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

Abstract

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.

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

“…Genetic variation in CPT1A was not associated with lipoprotein diameters in our previous analysis across two populations, nor with any lipoprotein measures in a meta-analysis of genome-wide association study across three independent populations ( 10,11 ). Variation in CPT1A has been associated with lipid traits ( 29 ) [although other studies have failed to replicate this fi nding ( 30 )] and with glycemic control ( 31 ). Thus, we suspected that the association of genetic variation at this locus with cardiometabolic traits may be mediated by altered methylation; however, our meQTL analysis did not support this.…”

Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup’ik people

“…Our isolated study population of Yup'ik people were ideally suited to test the contribution of interactions between n-3 PUFA intake (Makhoul et al 2010(Makhoul et al , 2011 and genetic factors (Lemas et al 2012) to changes in adiposity phenotypes. Given the 50-fold range of n-3 PUFA consumption from naturally harvested foods in the region that this study population resides in (Bersamin et al 2008), an additional strength of this study includes a biomarker of EPA and DHA intake (d 15 N) that can be precisely estimated in large epidemiological studies (O'Brien et al 2009).…”

Polymorphism of the genes encoding for the carnitine acyltransferases in native populations of Siberia

“…В единичных случаях этот вариант гена был обнаружен у эвенков Центральной Сибири (частота 1 %) [7], долган и нганасан Таймыра (частота -0,9 %) [8]. В популяциях эскимосов Аляски, Канады и Гренландии частота «арктического» варианта составляет более 70 % [6,9,10]. Предполагается, что этот вариант полиморфизма возник у предков эскимо-сов в результате адаптации к диете, обогащенной поли-ненасыщенными жирными кислотами [3,7].…”

“…По-ниженная активность CPT1A, по-видимому, защищает от сверхпродукции кетоновых тел. У эскимосов высокая частота «арктического» варианта гена CPT1A ассоции-руется также с повышенным содержанием липопротеи-нов высокой плотности и аполипопротеина A1 в плазме крови и уменьшением степени ожирения [9,10]. Однако среди гомозиготных носителей «арктического» варианта выявляются случаи заболеваний, связанных с дефицитом фермента CPT1A и, как следствие, с гипокетонной гипо-гликемией и синдромом внезапной детской смерти [11].…”