Prevalence and Distribution of the c.1436C→T Sequence Variant of Carnitine Palmitoyltransferase 1A among Alaska Native Infants

Gessner, Bradford D.; Gillingham, Melanie B.; Johnson, Monique; Richards, C. Sue; Lambert, William E.; Sesser, David E.; Rien, Leanne; Hermerath, Cheryl A.; Skeels, Michael R.; Birch, Stephanie; Harding, Cary O.; Wood, Tyler; Koeller, David M.

doi:10.1016/j.jpeds.2010.07.031

Cited by 32 publications

(36 citation statements)

References 18 publications

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“…CPT1A defi ciency has been associated with risk for hypoketotic hypoglycemia, hepatic encephalopathy, and sudden infant death syndrome (61)(62)(63)(64), as well as muscle cramps, vomiting, and occasional loss of consciousness ( 59,64 ). Nevertheless, the high frequency of the L479 allele in Inuit and Yup'ik Eskimo people suggested to us and several others that it may confer a selective advantage ( 35,60,65,66 ). We hypothesized that genetic variants in CPT1A may be associated with obesity because of the central role of the CPT1A enzyme in fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos

Lemas

Wiener

O’Brien

et al. 2012

Journal of Lipid Research

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Obesity is associated with a series of metabolic conditions clinically referred to as metabolic syndrome, which includes hypertension, dyslipidemia, hyperglycemia, and the development of type 2 diabetes (T2D). Approximately sixty percent of obese individuals have metabolic complications ( 1 ); however, "healthy obese" individuals have been identifi ed with excessive accumulation of body fat that does not translate to dyslipidemia and insulin resistance ( 2, 3 ). For example, some Eskimo/Inuit people indigenous to Alaska are obese, but they have historically demonstrated low prevalence of insulin resistance, metabolic syndrome, and T2D ( 4-7 ). Specifi cally, Yup'ik Eskimo peoples living in Southwest Alaska have obesity prevalence comparable to the general US population, yet the prevalence of metabolic syndrome ( 8 ) and T2D ( 9 ) is signifi cantly less than that observed in the general US population ( 10, 11 ). Although the mechanisms that allow Abstract Variants of carnitine palmitoyltransferase 1A ( CPT1A ), a key hepatic lipid oxidation enzyme, may infl uence how fatty acid oxidation contributes to obesity and metabolic outcomes. CPT1A is regulated by diet, suggesting interactions between gene variants and diet may infl uence outcomes. The objective of this study was to test the association of CPT1A variants with body composition and lipids, mediated by consumption of polyunsaturated fatty acids (PUFA). Obesity phenotypes and fasting lipids were measured in a cross-sectional sample of Yup'ik Eskimo individuals (n = 1141) from the Center of Alaska Native Health Research (CANHR) study. Twenty-eight tagging CPT1A SNPs were evaluated with outcomes of interest in regression models accounting for family structure. Several CPT1A polymorphisms were associated with HDL-cholesterol and obesity phenotypes. The P479L (rs80356779) variant was associated with all obesity-related traits and fasting HDLcholesterol. Interestingly, the association of P479L with HDL-cholesterol was still signifi cant after correcting for body mass index (BMI), percentage body fat (PBF), or waist circumference (WC). Our fi ndings are consistent with the hypothesis that the L479 allele of the CPT1A P479L variant confers a selective advantage that is both cardioprotective (through increased HDL-cholesterol) and associated with reduced adiposity. -Lemas, D.

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos

Lemas

Wiener

O’Brien

et al. 2012

Journal of Lipid Research

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“…While MS/MS is effective at identifying infants with homozygosity for the G710E variant resulting in classic CPT1A deficiency, detection of P479L homozygosity is less efficient due to median C0/(C16+C18) ratios below those published for classic CPT1A deficiency. 3,16,45 All of the AN infants identified in published literature with CPT1A deficiency have been identified during follow-up from other abnormal results and were not initially identified from abnormal C0/(C16+C18) ratios in MS/MS screening. 46 Presumably, the lower ratios and reduced detection reflect the partial enzyme activity associated with P479L homozygosity.…”

Section: Policy Implicationsmentioning

confidence: 99%

Carnitine palmitoyltransferase 1A P479L and infant death: policy implications of emerging data

Fohner

Garrison

Austin

et al. 2017

Genetics in Medicine

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Carnitine Palmitoyltransferase 1 Isoform A (CPT1A) is a crucial enzyme for the transport of long chain fatty acids into the mitochondria. The CPT1A P479L variant is found in high frequencies among indigenous populations residing on the west and north coasts of Alaska and Canada and in northeast Siberia and Greenland. Epidemiological studies have reported a statistical association between P479L homozygosity and infant death in Alaska Native and Canadian Inuit populations. Here, we review the available evidence about the P479L variant and apply to these data the epidemiological criteria for assessing causal associations. We find insufficient evidence to support a causal association with infant death and further, that if a causal association is present, the genotype is likely to be only one of a complex set of factors contributing to an increased risk of infant death. We conclude that additional research is needed to clarify the observed association and to inform effective preventative measures for infant death. In light of these findings, we discuss the policy implications for public health efforts, as policies based on the observed association between P479L homozygosity and infant death data are premature.

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“…CPT1A deficiency is an inherited disorder of hepatic fatty acid oxidation that affects the tolerance to fasting and presents clinically with hypoketotic hypoglycemia. A unique polymorphism in the CPT1A gene (c.1436C>T) is associated with decreased enzyme activity and altered regulation [1], and has been identified among the Canadian and Greenland Inuit, and some Alaska Native populations [2–4]. This sequence variant results in a proline to leucine substitution at amino acid 479 (p.P479L) of the CPT1A protein.…”

Section: Introductionmentioning

confidence: 99%

“…This sequence variant results in a proline to leucine substitution at amino acid 479 (p.P479L) of the CPT1A protein. The prevalence of this genetic variant is extremely high in some regions, with reports of up to 80% of individuals being homozygous in some Native populations [2, 3]. The observation that the c.1436C>T variant is the most prevalent or “normal” allele within certain populations suggests positive selection for some unknown beneficial effect.…”

Section: Introductionmentioning

confidence: 99%

Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant

Gillingham

Hirschfeld

Lowe

et al. 2011

Molecular Genetics and Metabolism

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A high prevalence of the sequence variant c.1436C>T in the CPT1A gene has been identified among Alaska Native newborns but the clinical implications of this variant are unknown. We conducted medically supervised fasts in 5 children homozygous for the c.1436C>T variant. Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted. The fast was terminated early in two subjects due to symptoms of hypoglycemia. Homozygosity for the c.1436C>T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children.

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Prevalence and Distribution of the c.1436C→T Sequence Variant of Carnitine Palmitoyltransferase 1A among Alaska Native Infants

Cited by 32 publications

References 18 publications

Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos

Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos

Carnitine palmitoyltransferase 1A P479L and infant death: policy implications of emerging data

Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant

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