Laura Arbour

Professor

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2020)
The role of the carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant in Inuit infant and child health outcomes in Nunavut (2020)

Nunavut leads the country for a number of adverse early child health outcomes, including infant hospitalizations for lower respiratory tract infection (LRTI; ~306/1,000), otitis media (85%) and infant mortality (21.5/1,000). The p.P479L (c.1436C>T, rs80356779) variant of carnitine palmitoyltransferase 1A (CPT1A), an enzyme required for long-chain fatty acid oxidation in the liver, pancreas, lymphocytes and other tissues, is prevalent in northern Indigenous populations of Canada. Although evidence is limited, the p.P479L variant has been associated with childhood infectious illness, hypoglycemia, seizures and with unexpected infant death and infant death due to infection. This dissertation investigated the association of p.P479L variant with infant and child morbidity (up to five years) in the context of relevant prenatal, postnatal and socioeconomic variables in a cohort of 2523 Inuit children living in Nunavut born from Jan-2010 to Dec-2013. The results demonstrate that the CPT1A p.P479L variant was associated with infectious illness in early childhood including LRTI admission, otitis media and gastroenteritis, after adjustment for socioeconomic and other confounding variables. In considering the potential effect on fatty acid oxidation and possible risk for hypoglycemia, I also determined that the incidence of neonatal hypoglycemia was higher in term Inuit newborns than expected, and, although not statistically significant, p.P479L homozygous and heterozygous newborns had higher incidence of neonatal hypoglycemia than non-carriers. Taken together, these results suggest that children homozygous for the p.P479L variant may be more susceptible to infectious illness compared to non-carriers and may be more likely to experience hypoglycemia in the first days of life. My results replicate and expand on previous, smaller studies. Multidisciplinary local input and community engagement is indicated to determine if routine neonatal glucose screening and/or other management is indicated for Inuit infants. Further studies are needed to understand the role of the p.P479L variant in infection susceptibility, immune and inflammatory response and vaccination effectiveness in Inuit communities.

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Master's Student Supervision (2010 - 2018)
Prevalence of Carnitine Palmitoyltransferase 1A(CPT1A) Variant p.P479L and Risk of Infant Mortality in Nunavut, Northwest Territories, and Yukon (2011)

The p.P479L (c.1436C>T) variant of hepatic CPT1A is frequent in Inuit and British Columbia First Nations populations of Canada. CPT1A is a major regulatory point in long chain fatty acid oxidation in the liver. CPT1A deficiency is an autosomal recessive disorder that causes metabolic decompensation triggered by fasting, which can progress to seizures and sudden death, if not treated. This study assesses prevalence and clinical impact of the P479L variant in the Canadian territories and reviews modifiable risk factors associated with infant mortality (IM) in Nunavut.Methods: Ethics approval was obtained from university REBs and local research institutes, with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 (n=1584) and sudden death in infancy cases (n=31; 1999-2008) in the territories were genotyped for the P479L variant. Results: P479L homozygosity in each territory was 64%, 3%, and 1% for Nunavut, NWT, and Yukon, respectively. Within NWT, homozygosity was highest in Inuvialuit (21%) and very low in First Nations (1%). Homozygosity in sudden death cases was highest in Nunavut (18/20) and associated with an increased risk (OR: 5.15; 95% CI: 1.19-22.38). Homozygosity was 29% for NWT cases (2/7), 67% in NWT Inuvialuit (2/3), and was not present in Yukon cases (0/4). Review of Nunavut IM cases (n=78; 1999-2008) identified Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Death in Infancy (SUDI) as the leading causes of infant death (47%), followed by death due to infectious disease (28%). At least 23% of IM cases were premature. Discussion: The P479L variant is very frequent in the Inuit/Inuvialuit of Canada. Although the sample size was small, there was an associated risk for sudden death in infants homozygous for the variant in Nunavut. SIDS and SUDI are the leading causes of infant death in Nunavut, followed by death due to infectious disease. Since deaths in these two categories are largely preventable, prevention strategies and further exploration into the P479L variant and other determinants are indicated. Management strategies, including newborn screening for the P479L variant, need to be developed in consultation with health authorities, local medical professionals, and local communities.

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