86% of women reported smoking postnatally and 17.5% of children lived in homes with three or more people/bedroom. In pairwise correlation tests, p.P479L homozygosity was significantly correlated with maternal postnatal smoking, food insecurity and CWB, suggesting that some risk associated with the p.P479L variant may be due to these underlying factors; however, p.P479L homozygosity remained significantly associated with LRTI admission, otitis media, gastroenteritis and dental interventions after adjustment for these variables. Breastfeeding is associated with reduced risk for adverse early child health outcomes, including infant mortality and infectious illness (2, 40). Health Canada recommends breastfeeding for at least 6 months since longer duration of breastfeeding is protective against infectious illness in infancy (41); however, adjustment for breastfeeding 6 months or longer did not impact the association of p.P479L homozygosity with infectious illness outcomes.

The results of this study need to be interpreted in the context of the population where the study was conducted, which, as demonstrated in this study, has significant challenges with housing, food security and access to secondary and tertiary medical care due to the remote nature of Nunavut communities. Of consideration, genetic research in Indigenous communities may inadvertently cause harm by creating stigma for those with a described “risk” allele (9). However, there is also harm in avoiding research that may provide insights into health disparity. Health related research, and in particular, genetic research, is best carried out in partnership with Indigenous people to ensure that the balance of harms and benefits are fully considered throughout the process (42). It is important to note that this research was carried out with the support and on-going partnership of the Inuit organization that is responsible for the land and the people of Nunavut (NTI), and the grass roots Inuit research organization that leads relevant health research within the territory (QHRC). Next steps to address the impact of the p.P479L variant need to be developed in partnership with Inuit leadership and engagement with communities.

This was a retrospective chart review study. In the study cohort, 9% of records did not have CPT1A genotype information and were excluded from analysis. The CPT1A p.P479L variant was the only genetic variant studied; we cannot rule out that other genetic variants may have contributed to the results. The p.P479L variant departed from HWE in two Nunavut regions, which may be due to positive selection for the variant (16–18) since selection can cause deviations of HWE, or may be due to other unknown contributors or underlying differences in population structure. To mitigate the latter risk, the analysis was limited to Inuit children (as recorded on chart after self-identification); however, we were not able to assess non-Inuit admixture within the self-identified Inuit population.

Children homozygous for the p.P479L variant were more likely to be admitted for lower respiratory tract infections and were more likely to have otitis media, gastroenteritis and dental interventions, supporting a role of the variant in infant and child health and well-being. Our results have international implications given the known prevalence of the p.P479L variant in circumpolar populations and should be further addressed with the goal of reducing infant and child morbidity and mortality. Further studies to determine if the CPT1A p.P479L variant impacts immune response to infection are needed, information that will be important for the development of culturally relevant public health strategies in reducing childhood morbidity and mortality.

The data analyzed in this study is subject to the following licenses/restrictions: UBC-UVic-Government of Nunavut Research Disclosure Agreement M17-00229. Requests to access these datasets should be directed to Dr. Laura Arbour, larbour@uvic.ca.

SC: participated in all aspects of the study including study conception and design, acquisition, analysis and interpretation of data, drafting of the initial manuscript, and revision of the manuscript. CR-G: participated in the study conception and design, acquisition, and interpretation of data along with revision of the manuscript. JRT: participated in design and acquisition of study data along with revision of the manuscript. SE, AE, EH-R, DG, AM, and MS: participated in the study design and interpretation of the data along with revision of the manuscript. LA: participated in the study conception and design, analysis, interpretation of data, and revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.