Neonatal hypoglycemia and the CPT1A P479L variant in term newborns: A retrospective cohort study of Inuit newborns from Kivalliq Nunavut.

INTRODUCTION: Neonatal hypoglycemia (NH) in the first days of life can largely be prevented by recognizing those at risk and managing accordingly. The CPT1A P479L variant is prevalent in northern Indigenous populations and is a possible risk factor for hypoglycemia. We report on NH incidence in the Kivalliq region of Nunavut, where all Inuit newborns are screened for NH. METHODS: We reviewed clinical charts of 728 Inuit newborns from Kivalliq (January 1, 2010 to December 31, 2013) for blood glucose (BG) levels and infant/maternal characteristics, linking to CPT1A genotype; 616 newborns had BG data from 2 to 48 hours of life. NH was defined using Canadian Paediatric Society guidelines (≤2.0 mmol/L at 2 hours, <2.6 mmol/L at 2 to 48 hours). RESULTS: NH was documented in 21.4% overall, 24.4% of at-risk newborns and 19.5% of term newborns with no risk factors (≥37 weeks gestation, term-NRF). NH was documented in 22.0% of CPT1A P479L homozygous, 19.8% of P479L heterozygous and 4.8% of noncarrier term-NRF newborns. With multivariable logistic regression, the adjusted ORs for developing NH in term-NRF newborns was 4.97 for CPT1A P479L homozygotes (95% confidence interval [CI]:0.65-38.35, P=0.19) and 4.71 for P479L heterozygotes (95% CI:0.57-37.89, P=0.15). CONCLUSION: Term-NRF newborns had a higher NH incidence than previously reported, similar to that for at-risk newborns, possibly due to the CPT1A P479L variant. Since only Inuit newborns from Kivalliq are screened for NH, further study of long-term outcomes of NH in this population and the role of the P479L variant are warranted to determine if neonatal BG screening is indicated in all Inuit newborns.

The p.P479L variant in CPT1A is associated with infectious disease in a BC First Nation.

BACKGROUND: The hepatic carnitine palmitoyltransferase I (CPT1A) p.P479L variant is common in Aboriginal populations across coastal British Columbia, Alaska, the Canadian North, and Greenland. While the high frequency of this variant suggests positive selection, other studies have shown an association with sudden unexpected death in infancy and infection. We utilized administrative health data to evaluate hospitalizations for a single year cohort of children of First Nations descent genotyped for the variant and, matched for location of birth. Seven years of data were reviewed for 150 children split evenly between CPT1A genotypes (homozyous, heterozygous, and noncarrier of the p.P479L variant). RESULTS: Children homozygous for the p.P479L allele had a higher rate of hospital admissions at 2.6 per individual as compared to noncarriers at 0.86. Heterozygous children also showed a significant increase at 1.9 per person. Length of stay per admission was increased for both p.P479L homozygotes and heterozygotes. The odds ratio (OR) for at least one hospitalization for any reason was increased for p.P479L homozygotes relative to noncarriers (OR=10.2, confidence interval [CI] 3.5 to 30.0) as were admissions for dental caries (OR=3.4, CI 1.5 to 7.8), acute lower respiratory tract infections (OR=6.0, CI 1.6 to 22.4), and otitis media (OR=13.5, CI 1.7 to 109.4). CONCLUSIONS: The CPT1A p.P479L variant is associated with an increased rate of hospitalization for those homozygous, primarily for infectious disease causes. Heterozygotes also showed a small but significant increase in hospitalization rates suggesting some dosage effect. Functional studies will be required to identify the underlying pathological mechanism.

Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011.

BACKGROUND: The northern territory Nunavut has Canada's largest jurisdictional land mass with 33,322 inhabitants, of which 85% self-identify as Inuit. Nunavut has rates of infant mortality, postneonatal mortality and hospitalisation of infants for respiratory infections that greatly exceed those for the rest of Canada. The infant mortality rate in Nunavut is 3 times the national average, and twice that of the neighbouring territory, the Northwest Territories. Nunavut has the largest Inuit population in Canada, a population which has been identified as having high rates of Sudden Infant Death Syndrome (SIDS) and infant deaths due to infections. METHODS: To determine the causes and potential risk factors of infant mortality in Nunavut, we reviewed all infant deaths (<1 yr) documented by the Nunavut Chief Coroner's Office and the Nunavut Bureau of Statistics (n=117; 1999-2011). Rates were compared to published data for Canada. RESULTS: Sudden death in infancy (SIDS/SUDI; 48%) and infection (21%) were the leading causes of infant death, with rates significantly higher than for Canada (2003-2007). Of SIDS/SUDI cases with information on sleep position (n=42) and bed-sharing (n=47), 29 (69%) were sleeping non-supine and 33 (70%) were bed-sharing. Of those bed-sharing, 23 (70%) had two or more additional risk factors present, usually non-supine sleep position. CPT1A P479L homozygosity, which has been previously associated with infant mortality in Alaska Native and British Columbia First Nations populations, was associated with unexpected infant death (SIDS/SUDI, infection) throughout Nunavut (OR:3.43, 95% CI:1.30-11.47). CONCLUSION: Unexpected infant deaths comprise the majority of infant deaths in Nunavut. Although the CPT1A P479L variant was associated with unexpected infant death in Nunavut as a whole, the association was less apparent when population stratification was considered. Strategies to promote safe sleep practices and further understand other potential risk factors for infant mortality (P479L variant, respiratory illness) are underway with local partners.

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.

Objective: Infectious illness, including lower respiratory tract infection (LRTI), is a leading cause of childhood morbidity and infant mortality in Inuit children in Nunavut Canada. The carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant is common in arctic Indigenous populations of Alaska, Canada, and Greenland. CPT1A is a fatty acid oxidation enzyme expressed in the liver, immunocytes and other tissues, and is needed to use fats for energy during fasting. Previous association of the variant with early childhood infectious illness and infant death has been challenged because of sample size and limited adjustment for confounders. We evaluated whether the p.P479L variant is associated with infectious illness in Inuit children of Nunavut, Canada. Methods: We conducted a retrospective clinical chart review of 2,225 Inuit children (0-5 years) for infectious illness (including otitis media, gastroenteritis, and hospital admission for LRTI), prenatal, perinatal, and socioeconomic indicators, subsequently linking to CPT1A genotype. Multivariable logistic regression adjusted for birth characteristics, breastfeeding, maternal smoking, food insecurity, and socioeconomic indicators. Results: Overall, 27% of children were hospitalized for LRTI, 86% had otitis media and 50% had gastroenteritis. The p.P479L allele frequency was 0.82. In multivariable analysis, 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), and gastroenteritis (aOR:1.74, 95%CI:1.09-2.77), compared to non-carriers. Conclusion: Children homozygous for the p.P479L variant were more likely to experience infectious illness than non-carriers, including hospitalization for respiratory tract infections. Given the role of CPT1A in immunocytes, our findings indicate that more study is needed to determine if there is a role of the variant in immune response. Continued Inuit involvement is essential when considering next steps.

Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.

Carnitine palmitoyltransferase 1A (CPT1A), encoded by the gene CPT1A, is the hepatic isoform of CPT1 and is a major regulatory point in long-chain fatty acid oxidation. CPT1A deficiency confers risk for hypoketotic hypoglycaemia, hepatic encephalopathy, seizures, and sudden unexpected death in infancy (SUDI). It remains controversial whether the CPT1A gene variant, c.1436C>T (p.P479L), identified in Inuit, First Nations, and Alaska Native infants, causes susceptibility to decompensation, in particular during times of fever and intercurrent illness. Although newborn screening for the P479L variant occurs in some jurisdictions, background knowledge about the presence of the variant in Canadian Aboriginal populations is lacking. In an effort to understand the population implications of the variant in northern Canada, overall frequencies of the variant were assessed. Further studies are underway to determine associated risk. Ethics approval was obtained from university REBs, local research institutes, and with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 in the three territories were genotyped for the p.P479L variant. p.P479L (c.1436C>T) allele frequencies in the three territories were 0.02, 0.08, and 0.77 in Yukon (n=325), Northwest Territories (n=564), and Nunavut (n=695), respectively. Homozygosity rates were 0%, 3%, and 64%. Aboriginal status was available only in NWT, with allele frequencies of 0.04, 0.44, 0.00, and 0.01 for First Nations, Inuvialuit/Inuit, Métis, and non-Aboriginal populations. Although individual blood spots were not identified for Aboriginal ethnicity in Nunavut infants, ~90% of infants in Nunavut are born to Inuit women. The allele frequency and rate of homozygosity for the CPT1A P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories. The significance of the population and geographic distribution remains unclear, but the high population frequencies of the variant suggest a historically low penetrance for adverse outcomes. Further evidence is needed to determine if there is an increased risk for infant mortality and morbidity and whether newborn screening will be indicated on a population basis.

Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations.

OBJECTIVE: Infant mortality in British Columbia (BC) First Nations remains elevated relative to other residents. The p.P479L (c.1436C>T) variant of carnitine palmitoyltransferase 1 (CPT1A) is frequent in some aboriginal populations and may be associated with increased infant deaths. This work was initiated to determine the performance of acylcarnitine profiling for detecting this variant, to determine its frequency in BC, and to determine if it is associated with sudden infant deaths in this population. METHODS: Newborn screening cards from all BC First Nations infants in 2004 and all sudden unexpected deaths in BC First Nations infants (1999-2009) were genotyped for the CPT1A p.P479L variant and linked to archival acylcarnitine data. RESULTS: The CPT1A p.P479L variant is frequent in BC First Nations but is not evenly distributed, with higher rates in coastal regions (up to 25% homozygosity) with historically increased infant mortality. There is also an overrepresentation of p.P479L homozygotes in unexpected infant deaths from these regions, with an odds ratio of 3.92 (95% confidence interval: 1.69-9.00). Acylcarnitine profiling will identify p.P479L homozygotes with a 94% sensitivity and specificity. CONCLUSIONS: The CPT1A p.P479L variant is common to some coastal BC First Nations, and homozygosity for this variant is associated with unexpected death in infancy. The high frequency of this variant in a wide range of coastal aboriginal communities, however, suggests a selective advantage, raising the possibility that this variant may have differing impacts on health depending on the environmental or developmental context.