Genetic variants of the lipoprotein lipase gene and myocardial infarction in the Central Valley of Costa Rica

To assess common variants of the LPL gene that could influence susceptibility to myocardial infarction (MI), we assessed three functional single-nucleotide polymorphisms (SNPs), D9N, N291S, and S447X, in 1,321 survivors of a first acute MI and 1,321 population-based controls, matched for age, gender, and area of residence, all living in the Central Valley of Costa Rica. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The frequency of the X447 mutant allele was significantly lower in cases than in controls (6.2% vs. 7.6%; P < 0.01), whereas no association with MI was found for D9N or N291S. The OR (95% CI) for carriers vs. noncarriers of the X447 allele was 0.80 (0.63–1.01); when considering the haplotype that contained X447 and normal alleles of D9N and N291S, the OR (95% CI) was 0.66 (0.48–0.91). Twelve other SNPs were assessed in a subgroup of the population, of which the four functional SNPs were found to be monomorphic, and no correlation with MI was observed for the other eight neutral SNPs.The X447 mutant allele of the LPL gene may protect from MI risk, although this effect is small. To assess common variants of the LPL gene that could influence susceptibility to myocardial infarction (MI), we assessed three functional single-nucleotide polymorphisms (SNPs), D9N, N291S, and S447X, in 1,321 survivors of a first acute MI and 1,321 population-based controls, matched for age, gender, and area of residence, all living in the Central Valley of Costa Rica. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The frequency of the X447 mutant allele was significantly lower in cases than in controls (6.2% vs. 7.6%; P < 0.01), whereas no association with MI was found for D9N or N291S. The OR (95% CI) for carriers vs. noncarriers of the X447 allele was 0.80 (0.63–1.01); when considering the haplotype that contained X447 and normal alleles of D9N and N291S, the OR (95% CI) was 0.66 (0.48–0.91). Twelve other SNPs were assessed in a subgroup of the population, of which the four functional SNPs were found to be monomorphic, and no correlation with MI was observed for the other eight neutral SNPs. The X447 mutant allele of the LPL gene may protect from MI risk, although this effect is small. Lipoprotein lipase is a major enzyme responsible for the hydrolysis of circulating triglyceride (1Mead J.R. Irvine S.A. Ramji D.P. Lipoprotein lipase: structure, function, regulation, and role in disease.J. Mol. Med. 2002; 80: 753-769Crossref PubMed Scopus (639) Google Scholar). Independent of its lipolytic activity, LPL is capable of anchoring lipoproteins to the vessel wall (2Merkel M. Heeren J. Dudeck W. Rinninger F. Radner H. Breslow J.L. Goldberg I.J. Zechner R. Greten H. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake.J. Biol. Chem. 2002; 277: 7405-7411Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar); it can act as a ligand for the LDL receptor family (3Takahashi S. Suzuki J. Kohno M. Oida K. Tamai T. Miyabo S. Yamamoto T. Nakai T. Enhancement of the binding of triglyceride-rich lipoproteins to the very low density lipoprotein receptor by apolipoprotein E and lipoprotein lipase.J. Biol. Chem. 1995; 270: 15747-15754Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar), and it can mediate the selective uptake of lipoprotein-associated lipids and lipophilic vitamins (2Merkel M. Heeren J. Dudeck W. Rinninger F. Radner H. Breslow J.L. Goldberg I.J. Zechner R. Greten H. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake.J. Biol. Chem. 2002; 277: 7405-7411Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 4van Bennekum A.M. Kako Y. Weinstock P.H. Harrison E.H. Deckelbaum R.J. Goldberg I.J. Blaner W.S. Lipoprotein lipase expression level influences tissue clearance of chylomicron retinyl ester.J. Lipid Res. 1999; 40: 565-574Abstract Full Text Full Text PDF PubMed Google Scholar). The LPL gene is located on chromosome 8p22, spans ∼30 kb containing 10 exons, and ∼100 naturally occurring mutations have been described in this gene (5Murthy V. Julien P. Gagne C. Molecular pathobiology of the human lipoprotein lipase gene.Pharmacol. Ther. 1996; 70: 101-135Crossref PubMed Scopus (155) Google Scholar). A few of these mutations are relatively common in the general population, although their individual frequency differs widely across populations (6Hokanson J.E. Lipoprotein lipase gene variants and risk of coronary disease: a quantitative analysis of population-based studies.Int. J. Clin. Lab. Res. 1997; 27: 24-34Crossref PubMed Scopus (76) Google Scholar). Two common mutations, D9N and N291S, reduce LPL activity (7Zhang H. Henderson H. Gagne S.E. Clee S.M. Miao L. Liu G. Hayden M.R. Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function.Biochim. Biophys. Acta. 1996; 1302: 159-166Crossref PubMed Scopus (102) Google Scholar). Other highly frequent LPL mutations are population-specific, such as P207L and G188E in French Canadians (8Minnich A. Kessling A. Roy M. Giry C. DeLangavant G. Lavigne J. Lussier-Cacan S. Davignon J. Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent.J. Lipid Res. 1995; 36: 117-124Abstract Full Text PDF PubMed Google Scholar). Overall, these mutations are associated with increased triglycerides and decreased HDL cholesterol in plasma (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar). Two common LPL mutations, the S447X that causes a C-terminal truncation by two amino acids and −93 T/G, are associated with low triglyceride concentrations (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar, 10Ehrenborg E. Clee S.M. Pimstone S.N. Reymer P.W. Benlian P. Hoogendijk C.F. Davis H.J. Bissada N. Miao L. Gagne S.E. Greenberg L.J. Henry R. Henderson H. Ordovas J.M. Schaefer E.J. Kastelein J.J. Kotze M.J. Hayden M.R. Ethnic variation and in vivo effects of the −93t→g promoter variant in the lipoprotein lipase gene.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2672-2678Crossref PubMed Scopus (41) Google Scholar). Despite the relatively consistent LPL gene effects on plasma lipids and enzyme activity, results from studies addressing the effect of LPL genetic mutations on clinical end points in the general population are sparse. The N9 allele has been associated with increased coronary heart disease risk (11van Bockxmeer F.M. Liu Q. Mamotte C. Burke V. Taylor R. Lipoprotein lipase D9N, N291S and S447X polymorphisms: their influence on premature coronary heart disease and plasma lipids.Atherosclerosis. 2001; 157: 123-129Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar), but most studies do not show an association (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar). A strong association between the S291 allele and ischemic heart disease was found in a large study (12Wittrup H.H. Tybjaerg-Hansen A. Abildgaard S. Steffensen R. Schnohr P. Nordestgaard B.G. A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease.J. Clin. Invest. 1997; 99: 1606-1613Crossref PubMed Scopus (117) Google Scholar) but not in others (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar). On the other hand, the X447 allele is likely to be protective, although not conclusively (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar, 13Clee S.M. Loubser O. Collins J. Kastelein J.J. Hayden M.R. The LPL S447X cSNP is associated with decreased blood pressure and plasma triglycerides, and reduced risk of coronary artery disease.Clin. Genet. 2001; 60: 293-300Crossref PubMed Scopus (48) Google Scholar, 14Chen W. Srinivasan S.R. Elkasabany A. Ellsworth D.L. Boerwinkle E. Berenson G.S. Influence of lipoprotein lipase serine 447 stop polymorphism on tracking of triglycerides and HDL cholesterol from childhood to adulthood and familial risk of coronary artery disease: the Bogalusa Heart Study.Atherosclerosis. 2001; 159: 367-373Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 15Humphries S.E. Nicaud V. Margalef J. Tiret L. Talmud P.J. Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS).Arterioscler. Thromb. Vasc. Biol. 1998; 18: 526-534Crossref PubMed Scopus (153) Google Scholar, 16Gagne S.E. Larson M.G. Pimstone S.N. Schaefer E.J. Kastelein J.J. Wilson P.W. Ordovas J.M. Hayden M.R. A common truncation variant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study.Clin. Genet. 1999; 55: 450-454Crossref PubMed Scopus (106) Google Scholar). In the present study, we examined 15 single-nucleotide polymorphisms (SNPs) in the LPL gene to test whether these genetic variants are associated with the risk of nonfatal myocardial infarction (MI) in the Central Valley of Costa Rica. The catchment area consisted of the 34 counties that constitute the Central Valley of Costa Rica. All MI cases and population-based controls were ascertained between 1994 and 2000. Eligible case subjects were men and women who were diagnosed as survivors of a first acute MI by two independent cardiologists at any of the six recruiting hospitals in the catchment area, according to the World Health Organization criteria for MI, which require typical symptoms plus either increases in cardiac enzyme levels or diagnostic changes in the electrocardiogram (17Tunstall-Pedoe H. Kuulasmaa K. Amouyel P. Arveiler D. Rajakangas A.M. Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents.Circulation. 1994; 90: 583-612Crossref PubMed Google Scholar). One free-living control subject for each case, matched for age (±5 years), sex, and area of residence (county), was randomly selected using the information available at the National Census and Statistics Center of Costa Rica. Participation was 97% for cases and 89% for controls. All subjects gave informed consent on documents approved by the Human Subjects Committee of the Harvard School of Public Health and the University of Costa Rica. Seven functional and eight neutral SNPs were selected for assessment. After the initial genotyping of 300 subjects, the −39 T/C, G188E, and P207L polymorphisms were found to be monomorphic, and the −93 T/G had very low frequency; therefore, they were not genotyped further. The neutral SNPs (rs252, rs258, rs270, rs285, rs301, rs314, rs320, and rs326) (http://www.ncbi.nlm.nih.gov/SNP/) were genotyped in 492 cases and 520 controls. Genotyping was carried out using a variation of the allele-specific assay (ASA). DNA fragments were obtained using PCR primers designed according to each SNP's vicinity sequence. The reverse primers contained an artificially introduced sequence (derived from the bacteriophage M13) at the 5′ end, which was identical across all SNPs. SNPs were genotyped in three different multiplex reactions, with allele-specific forward primers and a reverse primer whose sequence was universal for all SNPs. Universal primers were labeled at the 5′ end with one of three fluorescent dyes (FAM, HEX, and TET). ASA products were separated by capillary electrophoresis with the ABI Prism 310 genetic analyzer (Applied Biosystems, Perkin-Elmer) and analyzed using Genotyper software. The two alleles of each polymorphism were distinguished by size and fluorescent label. Eight randomly selected QA/QC samples were genotyped on each plate throughout the study, and reproducibility was >99%. Overall, less than 1% of genotypes had missing values. All data were analyzed with the Statistical Analysis Systems software version 8 (SAS Institute, Inc., Cary, NC). Of the 2,886 subjects recruited, 1,321 cases and 1,321 controls with no missing general information or genotyping data were used in this analysis. Differences in health characteristics and potential confounders between cases and controls were assessed by Wilcoxon rank-sum tests for continuous variables and with Chi-square tests for categorical variables. Haplotype frequencies were estimated with the Arlequin software (Arlequin version 2.000) (18Schneider, S., D. Roessli, and L. Excoffier. 2000. Arlequin Version 2.000: A Software for Population Genetics Data Analysis. Genetics and Biometry Laboratory, Department of Anthropology, University of Geneva, Geneva, Switzerland.Google Scholar). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression for single loci of D9N, N291S, and S447X and for haplotypes defined by these loci. The effect estimation of haplotypes was carried out in 1,255 case-control pairs with no phase ambiguity. Models were adjusted for waist-to-hip ratio, physical activity, household income, smoking, history of diabetes, and history of hypertension. Table 1 shows the general characteristics of the study subjects, mutant allele frequencies of functional polymorphisms, and frequencies of haplotypes defined by the functional polymorphisms. The frequencies of the mutant alleles were all <10%. The X447 allele frequency was significantly lower in cases than in controls (6.2% vs. 7.6%; P = 0.007). No significant case-control differences were observed for D9N or N291S. Among the haplotypes defined by the functional polymorphisms, the H0 haplotype was the most prevalent, and it was lower in controls, 77.8%, than in cases, 80.3% (P = 0.002). All haplotypes containing mutant alleles were more prevalent in controls than in cases, but significant differences were detected only for the H3 haplotype, which contained the X447 allele and normal alleles at the other two loci (6.7% vs. 5.0%, respectively; P = 0.0003). All other haplotypes were rare (∼1% combined).TABLE 1General characteristics and allele and haplotype frequencies of D9N, N291S, and S447X in myocardial infarction cases and population-based controls from the Central Valley of Costa RicaCharacteristicsControls (n = 1,321)Cases (n = 1,321)Age (years)aMean (SD). 58 (11) 58 (11)Sex (% female)2626Area (% rural)3333Waist-to-hip ratioaMean (SD).0.95 (0.08)0.97 (0.07)bP < 0.01 compared with controls.Physical activity (METS)aMean (SD).,cMETS, metabolic equivalent tasks.1.55 (0.75)1.50 (0.76)bP < 0.01 compared with controls.Monthly household income (U.S $)aMean (SD). 565 (449) 475 (410)bP < 0.01 compared with controls.Current smokers (%)dAt least one cigarette per day.2341bP < 0.01 compared with controls.History of diabetes (%)1323bP < 0.01 compared with controls.History of hypertension (%)2738bP < 0.01 compared with controls.Single-locus alleleD9N (%)8.4 7.9N291S (%)7.5 7.0S447X (%)7.6 6.2bP < 0.01 compared with controls.Three-loci haplotypeeDefined by alleles in the order D9N, N291S, and S447X. +, normal allele; −, mutant allele.+++ (H0)77.8 80.3bP < 0.01 compared with controls.− ++ (H1)7.5 6.9+ − + (H2)6.9 6.6++ − (H3)6.7 5.0bP < 0.01 compared with controls.Others1.1 1.2a Mean (SD).b P < 0.01 compared with controls.c METS, metabolic equivalent tasks.d At least one cigarette per day.e Defined by alleles in the order D9N, N291S, and S447X. +, normal allele; −, mutant allele. Open table in a new tab Table 2 shows the frequencies of neutral SNP variants. The frequencies ranged between 24.7% and 49.5% in the control group. There were no significant case-control differences in allele frequency of these nonfunctional SNPs. Hardy-Weinberg proportions were observed for all SNPs studied.TABLE 2Allele frequencies of LPL gene polymorphisms assessed in a subgroup of myocardial infarction cases and population-based controls from the Central Valley of Costa RicaLocusaFour other loci were genotyped in 300 subjects: three (G188E, P207L, and −39 T/C) were monomorphic, and the allele frequency of −93 T/G was the same (2.3%) in both cases and controls.Controls (n = 520)Cases (n = as polymorphism in other loci were genotyped in 300 subjects: three (G188E, P207L, and −39 T/C) were monomorphic, and the allele frequency of −93 T/G was the same (2.3%) in both cases and as polymorphism in Open table in a new tab of the X447 allele had a lower risk of MI compared with noncarriers = 95% = After for potential confounders and the effect of D9N and N291S, the estimate was not the SNP effect was estimated for the haplotype which contained the X447 allele and normal alleles of loci D9N and N291S, the OR for MI was 0.66 (95% = All were adjusted for waist-to-hip ratio, physical activity, household income, smoking, history of diabetes, and history of hypertension. the analysis carriers of the gene variants and and the the the effect of genetic variation in the LPL gene and risk of MI in a large population-based study in the Central Valley of Costa Rica. functional D9N, N291S, and S447X, were found in this population, but promoter variants were The carriers of the X447 to triglyceride levels in had a decreased risk of The of is by the population-based case-control with the standardized study for of cases of a first MI and randomly selected controls, and the large of case of a effect of the mutant X447 although is by studies (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar). this effect has been observed of the relatively effects of this SNP on triglyceride and HDL compared with the effects of the D9N and N291S polymorphisms on these lipids (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar). it is that the X447 allele MI other that be using in is that LPL is in and D. S. M. A. Lipoprotein lipase is by in human coronary Clin. Invest. PubMed Scopus Google Scholar), it can lipoproteins by between lipoproteins and or in the wall G. T. and 1995; PubMed Scopus Google Scholar). this the X447 LPL mutant may have a decreased to lipoproteins and mediate ester and with studies F. Y. Reymer P.W. T. M. A. D. Kastelein A. G. S.E. Talmud P.J. A common variant in the gene for lipoprotein lipase and in normal and Thromb. Vasc. Biol. 1995; PubMed Scopus Google Scholar, Q. J. W. W. Common genetic variants of lipoprotein lipase that to in patients with premature coronary artery disease.Clin. Genet. 1995; PubMed Scopus Google Scholar, F. Nicaud V. P. G. Arveiler D. J.M. O. Talmud P.J. S.E. between the in the lipoprotein lipase gene and plasma in myocardial infarction survivors from the Study.Atherosclerosis. 1996; Full Text PDF PubMed Scopus Google Scholar, P.W. Gagne E. H. H. D. Kastelein J. Hayden M.R. A lipoprotein lipase (Asn291Ser) is associated with reduced HDL cholesterol levels in premature Genet. 1995; PubMed Scopus Google Scholar, F. A. M. G. G. S.E. Talmud P.J. of the lipoprotein lipase with plasma a study in subjects, myocardial infarction and Lipid Res. 1995; 36: Full Text PDF PubMed Google Scholar, R. F. O. L. A. Arveiler D. G. J.M. M. F. Tiret L. Lipoprotein lipase gene polymorphisms: with myocardial infarction and lipoprotein the Lipid Res. 1995; 36: Full Text PDF PubMed Google Scholar) one (12Wittrup H.H. Tybjaerg-Hansen A. Abildgaard S. Steffensen R. Schnohr P. Nordestgaard B.G. A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease.J. Clin. Invest. 1997; 99: 1606-1613Crossref PubMed Scopus (117) Google Scholar), we found no association between the D9N and N291S polymorphisms and is in to the results on the effect of their mutant alleles on plasma The N9 and S291 alleles are associated with and triglyceride and and lower HDL cholesterol (9Wittrup H.H. Tybjaerg-Hansen A. Nordestgaard B.G. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907Crossref PubMed Scopus (300) Google Scholar), which are risk for coronary disease J.E. triglyceride level is a risk for disease independent of lipoprotein cholesterol a of population-based 1996; PubMed Google Scholar, F.M. The role of lipoprotein cholesterol in the and of coronary heart disease: J. 2002; 90: Full Text Full Text PDF PubMed Scopus Google Scholar). it is an that D9N and N291S may be in with other functional SNPs of the LPL gene that have effects on MI, data that this is not Among the 15 SNPs we examined across the LPL we found no other between MI and these SNPs or the of S447X. Other relatively common SNPs in other populations that may have large effects on MI, such as G188E and P207L, were in this population, and the −93 T/G in the promoter had very low carriers of the variants were from the the results In the X447 mutant allele is associated with a of MI risk of the Central Valley of Costa Rica. The observed effect is consistent with the role of the X447 allele on plasma study was by and from the National of The for in genotyping and for data

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