Abstract
Dyslipidemia and insulin resistance contribute to the endothelial cell dysfunction in hypertensive disorders of pregnancy (HDP) and increase the long-term risk of cardiovascular disease (CVD). The genes linking susceptibility to gestational hypertension (GH) and/or preeclampsia (PE) to the long-term risk of CVD are still unknown. We evaluated the potential association between 14 polymorphisms from six genes involved in lipid metabolism and insulin action and the risk of HDP: namely the lipoprotein lipase (LPL), hepatic lipase (LIPC), hormone sensitive lipase (LIPE), cholesteryl ester transfer protein (CETP), ApoCIII and ApoE gene polymorphisms. Overall, 169 women with HDP [proteinuria (PE) and gestational hypertension without proteinuria (GH)] and 169 controls matched for age and year of delivery were genotyped. Homozygosity of the −514T allele of the −514C > T polymorphism (LIPC gene) decreased the risk of GH (OR = 0.17, CI95: 0.02–0.76), while there were more −60G carriers of the −60C > G LIPE gene polymorphism (OR = 3.51, CI95:1.02–12.10) among GH cases, but not in PE cases. The common ApoCIII two-locus −482CC/3238CC genotype was lower in women with GH compared with controls (OR = 0.53, CI95: 0.3–0.9). The combined frequency of at-risk genotypes was higher in cases of GH compared with controls [one at-risk genotype: OR = 3.38 (95% CI: 0.48–41.8); two or more at-risk genotypes: OR = 7.14 (95% CI: 1.21–92.3, P = 0.01)], suggesting a gene-dose effect. We conclude that the combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of GH, but seemingly not of PE.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Arngrimsson R, Bjornsson H, Geirsson R (1995) Analysis of different inheritance patterns in preeclampsia/eclampsia syndrome. Hypertens Pregnancy 14:27–38
Belo L, Gaffney D, Caslake M, Santos-Silva A, Pereira-Leite L, Quintanilha A, Rebelo I (2004) Apolipoprotein E and cholesteryl ester transfer protein polymorphisms in normal and preeclamptic pregnancies. Eur J Obstet Gynecol Reprod Biol 112:9–15
van Bockxmeer FM, Liu Q, Mamotte C, Burke V, Taylor R (2001) Lipoprotein lipase D9N, N291S and S447X polymorphisms: their influence on premature coronary heart disease and plasma lipids. Atherosclerosis 157:123–129
Broughton Pipkin F (2001) Risk factors for preeclampsia. N Engl J Med 344:925–926
Broughton Pipkin F, Roberts JM (2000) Hypertension in pregnancy. J Hum Hypertens 14:705–724
Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIV
Caruso A, Ferrazzani S, De Carolis S, Lucchese A, Lanzone A, De Santis L, Paradisi G (1999) Gestational hypertension but not pre-eclampsia is associated with insulin resistance syndrome characteristics. Hum Reprod 14:219–223
Chappell LC, Seed PT, Briley A, Kelly FJ, Hunt BJ, Charnock-Jones DS, Mallet AI, Poston L (2002) A longitudinal study of biochemical variables in women at risk of preeclampsia. Am J Obstet Gynecol 187:127–136
Chen W, Srinivasan SR, Boerwinkle E, Berenson GS (2003) Hepatic lipase promoter C-514T polymorphism influences serial changes in HDL cholesterol levels since childhood: the Bogalusa Heart Study. Atherosclerosis 169:175–182
Chesley LC, Cooper DW (1986) Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women. Br J Obstet Gynaecol 93:898–908
Chesley LC, Annitto JE, Cosgrove RA (1968) The familial factor in toxemia of pregnancy. Obstet Gynecol 32:303–311
Cooper D (1993) Hypertension in pregnancy. Marcel Dekker Inc., New York
Cooper DW, Brennecke SP, Wilton AN (1993) Genetics of pre-eclampsia. Hypertens Pregnancy 12:1–23
Dammerman M, Sandkuijl LA, Halaas JL, Chung W, Breslow JL (1993) An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3’ untranslated region polymorphisms. Proc Natl Acad Sci USA 90:4562–4566
Deeb SS, Peng R (2000) The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity. J Lipid Res 41:155–158
Deeb SS, Zambon A, Carr MC, Ayyobi AF, Brunzell JD (2003) Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet. J Lipid Res 44:1279–1286
Dekker GA, Sibai BM (1998) Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 179:1359–1375
Efron B, Tibshirani RJ (1995) An introduction to the bootstrap. CRC Press, Boca Raton
Fisher KA, Luger A, Spargo BH, Lindheimer MD (1981) Hypertension in pregnancy: clinical-pathological correlations and remote prognosis. Medicine (Baltimore) 60:267–276
Forest JC, Girouard J, Masse J, Moutquin JM, Kharfi A, Ness RB, Roberts JM, Giguere Y (2005) Early occurrence of metabolic syndrome after hypertension in pregnancy. Obstet Gynecol 105:1373–1380
Garenc C, Perusse L, Chagnon YC, Rankinen T, Gagnon J, Borecki IB, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C (2002) The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study. Int J Obes Relat Metab Disord 26:220–227
Garenc C, Aubert S, Laroche J, Girouard J, Vohl MC, Bergeron J, Rousseau F, Julien P (2004) Population prevalence of APOE, APOC3 and PPAR-alpha mutations associated to hypertriglyceridemia in French Canadians. J Hum Genet 49:691–700
GOPEC Consortium (2005) Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study. Am J Hum Genet 77:127–131
Heyer E, Tremblay M (1995) Variability of the genetic contribution of Quebec population founders associated to some deleterious genes. Am J Hum Genet 56:970–978
Hubel CA, McLaughlin MK, Evans RW, Hauth BA, Sims CJ, Roberts JM (1996) Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum. Am J Obstet Gynecol 174:975–982
Hubel CA, Roberts JM, Ferrell RE (1999) Association of pre-eclampsia with common coding sequence variations in the lipoprotein lipase gene. Clin Genet 56:289–296
Irion O, Masse J, Forest JC, Moutquin JM (1998) Prediction of pre-eclampsia, low birthweight for gestation and prematurity by uterine artery blood flow velocity waveforms analysis in low risk nulliparous women. Br J Obstet Gynaecol 105:422–429
Ishimura-Oka K, Semenkovich CF, Faustinella F, Goldberg IJ, Shachter N, Smith LC, Coleman T, Hide WA, Brown WV, Oka K, et al. (1992) A missense (Asp250-Asn) mutation in the lipoprotein lipase gene in two unrelated families with familial lipoprotein lipase deficiency. J Lipid Res 33:745–754
Jansen H, Waterworth DM, Nicaud V, Ehnholm C, Talmud PJ (2001) Interaction of the common apolipoprotein C-III (APOC3 -482C > T) and hepatic lipase (LIPC −514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS-II). Ann Hum Genet 65:237–243
Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson N (1995) Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 74:772–776
Kim YJ, Williamson RA, Chen K, Smith JL, Murray JC, Merrill DC (2001) Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia. Hypertension 38:992–996
Klannemark M, Orho M, Langin D, Laurell H, Holm C, Reynisdottir S, Arner P, Groop L (1998) The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity. Diabetologia 41:1516–1522
Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB (2000) Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 96:45–49
Levesque S, Moutquin JM, Lindsay C, Roy MC, Rousseau F (2004) Implication of an AGT haplotype in a multigene association study with pregnancy hypertension. Hypertension 43:71–78
Makkonen N, Heinonen S, Hiltunen M, Helisalmi S, Mannermaa A, Kirkinen P (2001) Apolipoprotein E alleles in women with pre-eclampsia. J Clin Pathol 54:652–654
Masse J, Forest JC, Moutquin JM, Marcoux S, Brideau NA, Belanger M (1993) A prospective study of several potential biologic markers for early prediction of the development of preeclampsia. Am J Obstet Gynecol 169:501–508
Masse J, Forest JC, Moutquin JM, Degrandpre P, Forest VI (1998) A prospective longitudinal study of platelet angiotensin II receptors for the prediction of preeclampsia. Clin Biochem 31:251–255
Morgan T, Ward K (1999) New insights into the genetics of preeclampsia. Semin Perinatol 23:14–23
NHBPEP Working Group (2000) Report of the national high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 183:S1–S22
Ozcan T, Rinder HM, Murphy J, Kohn C, Copel JA, Magriples U (2001) Genetic thrombophilia and hypertensive complications of pregnancy. Obstet Gynecol 97:S40
Pihlajamaki J, Valve R, Karjalainen L, Karhapaa P, Vauhkonen I, Laakso M (2001) The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest 31:302–308
Pouta A, Hartikainen AL, Sovio U, Gissler M, Laitinen J, McCarthy MI, Ruokonen A, Elliott P, Jarvelin MR (2004) Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 43:1–7
Roberts JM (2000) Preeclampsia: what we know and what we do not know. Semin Perinatol 24:24–28
Roberts JM, Cooper DW (2001) Pathogenesis and genetics of pre-eclampsia. Lancet 357:53–56
Roberts RN, Traub AI, Kennedy AL, Hadden DR (1998) Glycosylated haemoglobin and hypertension arising in pregnancy. Br J Obstet Gynaecol 105:1122–1124
Roberts JM, Pearson G, Cutler J, Lindheimer M (2003) Summary of the NHLBI Working Group on research on hypertension during pregnancy. Hypertension 41:437–445
Salonen Ros H, Lichtenstein P, Lipworth L, Cnattingius S (2000) Genetic effects on the liability of developing pre-eclampsia and gestational hypertension. Am J Med Genet 91:256–260
Santé Québec (1995) Et la santé, comment ça va en 1992–1993? Rapport de l’enquête sociale et de santé 1992-1993. Ministère de la santé et des services sociaux, Gouvernement du Québec, Montreal
Seely EW, Solomon CG (2003) Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab 88:2393–2398
Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799
Skoglund-Andersson C, Ehrenborg E, Fisher RM, Olivecrona G, Hamsten A, Karpe F (2003) Influence of common variants in the CETP, LPL, HL and APO E genes on LDL heterogeneity in healthy, middle-aged men. Atherosclerosis 167:311–317
Solomon CG, Seely EW (2001) Brief review: hypertension in pregnancy: a manifestation of the insulin resistance syndrome? Hypertension 37:232–239
Tahvanainen E, Syvanne M, Frick MH, Murtomaki-Repo S, Antikainen M, Kesaniemi YA, Kauma H, Pasternak A, Taskinen MR, Ehnholm C (1998) Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. The LOCAT Study Invsestigators. J Clin Invest 101:956–960
Talmud PJ, Humphries SE (1997) Apolipoprotein C-III gene variation and dyslipidaemia. Curr Opin Lipidol 8:154–158
Talmud PJ, Palmen J, Walker M (1998) Identification of genetic variation in the human hormone-sensitive lipase gene and 5′ sequences: homology of 5′ sequences with mouse promoter and identification of potential regulatory elements. Biochem Biophys Res Commun 252:661–668
Talosi G, Endreffy E, Turi S, Nemeth I (2000) Molecular and genetic aspects of preeclampsia: state of the art. Mol Genet Metab 71:565–572
Thornton JG, Macdonald AM (1999) Twin mothers, pregnancy hypertension and pre-eclampsia. Br J Obstet Gynaecol 106:570–575
Vatten LJ, Skjaerven R (2004) Is pre-eclampsia more than one disease? Bjog 111:298–302
Walker JJ (2000) Pre-eclampsia. Lancet 356:1260–1265
Wang Y, Walsh SW (1996) TNF alpha concentrations and mRNA expression are increased in preeclamptic placentas. J Reprod Immunol 32:157–169
Williams D (2003) Pregnancy: a stress test for life. Curr Opin Obstet Gynecol 15:465–471
Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, Smith WC (2003) Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 326:845
Zambon A, Deeb SS, Hokanson JE, Brown BG, Brunzell JD (1998) Common variants in promoter of the hepatic lipase gene are associated with lower levels of hepatic lipase activity, buoyant LDL, and higher HDL2 cholesterol. Arterioscler Thromb Vasc Biol 18:1723–1729
Zhang Q, Liu Y, Liu BW, Fan P, Cavanna J, Galton DJ (1998) Common genetic variants of lipoprotein lipase and apolipoproteins AI- CIII that relate to coronary artery disease: a study in Chinese and European subjects. Mol Genet Metab 64:177–183
Zhao JH, Curtis D, Sham PC (2000) Model-free analysis and permutation tests for allelic associations. Hum Hered 50:133–139
Acknowledgments
This work was supported by grants to Yves Giguère from the Fond de la Recherche en Santé du Québec (FRSQ) and to Jean-Claude Forest et al. from the Canadian Institutes of Health Research (CIHR). Joël Girouard is a fellow of the FRSQ, and Yves Giguère is a clinical investigator funded by the FRSQ. We thank Pastelle Ladouceur-Keigle, M.Sc., for her expertise in biostatistics.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bernard, N., Girouard, J., Forest, JC. et al. The combination of ApoCIII, hepatic lipase and hormono sensitive lipase gene polymorphisms suggests an association with susceptibility to gestational hypertension. J Hum Genet 52, 244–254 (2007). https://doi.org/10.1007/s10038-006-0106-1
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-006-0106-1
Keywords
This article is cited by
-
Association of LIPC -250G/A and -514C/T polymorphisms and hypertension: a systematic review and meta-analysis
Lipids in Health and Disease (2018)
-
Meta-based association of the lipoprotein lipase gene S447X variant with hypertension and blood pressure variation
Journal of Human Hypertension (2011)
