Genetic association with lipids in Filipinos: waist circumference modifies an APOA5 effect on triglyceride levels
2013; Elsevier BV; Volume: 54; Issue: 11 Linguagem: Inglês
10.1194/jlr.p042077
ISSN1539-7262
AutoresYing Wu, Amanda F. Marvelle, Jin Li, Damien C. Croteau‐Chonka, Alan B. Feranil, Christopher W. Kuzawa, Yun Li, Linda S. Adair, Karen L. Mohlke,
Tópico(s)Genetic Mapping and Diversity in Plants and Animals
ResumoBlood levels of lipoprotein cholesterol and triglycerides (TGs) are highly heritable and are major risk factors for cardiovascular disease (CVD). Approximately 100 lipid-associated loci have been identified in populations of European ancestry. We performed a genome-wide association study of lipid traits in 1,782 Filipino women from the Cebu Longitudinal Health and Nutrition Survey, and tested for evidence of interactions with waist circumference. We conducted additional association and interaction analyses in 1,719 of their young adult offspring. Genome-wide significant associations (P < 5 × 10−8) were detected at APOE for low density lipoprotein cholesterol and total cholesterol, and at APOA5 for TGs. Suggestive associations (P < 10−6) were detected at GCKR for TGs, and at CETP and TOM1 for high density lipoprotein cholesterol. Our data also supported the existence of allelic heterogeneity at APOA5, CETP, LIPC, and APOE. The secondary signal (Gly185Cys) at APOA5 exhibited a single nucleotide polymorphism (SNP)-by-waist circumference interaction affecting TGs (Pinteraction = 1.6 × 10−4), manifested by stronger SNP effects as waist circumference increased. These findings provide the first evidence that central obesity may accentuate the effect of the TG-increasing allele of the APOA5 signal, emphasizing that CVD risk could be reduced by central obesity control. Blood levels of lipoprotein cholesterol and triglycerides (TGs) are highly heritable and are major risk factors for cardiovascular disease (CVD). Approximately 100 lipid-associated loci have been identified in populations of European ancestry. We performed a genome-wide association study of lipid traits in 1,782 Filipino women from the Cebu Longitudinal Health and Nutrition Survey, and tested for evidence of interactions with waist circumference. We conducted additional association and interaction analyses in 1,719 of their young adult offspring. Genome-wide significant associations (P < 5 × 10−8) were detected at APOE for low density lipoprotein cholesterol and total cholesterol, and at APOA5 for TGs. Suggestive associations (P < 10−6) were detected at GCKR for TGs, and at CETP and TOM1 for high density lipoprotein cholesterol. Our data also supported the existence of allelic heterogeneity at APOA5, CETP, LIPC, and APOE. The secondary signal (Gly185Cys) at APOA5 exhibited a single nucleotide polymorphism (SNP)-by-waist circumference interaction affecting TGs (Pinteraction = 1.6 × 10−4), manifested by stronger SNP effects as waist circumference increased. These findings provide the first evidence that central obesity may accentuate the effect of the TG-increasing allele of the APOA5 signal, emphasizing that CVD risk could be reduced by central obesity control. Blood concentrations of lipoprotein cholesterol and triglycerides (TGs) are major risk factors for cardiovascular disease (CVD), the current leading cause of mortality worldwide (1.World Health Organization. 2011. Cardiovascular Diseases (CVDs): Fact Sheet No. 317. World Health Organization (WHO), Geneva.Google Scholar). The most rapid increase in the prevalence of CVD is taking place in Asia, including the Philippines (1.World Health Organization. 2011. Cardiovascular Diseases (CVDs): Fact Sheet No. 317. World Health Organization (WHO), Geneva.Google Scholar), although the obesity-related anthropometric measures remain lower in these Asian populations compared with those in populations of Europeans (2Rutherford J.N. McDade T.W. Feranil A.B. Adair L.S. Kuzawa C.W. High prevalence of low HDL-c in the Philippines compared to the US: population differences in associations with diet and BMI.Asia Pac. J. Clin. Nutr. 2010; 19: 57-67PubMed Google Scholar). 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Despite considerable evidence that genetic variants and obesity traits independently and jointly influence lipid levels, few studies have explicitly examined the modifying effect of waist circumference on lipid associations identified by GWA studies. To test the hypothesis that central obesity would influence the association between genetic variation and lipid levels, we performed a GWA study to investigate single nucleotide polymorphism (SNP) associations with lipoprotein cholesterol and TG levels in 1,782 Filipino mothers from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) and tested for interactions between lipid-associated variants and waist circumference affecting lipid levels. We also conducted analyses in 1,719 young adult offspring of the CLHNS mothers using Metabochip genotypes to confirm SNP associations and interactions with waist circumference. The CLHNS is an ongoing population-based birth cohort study that began in 1983. The original study population, study design, and recruitment protocols have been described in detail previously (26Adair L.S. Popkin B.M. Akin J.S. Guilkey D.K. Gultiano S. Borja J. Perez L. Kuzawa C.W. McDade T. Hindin M.J. Cohort profile: the Cebu longitudinal health and nutrition survey.Int. J. Epidemiol. 2011; 40: 619-625Crossref PubMed Scopus (172) Google Scholar). Briefly, the baseline survey randomly recruited 3,327 pregnant women from the Metropolitan Cebu area of the Philippines in 1983–1984 (3,080 singleton live births), and since followed them and their offspring to the present. Trained field staff conducted in-home interviews and collected anthropometric measurements at each visit. Overnight fasting plasma samples for DNA extraction and biomarker measurements were obtained in 2005. Written informed consent was obtained from all participants, and study protocols were approved by the University of North Carolina Institute Review Board for the Protection of Human Subjects. The current study used cross-sectional data from the 2005 survey available for 1,782 mothers and 1,719 male and female young adult offspring. Three measurements of waist circumference were taken to the nearest 0.1 cm, placing a plastic tape about two inches above the navel, after normal exhalation (27Carba D.B. Bas I.N. Gultiano S.A. Lee N.R. Adair L.S. Waist circumference and the risk of hypertension and prediabetes among Filipino women.Eur. J. Nutr. 2013; 52: 825-832Crossref PubMed Scopus (9) Google Scholar). The three measurements of waist circumference were taken at the same time and their average was used for analyses. TC was measured using enzymatic methods on the Beckman Diagnostics CX5 chemistry analyzer (Beckman Coulter Diagnostics, Fullerton, CA). HDL-C and LDL-C were determined using the homogenous assays Direct HDL-C and Direct LDL-C (Equal Diagnostics, Exton, PA). TGs were measured with a glycerol blank as a two-step reaction (28Kuzawa C.W. Adair L.S. Avila J.L. Cadungog J.H. Le N.A. Atherogenic lipid profiles in Filipino adolescents with low body mass index and low dietary fat intake.Am. J. Hum. Biol. 2003; 15: 688-696Crossref PubMed Scopus (22) Google Scholar). Only one of the CLHNS mothers and one of the young adult offspring were taking lipid-altering medication. SNP genotyping of the CLHNS mothers was performed with the Affymetrix Genomewide Human SNP Array 5.0 at the Vanderbilt Microarray Shared Resource at Vanderbilt University Medical Center, Nashville, TN, using the standard protocol recommended by the manufacturer. The quality control procedures have been previously described (29Lange L.A. Croteau-Chonka D.C. Marvelle A.F. Qin L. Gaulton K.J. Kuzawa C.W. McDade T.W. Wang Y. Li Y. Levy S. et al.Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults.Hum. Mol. Genet. 2010; 19: 2050-2058Crossref PubMed Scopus (62) Google Scholar). As the imputation using the 1000 Genomes CEU+CHB+JPT reference panel (error rate 3.6% and MACH r2 0.86) led to a better imputation quality compared with that using the CHB+JPT panel (error rate 3.3% and MACH r2 0.81), we applied MACH to impute genotypes based on phased reference haplotypes from the 1000 Genomes Project CEU+CHB+JPT samples (June 2010 release). After exclusion of SNPs with poor imputation quality (MACH r2 < 0.3), ∼3.7 million imputed SNPs were tested for association with TC, HDL-C, LDL-C, and TGs. The candidate SNP APOE rs7412 was not available in the genome-wide data and was genotyped using TaqMan allelic discrimination (Applied Biosystems, Foster City, CA). The 1,719 CLHNS offspring were genotyped by the University of North Carolina Mammalian Genotyping using the Metabochip (Illumina, San Diego, CA), a custom high-density genotyping array of SNPs designed to provide a high-density coverage for both overall SNPs and low frequency variants concentrated around GWA loci and/or signals for cardiovascular and metabolic traits (30Voight B.F. Kang H.M. Ding J. Palmer C.D. Sidore C. Chines P.S. Burtt N.P. Fuchsberger C. Li Y. Erdmann J. et al.The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.PLoS Genet. 2012; 8: e1002793Crossref PubMed Scopus (397) Google Scholar). The genotyping and quality control of Metabochip SNPs in the CLHNS offspring were described previously (31Croteau-Chonka D.C. Wu Y. Li Y. Fogarty M.P. Lange L.A. Kuzawa C.W. McDade T.W. Borja J.B. Luo J. AbdelBaky O. et al.Population-specific coding variant underlies genome-wide association with adiponectin level.Hum. Mol. Genet. 2012; 21: 463-471Crossref PubMed Scopus (37) Google Scholar). In the CLHNS mothers, ∼350,000 markers were directly genotyped, and imputation was performed for all markers based on the 1000 Genomes Project; we used the imputed genotypes for all markers (29Lange L.A. Croteau-Chonka D.C. Marvelle A.F. Qin L. Gaulton K.J. Kuzawa C.W. McDade T.W. Wang Y. Li Y. Levy S. et al.Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults.Hum. Mol. Genet. 2010; 19: 2050-2058Crossref PubMed Scopus (62) Google Scholar). In the offspring, all variants for analyses were directly genotyped by Metabochip. Values of TC and TGs were natural log-transformed (ln) to approximate the normal distributions of the traits. We applied multiple linear regression models and assumed an additive mode of inheritance to test for the association between genotypes and HDL-C, LDL-C, ln TC, and ln TGs. We constructed 10 principal components (PCs) of population substructure using EIGENSOFT (32Price A.L. Patterson N.J. Plenge R.M. Weinblatt M.E. Shadick N.A. Reich D. Principal components analysis corrects for stratification in genome-wide association studies.Nat. Genet. 2006; 38: 904-909Crossref PubMed Scopus (6860) Google Scholar). In the CLHNS mothers, we applied MACH2QTL to perform the GWA analyses, adjusting for age, age2, household assets (a score that counts the possession of land and house and household amenities, such as a TV or refrigerator) (33Adair L.S. Size at birth predicts age at menarche.Pediatrics. 2001; 107: E59Crossref PubMed Scopus (264) Google Scholar), natural ln household income, and the first seven PCs. To control for the effects of other potential factors that could confound the SNP-lipid associations, we also conducted additional analyses with additional covariates, including menopausal status, current smoking, and type 2 diabetes, in the CLHNS mothers. In the CLHNS offspring, we used SAS version 9.2 (SAS Institute, Cary, NC) to test the association between lipid traits and selected SNPs that were reported in previous GWA studies. As the ages of all offspring were within two years of each other, only sex, household assets, ln household income, and the first seven PCs were included as covariates. To examine the association in the combined cohort of mothers and offspring, we applied a general linear mixed model that accounted for the correlation of the outcome trait between mother-child pairs due to shared genetic and environmental exposures. Age, age2, sex, household assets, ln household income, the first seven PCs, and generation (mother/offspring) were used as covariates. For each SNP that showed evidence of a main effect association with a lipid trait in the CLHNS (P < 0.1 in both mothers and offspring analyzed separately), we further tested for a genotype interaction with waist circumference by including a SNP-by-waist circumference interaction term in the linear regression model or in the linear mixed model. The same sets of covariates used in the main effect analyses were included in the interaction analyses. For each SNP that showed significant evidence of interaction (Pinteraction < 0.05 in both mother and offspring cohorts), we conducted a stratified analysis by categorizing the study samples based on quartiles of waist circumference and testing for the main effects of the SNP on lipids within quartiles. All interaction analyses were conducted in SAS version 9.2 (SAS Institute, Cary, NC). The general characteristics of the 1,782 mothers and 1,719 young adult offspring from the CLHNS studied in these genetic analyses are shown in Table 1. Association analyses revealed genome-wide significant associations (P < 5 × 10−8) at APOE for both LDL-C (rs7412, P = 1.6 × 10−27) and TC (rs7412, P = 1.8 × 10−14), and at APOA5 for TGs (rs662799, P = 3.1 × 10−18) in the CLHNS mothers (Table 2). Suggestive evidence of association at a less stringent threshold of P < 10−6 was detected at the TG locus GCKR (rs780092, P = 1.6 × 10−7) and the HDL-C locus CETP (rs1800775, P = 6.3 × 10−7). In addition, we observed that variants at TOM1, a new HDL-C locus recently identified in a large-scale meta-analysis in individuals of European ancestry (9Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Discovery and refinement of loci associated with lipid levels..Nat. Genet. 2013; (In press)Google Scholar), also exhibited suggestive evidence of association in the mothers (rs138777, P = 5.0 × 10−7).TABLE 1General characteristics of CLHNS mothers and young adult offspringCharacteristicMothers (n = 1,782)Offspring (n = 1,719)Female (%)10047.6Age in 2005 (years)48.4 ± 6.121.5 ± 0.3Household assets in 2005 (0 to 11)5.2 ± 2.05.2 ± 2.0Household income in 2005 (pesos/week)396.4 (244.6, 623.9)357.7 (213.6, 586.7)TC (mmol/l)4.79 (4.09, 5.44)3.94 (3.44, 4.58)HDL-C (mmol/l)1.06 ± 0.271.09 ± 0.29LDL-C (mmol/l)3.10 ± 0.872.44 ± 0.75TGs (mmol/l)1.25 (0.91, 1.78)0.99 (0.74, 1.41)Waist circumference (cm)80.0 (73.5, 88.5)69.0 (65.0, 74.1)Data are mean ± SD, median (25th percentile, 75th percentile), or percent. Only one of the CLHNS mothers and one of the young adult offspring were taking lipid-altering medication. Open table in a new tab TABLE 2Loci associated with levels of lipoprotein cholesterol and TGs in the CLHNSLocusSNPTraitEffect AlleleOther AlleleMothers (n = 1,782)aAssociations in the CLHNS mothers were adjusted for age, age2, household assets, ln household income, and the first seven PCs of population substructure.Offspring (n = 1,719)bAssociations in the CLHNS offspring were adjusted for sex, household assets, ln household income, and the first seven PCs.CombinedcThe mixed model analysis of combined samples was adjusted for age, age2, sex, household assets, ln household income, the first seven PCs, and generation (mothers/offspring).EAFβ (SE)PEAFβ (SE)Pβ (SE)PAPOErs7412LDL-CTC0.12−0.48 (0.04)1.6E-270.11−0.49 (0.04)1.0E-35−0.48 (0.03)2.7E-53APOErs7412TCTC0.12−0.08 (0.01)1.8E-140.11−0.11 (0.01)1.7E-20−0.09 (0.01)1.5E-30APOA5rs662799TGsAG0.76−0.18 (0.02)3.1E-180.73−0.12 (0.02)2.6E-10−0.14 (0.01)5.7E-24GCKRrs780092TGsAG0.680.09 (0.02)1.6E-070.690.06 (0.02)3.5E-040.08 (0.01)1.8E-09CETPrs1800775HDL-CAC0.400.05 (0.01)6.3E-070.430.04 (0.01)1.7E-040.04 (0.01)3.4E-09TOM1rs138777HDL-CGA0.590.05 (0.01)5.0E-070.610.02 (0.01)0.0580.03 (0.01)4.0E-05Results are shown if P < 10−6 in the CLHNS mothers. EAF, effect allele frequency.a Associations in the CLHNS mothers were adjusted for age, age2, household assets, ln household income, and the first seven PCs of population substructure.b Associations in the CLHNS offspring were adjusted for sex, household assets, ln household income, and the first seven PCs.c The mixed model analysis of combined samples was adjusted for age, age2, sex, household assets, ln household income, the first seven PCs, and generation (mothers/offspring). Open table in a new tab Data are mean ± SD, median (25th percentile, 75th percentile), or percent. Only one of the CLHNS mothers and one of the young adult offspring were taking lipid-altering medication. Results are shown if P < 10−6 in the CLHNS mothers. EAF, effect allele frequency. We further evaluated these SNP associations in the CLHNS young adult offspring genotyped using the Metabochip (Table 2). We observed significant associations (P < 5 × 10−8) for the variants at APOE (P = 1.0 × 10−35 for LDL-C and 1.7 × 10−20 for TC) and APOA5 (P = 2.6 × 10−10), and nominal association for SNPs at GCKR (P = 3.5 × 10−4) and CETP (P = 1.7 × 10−4). For the SNP rs138777 at TOM1, we found marginal association with HDL-C in the offspring (P = 0.058). In the combined analysis including both mothers and offspring, all of these loci, except TOM1 (P = 4.0 × 10−5), reached significance at P < 5 × 10−8 (Table 2). We next assessed whether additional SNP-lipid associations identified in previous GWA studies could be extended to Filipino middle-aged and young adults, groups that have not been widely studied. As all the loci were previously reported, we defined the evidence of association as P < 0.1 for the reported GWA index SNPs or their proxies in both mothers and offspring with a consistent direction of effect. Among the 95 previously reported lipid loci (8Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. et al.Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2786) Google Scholar), 14 reached this threshold in the CLHNS. In addition to the four loci (APOE, APOA5, GCKR, and CETP) described in Table 2, the additional loci included three for TGs (LPL, MLXIPL, and ANGPTL3), three for HDL-C (LIPC, MMAB-MVK, and LIPG), two for LDL-C (ABO and APOB), and two for TC (TIMD4 and DNAH11) (Table 3). Analyses including both mothers and offspring showed that the variant rs588136 at LIPC also exhibited genome-wide significant association with HDL-C levels in the combined samples (P = 1.5 × 10−12).TABLE 3Additional previously reported SNPs that exhibited evidence of association with lipoprotein cholesterol and TGs in the CLHNSLocusTraitSNP Reported PreviouslyaSNPs were previously reported in (8), except MMAB-MVK rs2338104 was reported in (7).SNP Analyzed in CLHNSLD r2bLD r2 between the SNP pairs was estimated based on the 1000 Genomes Project phase I EUR data (November 2010 release).Mothers (n = 1,782)Offspring (n = 1,719)CombinedEAFβ (SE)PEAFβ (SE)Pβ (SE)PLPLTGsrs12678919rs3280.990.950.11 (0.04)7.9E-030.950.07 (0.04)0.100.09 (0.03)1.6E-03MLXIPLTGsrs17145738rs171457381.000.10−0.05 (0.03)0.0770.10−0.06 (0.03)0.040−0.06 (0.02)4.2E-03ANGPTL3TGsrs2131925rs21319251.000.710.04 (0.02)0.0360.690.04 (0.02)0.0340.04 (0.01)5.1E-03LIPCHDL-Crs2070895rs5881360.870.69−0.05 (0.01)5.1E-060.63−0.06 (0.01)1.1E-09−0.05 (0.01)1.5E-12LIPGHDL-Crs7241918rs21565520.940.14−0.02 (0.01)0.0750.15−0.03 (0.01)0.031−0.03 (0.01)4.6E-03MMAB-MVKHDL-Crs2338104rs107747081.000.62−0.02 (0.01)0.0760.61−0.03 (0.01)3.6E-03−0.02 (0.01)0.011ABOLDL-Crs9411489rs25190930.950.85−0.10 (0.05)0.0330.83−0.13 (0.03)1.6E-04−0.12 (0.03)3.0E-05APOBLDL-Crs1367117rs13671171.000.88−0.09 (0.05)0.0470.87−0.09 (0.04)0.023−0.08 (0.03)7.4E-03TIMD4TCrs6882076rs68820761.000.650.01 (0.01)0.0600.650.02 (0.01)0.0350.02 (0.01)4.0E-03DNAH11TCrs12670798rs50081480.940.550.02 (0.01)0.0720.580.01 (0.01)0.0520.02 (0.01)0.012Results are shown if P < 0.1 in both CLHNS mothers and offspring with a consistent direction of effect. EAF, effect allele frequency.a SNPs were previously reported in (8Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. et al.Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2786) Google Scholar), except MMAB-MVK rs2338104 wa
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