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APOC1 T45S polymorphism is associated with reduced obesity indices and lower plasma concentrations of leptin and apolipoprotein C-I in aboriginal Canadians

2009; Elsevier BV; Volume: 51; Issue: 4 Linguagem: Inglês

10.1194/jlr.p002014

ISSN

1539-7262

Autores

Piya Lahiry, Henian Cao, Matthew R. Ban, Rebecca L. Pollex, Mary Mamakeesick, Bernard Zinman, Stewart B. Harris, Anthony J. Hanley, Murray W. Huff, Philip W. Connelly, Robert A. Hegele,

Tópico(s)

Diabetes, Cardiovascular Risks, and Lipoproteins

Resumo

Apolipoprotein (apo) C-I is a constituent of chylomicrons, very low density lipoprotein, and high density lipoprotein. The role of apo C-I in human metabolism is incompletely defined. We took advantage of a naturally occurring amino acid polymorphism that is present in aboriginal North Americans, namely apo C-I T45S. We assessed the hypothesis that metabolic traits, including obesity-related and lipoprotein-related traits, would differ between carriers and noncarriers of apo C-I T45S. A genotyping assay was developed for APOC1 T45S and genotypes were determined in a sample of 410 Canadian Oji-Cree subjects. The allele frequency of the apo C-I S45 allele was ∼8% in this sample. We observed the apo C-I S45 allele was significantly associated with 1) lower percent body fat (P < 0.05), 2) lower waist circumference (P = 0.058), 3) lower serum leptin levels (P < 0.05), and 4) lower plasma apo C-I levels (P < 0.0001), using a newly developed ELISA-based method. Taken together, these results suggest that at the whole human phenotype level, apo C-I is associated with the complex metabolic trait of obesity as well as with serum leptin levels. Apolipoprotein (apo) C-I is a constituent of chylomicrons, very low density lipoprotein, and high density lipoprotein. The role of apo C-I in human metabolism is incompletely defined. We took advantage of a naturally occurring amino acid polymorphism that is present in aboriginal North Americans, namely apo C-I T45S. We assessed the hypothesis that metabolic traits, including obesity-related and lipoprotein-related traits, would differ between carriers and noncarriers of apo C-I T45S. A genotyping assay was developed for APOC1 T45S and genotypes were determined in a sample of 410 Canadian Oji-Cree subjects. The allele frequency of the apo C-I S45 allele was ∼8% in this sample. We observed the apo C-I S45 allele was significantly associated with 1) lower percent body fat (P < 0.05), 2) lower waist circumference (P = 0.058), 3) lower serum leptin levels (P < 0.05), and 4) lower plasma apo C-I levels (P < 0.0001), using a newly developed ELISA-based method. Taken together, these results suggest that at the whole human phenotype level, apo C-I is associated with the complex metabolic trait of obesity as well as with serum leptin levels. Complex quantitative traits such as obesity are influenced by both genetic and environmental factors. Moreover, evaluation of the genetic contribution identifies gene products and their interactions in biological pathways, aiding in overall understanding of these complex traits. We have previously identified significant associations between genomic variants and complex traits in the Oji-Cree, an isolated Canadian First Nations population (1Pollex R.L. Hanley A.J. Zinman B. Harris S.B. Hegele R.A. Clinical and genetic associations with hypertriglyceridemic waist in a Canadian aboriginal population.Int. J. Obes. 2006; 30: 484-491Crossref PubMed Scopus (34) Google Scholar, 2Pollex R.L. Mamakeesick M. Zinman B. Harris S.B. Hegele R.A. Hanley A.J. Peroxisome proliferator-activated receptor gamma polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes.J. Diabetes Complications. 2007; 21: 166-171Crossref PubMed Scopus (31) Google Scholar). The Oji-Cree are an ideal population to study association of genetic factors with complex traits because their background genetic and environmental variation is relatively low. Apolipoprotein (apo) C-I is a protein constituent of chylomicrons, VLDL, and HDL (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar). Apo C-I is a member of the human apo C family, which also includes apo C-II and apo C-III. In contrast to other extensively investigated apolipoproteins such as apo E, B, and AI, and even apo C-II and C-III, the physiological role of apo C-I is less well established. In vitro, apo C-I has been suggested to be positively involved in HDL metabolism through activation of LCAT (4Soutar A.K. Garner C.W. Baker H.N. Sparrow J.T. Jackson R.L. Gotto A.M. Smith L.C. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase.Biochemistry. 1975; 14: 3057-3064Crossref PubMed Scopus (263) Google Scholar), inhibition of HL (5Conde-Knape K. Bensadoun A. Sobel J.H. Cohn J.S. Shachter N.S. Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase.J. Lipid Res. 2002; 43: 2136-2145Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 6Kinnunen P.K. Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Crossref PubMed Scopus (144) Google Scholar), and inhibition of cholesteryl ester (CE) transfer protein (CETP) activity (7Gautier T. Masson D. de Barros J.P. Athias A. Gambert P. Aunis D. Metz-Boutigue M.H. Lagrost L. Human apolipoprotein C–I accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity.J. Biol. Chem. 2000; 275: 37504-37509Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). Using in vivo models of apo C-I-deficient and apo C-I-over-expressing mice, apo C-I has also been suggested to have a positive relationship with LDL. Apo C-I has been observed to affect metabolism of apo B-containing lipoproteins by attenuating VLDL clearance by inhibiting LPL, directly (8Berbee J.F. van der Hoogt C.C. Sundararaman D. Havekes L.M. Rensen P.C. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.J. Lipid Res. 2005; 46: 297-306Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) or indirectly (9Westerterp M. Van Eck M. de Haan W. Offerman E.H. Van Berkel T.J. Havekes L.M. Rensen P.C. Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages.Atherosclerosis. 2007; 195: e9-e16Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar), and by inhibiting liver-specific LDL receptor (LDLR) (10Sehayek E. Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.J. Biol. Chem. 1991; 266: 18259-18267Abstract Full Text PDF PubMed Google Scholar) and LDLR-related protein (LRP) (11Weisgraber K.H. Mahley R.W. Kowal R.C. Herz J. Goldstein J.L. 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Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL.J. Lipid Res. 2006; 47: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), triglyceride (TG) and cholesterol in mice (3Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (429) Google Scholar, 8Berbee J.F. van der Hoogt C.C. Sundararaman D. Havekes L.M. Rensen P.C. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.J. Lipid Res. 2005; 46: 297-306Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Human genetic studies have had limited success in better elucidating the physiological role of apo C-I. This is due in part to the paucity of naturally-occurring human variants in apo C-I compared with numerous common and rare variants affecting the protein sequences of apo E, B, A-I, A-II, A-IV, A-V, C-II, and C-III (14Lusis A.J. Fogelman A.M. Fonarow G.C. Genetic basis of atherosclerosis: part II: clinical implications.Circulation. 2004; 110: 2066-2071Crossref PubMed Scopus (70) Google Scholar). The human variants of these other apolipoproteins have often served to identify and specify key pathways and mechanisms for more intensive study (15Hegele R.A. Plasma lipoproteins: genetic influences and clinical implications.Nat. Rev. Genet. 2009; 10: 109-121Crossref PubMed Scopus (318) Google Scholar). Common noncoding DNA variants of APOC1 located in the promoter region were among the first to have been reported for genes affecting lipoprotein metabolism (16Frossard P.M. Coleman R.T. Malloy M.J. Kane J.P. Levy-Wilson B. Appleby V.A. 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Conde-Knape K. Cohn J.S. Deckelbaum R.J. Berglund L. Shea S. The common insertional polymorphism in the APOC1 promoter is associated with serum apolipoprotein C–I levels in Hispanic children.Atherosclerosis. 2005; 179: 387-393Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar) and neurological phenotypes (21Abildayeva K. Berbee J.F. Blokland A. Jansen P.J. Hoek F.J. Meijer O. Lutjohann D. Gautier T. Pillot T. De Vente J. et al.Human apolipoprotein C–I expression in mice impairs learning and memory functions.J. Lipid Res. 2008; 49: 856-869Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 22Li H. Wetten S. Li L. St Jean P.L. Upmanyu R. Surh L. Hosford D. Barnes M.R. Briley J.D. Borrie M. et al.Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.Arch. Neurol. 2008; 65: 45-53Crossref PubMed Scopus (425) Google Scholar, 23Tycko B. Lee J.H. Ciappa A. Saxena A. Li C.M. Feng L. Arriaga A. Stern Y. Lantigua R. 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Thus far, this variant has not been associated with biochemical traits nor has this association been replicated in other ethnic populations. In the process of systematically screening candidate genes in lipoprotein metabolism for new DNA sequence variants in Canadian subpopulations, we identified the nonsynonymous variant designated APOC1 T45S in the Oji-Cree. We took advantage of this naturally occurring polymorphism to genotype Oji-Cree who were nondiabetic in order to detect associations with clinical and biochemical traits. We found that individuals with the APOC1 T45S variant, when compared with other nondiabetic subjects, had lower indices for waist circumference, hypertriglyceridemic waist (HTGW) prevalence, percent body fat, as well as lower serum concentrations of leptin and apo C-I, the latter of which was measured using a newly developed quantitative assay. All subjects in the current study had formerly been participants in the original 1993–1995 Sandy Lake Health and Diabetes Project (26Hanley A.J.G. Harris S.B. Barnie A. Gittelsohn J. Wolever T.M.S. Logan A. Zinman B. The Sandy Lake Health and Diabetes Project: design, methods and lessons learned.Chronic Dis. Can. 1995; 16: 149-156Google Scholar). The Oji-Cree community of Sandy Lake, Ontario, is located ∼2000 km northwest of Toronto, in the subarctic boreal forest of central Canada. Seven hundred twenty-eight members of this community (72% of the total population) ≥10 years of age participated in the original survey. Detailed information on demographics, dietary habits, and physical fitness of the study participants has been previously reported (27Gittelsohn J. Wolever T.M. Harris S.B. Harris-Giraldo R. Hanley A.J. Zinman B. Specific patterns of food consumption and preparation are associated with diabetes and obesity in a Native Canadian community.J. Nutr. 1998; 128: 541-547Crossref PubMed Scopus (172) Google Scholar, 28Harris S.B. Zinman B. Hanley A. Gittelsohn J. Hegele R. Connelly P.W. Shah B. Hux J.E. The impact of diabetes on cardiovascular risk factors and outcomes in a native Canadian population.Diabetes Res. Clin. Pract. 2002; 55: 165-173Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 29Kriska A.M. Hanley A.J. Harris S.B. Zinman B. Physical activity, physical fitness, and insulin and glucose concentrations in an isolated Native Canadian population experiencing rapid lifestyle change.Diabetes Care. 2001; 24: 1787-1792Crossref PubMed Scopus (74) Google Scholar). The studies were approved by the Sandy Lake First Nation Band Council and the University of Toronto Ethics Review Committee and signed informed consent was obtained from all participants. Body weight, height, waist circumference, and blood pressure were measured by standardized procedures (26Hanley A.J.G. Harris S.B. Barnie A. Gittelsohn J. Wolever T.M.S. Logan A. Zinman B. The Sandy Lake Health and Diabetes Project: design, methods and lessons learned.Chronic Dis. Can. 1995; 16: 149-156Google Scholar). For waist circumference measurement, the natural waist was considered as the minimal circumference between the umbilicus and the xiphoid process. Hypertensive individuals were defined as those subjects having either blood pressure exceeding 130 mmHg (systolic) and/or 80 mmHg (diastolic), or those taking antihypertensive medications. Measurements of fasting blood analyses, including glucose, cholesterol, TGs, and leptin were performed as described elsewhere (26Hanley A.J.G. Harris S.B. Barnie A. Gittelsohn J. Wolever T.M.S. Logan A. Zinman B. The Sandy Lake Health and Diabetes Project: design, methods and lessons learned.Chronic Dis. Can. 1995; 16: 149-156Google Scholar). Leukocyte DNA was prepared as described elsewhere (30Hegele R.A. Evans A.J. Tu L. Ip G. Brunt J.H. Connelly P.W. A gene-gender interaction affecting plasma lipoproteins in a genetic isolate.Arterioscler. Thromb. 1994; 14: 671-678Crossref PubMed Scopus (41) Google Scholar, 31Hegele R.A. Harris S.B. Hanley A.J. Sun F. Connelly P.W. Zinman B. Angiotensinogen gene variation associated with variation in blood pressure in aboriginal Canadians.Hypertension. 1997; 29: 1073-1077Crossref PubMed Scopus (47) Google Scholar) and was used for genotype analysis. Genotypes for APOC1 codon 45 (T45S, exon 3) were determined using PCR. Exon 3 was amplified following established procedures (31Hegele R.A. Harris S.B. Hanley A.J. Sun F. Connelly P.W. Zinman B. Angiotensinogen gene variation associated with variation in blood pressure in aboriginal Canadians.Hypertension. 1997; 29: 1073-1077Crossref PubMed Scopus (47) Google Scholar) using primers 5′ GGG AGG TAG CTG CAC ACA GT and 3′ GGT GTG GGA AAT TTC AGA GG, followed by amplicon digestion using endonuclease BsmAI (New England Biolabs Inc., Ipswich, MA), as per manufacturer's recommendations. The digested fragments were electrophoresed in a 2% agarose gel. Using this restriction isotyping, the smaller (65 bp and 89 bp) and larger (154 bp) fragments represented the T45 and S45 variants, respectively. According to Lemieux et al. (32Lemieux I. Pascot A. Couillard C. Lamarche B. Tchernof A. Almeras N. Bergeron J. Gaudet D. Tremblay G. Prud'homme D. et al.Hypertriglyceridemic waist: a marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men?.Circulation. 2000; 102: 179-184Crossref PubMed Scopus (779) Google Scholar), subjects have a HTGW if they present with both of the following: 1) abdominal obesity, defined by waist circumference ≥ 90 cm, and 2) hypertriglyceridemia, defined by plasma TG concentration ≥ 2 mmol/L. On the other hand, National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines for HTGW is gender-specific such that the waist circumference cut-off for males is >102 cm and >88 cm for females (33Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). 2001. J. Am. Med. Assoc. 285: 2486–2497.Google Scholar). According to the NCEP ATP III criteria (33Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). 2001. J. Am. Med. Assoc. 285: 2486–2497.Google Scholar), metabolic syndrome (MetS) was identified if a subject had ≥3 of: 1) increased waist circumference [>102 cm (>40 inches) for men, >88 cm (>35 inches) for women]; 2) elevated plasma triglycerides [≥1.69 mmol/L (≥150 mg/dl)]; 3) low plasma HDL cholesterol [<1.04 mmol/L (<40 mg/dl) for men, <1.29 mmol/L (<50 mg/dl) for women]; 4) increased blood pressure (≥130 mmHg systolic and/or ≥85 mmHg diastolic) or on antihypertensive drug treatment; and 5) impaired fasting glucose [≥6.1 mmol/L (≥110 mg/dl)]. Apo C-I levels were quantified from frozen Oji-Cree serum samples by sandwich ELISA as described elsewhere (34Bury J. Michiels G. Rosseneu M. Human apolipoprotein C–II quantitation by sandwich enzyme-linked immunosorbent assay.J. Clin. Chem. Clin. Biochem. 1986; 24: 457-463PubMed Google Scholar). Briefly, polyclonal rabbit anti-human apo C-I antibody (Academy Biomedical Co., Houston, TX) was coated overnight at 7°C onto 96-well polystyrene plates (Nunc-Immuno MaxiSorp, NUNC, Rochester, NY) at a dilution of 1:200, followed by one wash with 300 µL PBS per well. Each well was then blocked for 1 h at 26°C with 300 µL PBS containing 0.05% Tween 20 (PBST) and 0.5% BSA (Sigma, St. Louis, MO) and followed by one wash with 300 µL PBS. Subsequently, serum samples (dilution, 1:8000) and apo C-I standard (dilution, 1-60ng/ml; Biomedical Co., Houston, TX) diluted with PBST and 0.1% BSA and, respectively, were added to each well and incubated for 1 h at 450 rpm at 26°C. Wells were then washed three times with 300 µL PBST and 0.5% BSA, followed by the addition of HRP-conjugated polyclonal goat anti-human apo C-I antibody (dilution, 1:8000; Academy Biomedical) diluted in PBST and 0.1% BSA. After two washes in PBST and one wash in PBS, color was developed by addition of 100 µL of freshly prepared substrate solution containing 10 mg o-phenylenediamine dihydrochloride (Pierce, Rockford, IL), 20 ml sodium phosphate/citrate buffer, and 20 µL of 30% H2O2. The reaction was stopped after 20 min (450 rpm at 26°C) with 100 µL of 2.0 M H2SO4. Color development was measured at 490 nm using a microplate reader. For this analysis, we studied a subset of Oji-Cree who were no closer than third-degree relatives to one another in order to control for confounding artifacts based on close kinship. SAS version 9.1 (SAS Institute, Cary, NC) was used for all statistical comparisons. Data are presented as mean ± SD or as percentages for categorical variables. Logarithmic transformations (natural log) were used when data were not normally distributed. Transformed variables were used for parametric statistical analyses, but untransformed values were presented in tables. P-values were adjusted for age and sex when comparing differences in demographic and laboratory characteristics between those with and those without the S45 allele, using either the general linear model or the logistic model. Statistical significance was taken at a nominal P < 0.05 for all comparisons. The baseline clinical and biochemical attributes of the 410 unrelated nondiabetic Oji-Cree subjects are shown in Table 1. This subset of the Oji-Cree had nearly even distribution of males and females. In addition to the traits indicated, their MetS status and their HTGW values were also recorded in Table 1.TABLE 1Baseline clinical and biochemical traits of male and female nondiabetic Oji-CreeMeasurementMalesFemalesn192217Age, y26.9 ± 13.2an = 193.23.7 ± 11.5Triglycerides, mmol/L1.32 ± 0.731.17 ± 0.46Total cholesterol, mmol/L4.43 ± 1.014.45 ± 0.71LDL cholesterol, mmol/L2.58 ± 0.872.34 ± 0.60HDL cholesterol, mmol/L1.25 ± 0.291.28 ± 0.26apo A-I, g/L1.46 ± 0.221.48 ± 0.21apo B, g/L1.05 ± 0.320.94 ± 0.21BMI, kg/m224.7 ± 4.93an = 193.25.8 ± 5.80Percent body fat, %24.4 ± 9.00bn = 191.39.3 ± 11.8WHR—iliac crest0.95 ± 0.07an = 193.0.94 ± 0.05WHR—natural waist0.91 ± 0.07an = 193.0.86 ± 0.05Waist circumference, cm89.9 ± 14.0an = 193.86.5 ± 13.2Leptin, ng/ml6.70 ± 6.77an = 193.18.8 ± 11.6Apo C-I, µg/ml220.7 ± 62.8cn = 77.203.9 ± 38.8dn = 102.MetS, %1.86 ± 0.351.87 ± 0.34HTGW, %1.84 ± 0.361.96 ± 0.19HTGW–NCEP waist, %1.91 ± 0.281.96 ± 0.19BMI, body mass index; WHR, waist to hip ratio; MetS, diagnosis of metabolic syndrome using the National Cholesterol Education Program Adult Treatment Panel III criteria (34Bury J. Michiels G. Rosseneu M. Human apolipoprotein C–II quantitation by sandwich enzyme-linked immunosorbent assay.J. Clin. Chem. Clin. Biochem. 1986; 24: 457-463PubMed Google Scholar); HTGW, diagnosis of 'hypertriglyceridemic waist"; HTGW-NCEP waist, diagnosis of hypertriglyceridemic waist using cut values from the National Cholesterol Education Program Adult Treatment Panel III criteria (34Bury J. Michiels G. Rosseneu M. Human apolipoprotein C–II quantitation by sandwich enzyme-linked immunosorbent assay.J. Clin. Chem. Clin. Biochem. 1986; 24: 457-463PubMed Google Scholar).a n = 193.b n = 191.c n = 77.d n = 102. Open table in a new tab BMI, body mass index; WHR, waist to hip ratio; MetS, diagnosis of metabolic syndrome using the National Cholesterol Education Program Adult Treatment Panel III criteria (34Bury J. Michiels G. Rosseneu M. Human apolipoprotein C–II quantitation by sandwich enzyme-linked immunosorbent assay.J. Clin. Chem. Clin. Biochem. 1986; 24: 457-463PubMed Google Scholar); HTGW, diagnosis of 'hypertriglyceridemic waist"; HTGW-NCEP waist, diagnosis of hypertriglyceridemic waist using cut values from the National Cholesterol Education Program Adult Treatment Panel III criteria (34Bury J. Michiels G. Rosseneu M. Human apolipoprotein C–II quantitation by sandwich enzyme-linked immunosorbent assay.J. Clin. Chem. Clin. Biochem. 1986; 24: 457-463PubMed Google Scholar). In this sample of Oji-Cree, 348 had the APOC1 T45/T45 genotype, 62 had the T45/S45 genotype, and none had the S45/S45 genotype (Table 2). Because there were no S45 homozygotes, T45 was treated as a dominant allele for the purpose of subsequent analyses. Overall, the APOC1 T45S genotype frequencies in the Oji-Cree do not deviate significantly from predictions of the Hardy-Weinberg equation. In addition, the allele frequencies for T45 and S45 carriers are indicated in Table 2.TABLE 2Genotype and allele frequencies in Oji CreeGenotype Frequenciesapercent in their respective populations given in parentheses.Allele FrequenciesT45/T45T45/S45S45/S45T45S45Male166 (0.86)27 (0.14)0 (0)0.930.07Female182 (0.84)35 (0.16)0 (0)0.920.08Total348 (0.85)62 (0.15)0 (0)0.920.08a percent in their respective populations given in parentheses. Open table in a new tab The clinical and biochemical attributes and significance of the nondiabetic Oji-Cree according to their APOC1 genotypes are shown in Table 3. Significance for each biochemical or clinical trait was derived after adjustment for age and sex. There were no significant differences (P > 0.05) in any of the plasma lipid concentrations. In addition, there were no significant between-genotype differences in the prevalence of MetS or in either mean (BMI) or waist-to-hip-ratio. The lower values in waist circumference and NCEP-defined HTGW prevalence in S45 carriers, compared with T45 homozygotes, was close to being statistically significant with P = 0.070 (P = 0.066, using logarithmic adjustment) and P = 0.077, respectively. There were significant differences (P < 0.05) in percent body fat, serum leptin levels, and HTGW prevalence, with lower levels of these traits in the APOC1 S45 carriers. In addition, we found that the APOC1 S45 allele was associated with a significantly lower serum apo C-I concentration (P < 0.0001).TABLE 3Clinical and biochemical traits of nondiabetic Oji-Cree according to APOC1 T45S genotypesTraitTT n = 347TS n = 62PTriglycerides, mmol/L log triglycerides1.25 ± 0.611.15 ± 0.57NS (0.15)NS (0.12)Total cholesterol, mmol/L log total cholesterol4.28 ± 0.884.27 ± 0.84NS (0.62)NS (0.66)LDL cholesterol, mmol/L log LDL2.45 ± 0.752.46 ± 0.72NS (0.82)NS (0.89)HDL cholesterol, mmol/L log HDL1.26 ± 0.271.29 ± 0.29NS (0.56)NS (0.61)BMI, kg/m2 log BMI25.4 ± 5.5an = 348.24.7 ± 5.1NS (0.15)NS (0.17)Percent body fat, % log percent body fat32.7 ± 12.930.0 ± 13.0cn = 59.0.00810.0131WHR - iliac crest0.94 ± 0.06an = 348.0.95 ± 0.06NS (0.89)WHR – natural waist log WHR (natural)0.88 ± 0.07an = 348.0.89 ± 0.07NS (0.68)NS (0.67)Waist circumference, cm log waist88.5 ± 13.6an = 348.86.2 ± 13.8NS (0.070)NS (0.066)Leptin, ng/ml log leptin13.6 ± 11.9an = 348.10.7 ± 7.80.00650.029Apo C-I, µg/ml221.7 ± 49.6bn = 119.190.2 ± 47.7dn = 60. 0.05. Data are means ± SD. P-values are adjusted for age and sex. The P-values in bold indicates the difference observed for the trait is significant or close to significant.a n = 348.b n = 119.c n = 59.d n = 60. Open table in a new tab BMI, body mass index; WHR, waist to hip ratio; HTGW, diagnosis of hypertriglyceridemic waist; HTGW-NCEP waist, diagnosis of hypertriglyceridemic waist using cut values from the National Cholesterol Education Program Adult Treatment Panel III criteria (33Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). 2001. J. Am. Med. Assoc. 285: 2486–2497.Google Scholar); NS, not significant with nominal P > 0.05. Data are means ± SD. P-values are adjusted for age and sex. The P-values in bold indicates the difference observed for the trait is significant or close to significant. The principal findings of this study in nondiabetic Oji-Cree subjects were significant associations between the APOC1 T45S polymorphism and variations in obesity indices, serum adipose-secreted hormone levels, and apo C-I levels. Specifically, in subjects carrying the APOC1 S45 allele we found: 1) lower waist circumference, including lower frequency of HTGW, 2) lower percent body fat, 3) lower serum leptin concentrations, and 4) lower serum apo C-I concentrations, using an ELISA-based quantitative method. Thus, the nonsynonymous T45S variant in APOC1 among the Canadian First Nations is associated with variations in adiposity, obesity, and lower serum apo C-I levels. Human apo C-I, C-II, and C-III, are protein constituents of chylomicrons, VLDL, and HDL. Although much is known about the roles of the apo C-II and C-III in lipoprotein metabolism, less is known about the biological function(s) of apo C-I. The gene coding

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