Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I

Rajakumar, Chandrew; Ban, Matthew R.; Cao, Henian; Young, T. Kue; Bjerregaard, Peter; Hegele, Robert A.

doi:10.1194/jlr.p900001-jlr200

Cited by 59 publications

(58 citation statements)

References 33 publications

(41 reference statements)

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“…We chose to relax our MAF criteria to include SNPs with MAF > 0.01 to genotype tagging SNPs in the CPT1A gene that may be common (MAF у 0.05) in Yup'ik Eskimos despite being rare (MAF < 0.05) in CEU and CHB populations. We also included the nonsynonymous P479L (rs80356779) CPT1A SNP for genotyping based on previous associations with elevated plasma HDL-cholesterol and apolipoprotein A-I levels in the Greenland Inuit ( 35 ). Genotyping of the 28 SNPs, including P479L, was carried out by allele-specifi c primer extension of multiplex amplifi ed products and detection using matrix-assisted laser desorption ionization time-of-fl ight spectrometry on a Sequenom iPLEX platform at the Broad Institute ( 41 ).…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

“…In a cross-sectional cohort of French-Canadians, Robitaille et al reported an association between the nonsynonymous A275T (rs17610395) SNP with BMI ( P = 0.05) and waist circumference ( P = 0.008) only after accounting for dietary fat intake ( 53 ). Finally, in Greenland Inuit, Rajakumar et al showed the L479 allele in the nonsynonymous P479L variant was associated with elevated fasting HDL-cholesterol and ApoA1 levels ( 35 ).…”

mentioning

confidence: 99%

“…Three studies have previously investigated the infl uence of CPT1A polymorphisms on obesity and lipid phenotypes in humans ( 35,53,54 ). Hirota and colleagues ( 54 ) found no association between CPT1A polymorphisms and obesity or fasting lipid phenotypes in Japanese individuals with T2D.…”

mentioning

confidence: 99%

“…Journal of Lipid Research Volume 53, 2012 candidate gene for obesity ( 34 ) and CPT1A SNPs are associated with elevated fasting HDL-cholesterol levels ( 35 ), it is unknown whether the interaction between n-3 PUFA intake and CPT1A SNPs infl uence changes in body composition and fasting lipids.…”

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confidence: 99%

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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: Snp Selection and Genotypingmentioning

confidence: 99%

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confidence: 99%

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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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“…Как известно, главны-ми продуктами питания эскимосов, а также береговых чукчей и коряков издревле были мясо и жир ластоногих и китов. Несмотря на жирную пищу, в сыворотке крови представителей этих народов наблюдаются довольно низкие уровни холестерина и липидов, что, по-видимому, свидетельствует о том, что в эволюции коренных наро-дов Крайнего Севера важную роль играли сопряженные процессы адаптации к диете и экстремальным факторам среды (Rajakumar et al, 2009;Lemas et al, 2012).…”

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Distribution of the arctic variant of the CPT1A gene in indigenous populations of Siberia

Малярчук¹,

Деренко²,

Denisova³

et al. 2016

Vestn. VOGiS

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Population screening of the Arctic variant, which has arisen due to the G > A mutation at locus rs80356779 in the CPT1A gene, has been performed for the first time among indigenous peoples of Siberia (Chukchi, Koryaks, Evens, Evenks, Yakuts, Buryats and Altaians) and East Asia (Koreans). It is assumed that CPT1A Arctic variant originated from Eskimo ancestors, probably as a result of adaptation to a high-fat diet and/or to the extremely cold environment. It is also known that the homozygous Arctic variant is associated with hypoketotic hypoglycemia attributable to CPT1A deficiency and high infant mortality and occurs at high frequency in American Eskimo. On the other hand, the association of CPT1A Arctic variant with increased levels of HDL-cholesterol and apolipoprotein A1 in blood plasma suggests that this mutation might have a cardioprotective role. In the present study, a high frequency of CPT1A Arctic variant has been found in coastal populations of Northeast Asia -in Koryaks (66 %), Chukchi (56 %) and Evens (30 %), and singularly (at a frequency of 1 %) in Evenks of Central Siberia. Five polymorphic loci relevant to the haplotypic structure of CPT1A gene (rs2278908, rs2278907, rs2924699, rs7112615 and rs2229738) were revealed by high-throughput DNA sequencing in addition to locus rs80356779 studied here. It was found that the Arctic variant haplotype has arisen only once on the basis of the haplotype, which is widespread in modern populations of Eurasia. We assume that the expansion of Eskimo culture of the sea mammal hunting as well as Eskimo assimilation by Chukchi and Koryaks have contributed to the spread of the CPT1A Arctic variant across the populations of indigenous peoples of Northeast Asia.

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How well do we understand the basis of classic selective sweeps in humans?

et al. 2019

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Classic selective sweeps occur when positive selection increases a variant's frequency from low to high in a population, and underlie some long‐studied human characteristics such as variation in skin, hair or eye colour. In such well‐studied ‘gold standard’ examples, a known variant has been associated with a plausible phenotype and underlying selective force. Signatures of classic sweeps have more recently been detected in population‐genetic data independently of any prior information about the corresponding phenotype or selective force, and usually without suggesting any insights into these. Motivated by the need to understand such candidates, we first review the gold standards and show that our understanding of them is often incomplete or unconvincing; only two of the examples we consider are compellingly explained. We assess approaches for large‐scale association of classic sweep candidate variants to phenotypes and selective forces, test these on the gold standards, and discuss the standards of evidence needed to adequately understand a selective sweep.

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Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I

Abstract: Carnitine palmitoyltransferase IA, encoded by CPT1A, is a key regulator of fatty acid metabolism.

Cited by 59 publications

References 33 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

Distribution of the arctic variant of the CPT1A gene in indigenous populations of Siberia

How well do we understand the basis of classic selective sweeps in humans?

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