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Obstetrics & Gynecology 2001;97:664-668
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Polymorphisms Within the Interleukin-1ß Gene Cluster and Preeclampsia

LUKAS A. HEFLER, MD, CLEMENS B. TEMPFER, MD and ANTHONY R. GREGG, MD

From the Departments of Obstetrics and Gynecology and Molecular Human Genetics, Baylor College of Medicine, Houston, Texas.

Address reprint requests to: Anthony R. Gregg, MD Department of Obstetrics and Gynecology Baylor College of Medicine 6550 Fannin, Suite 901 Houston, TX 77030 E-mail: agregg{at}bcm.tmc.edu


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To identify associations between polymorphisms within the interleukin-1ß gene cluster, all of which increase protein expression, and preeclampsia.

Methods: We genotyped a Hispanic population (69 women with preeclampsia and 47 controls) for two polymorphisms of the interleukin-1ß gene (promoter region and exon 5) and one polymorphism of the interleukin-1 receptor antagonist gene in intron 2. Clinical data were collected from medical records. Values are given as means or medians. Statistical power to identify a difference in occurrence of interleukin-1ß promoter, interleukin-1ß exon 5, and interleukin-1 receptor antagonist gene polymorphisms in women with preeclampsia compared with controls was 21%, 15.9%, and 30.9%, respectively.

Results: We found no association between any single polymorphism and occurrence of preeclampsia. Among women with preeclampsia, those with polymorphism of interleukin-1 receptor antagonist gene had higher mean systolic blood pressure (BP) at admission (178 ± 33.4 versus 159 ± 19.5 mmHg, P = .039). When all three polymorphisms combined were evaluated, women with preeclampsia and at least three mutant alleles (n = 8) had higher mean systolic BP at admission (182 ± 30 versus 160 ± 20.5 mmHg, P = .009) and increased alanine aminotransferase (67 [10–1024] versus 20 [3–407] IU/L, P = .04) and aspartate aminotransferase (119 [25–2239] versus 24 [4–489] IU/L, P = .002). At admission, BP in controls was independent of any polymorphism identified.

Conclusion: Although the power of this study was limited, our data do not support a role for polymorphisms of the interleukin-1ß and interleukin-1 receptor antagonist genes in the pathogenesis of preeclampsia among Hispanic women. Our findings do suggest that polymorphisms within the gene cluster might influence severity of preeclampsia.

The pregnancy-specific disorder preeclampsia, characterized by maternal hypertension and proteinuria, complicates 3–5% of pregnancies in the United States and is a major cause of maternal and fetal morbidity and mortality.1 The underlying pathophysiologic mechanisms remain elusive. An inherited component of this condition has been suggested.2 Several studies reported associations between preeclampsia and polymorphisms of various genes, including the angiotensinogen,3 tumor necrosis factor-alpha,4 factor V Leiden,5 and the 5,10 methylene tetrahydrofolate reductase6 genes. Endothelial cell dysfunction caused by a generalized intravascular inflammatory reaction is believed to be the final common pathway of pathogenesis of preeclampsia.7,8

Interleukin-1ß is a proinflammatory cytokine produced by monocytes, macrophages, and epithelial cells.9 Secretion of interleukin-1ß leads to a proinflammatory cascade, including production of tumor necrosis factor alpha, interferon gamma, interleukin-2, and interleukin-12. Interleukin-1ß activity is modulated by an endogenous factor, interleukin-1 receptor antagonist.9,10 By binding to the interleukin-1ß receptor without exerting an effector function, interleukin-1 receptor antagonist acts as a competitive antagonist for interleukin-1ß.11 In preeclampsia, increased placental expression of cytokines, such as interleukin-1ß, are believed to cause elevated circulating cytokine levels.8,12 Placental protein expression of interleukin-1ß has been upregulated,12 whereas data on circulating interleukin-1ß and interleukin-1 receptor antagonist levels are inconsistent.13–15

The genes encoding for interleukin-1ß and interleukin-1 receptor antagonist are within a 430-kb region on chromosome 2q14.2 in humans.16 Polymorphisms of the interleukin-1ß gene17,18 and a polymorphism of the interleukin-1 receptor antagonist gene19 correspond with altered interleukin-1ß and interleukin-1 receptor antagonist protein expression, respectively, in vitro and in vivo.17,20–22 The relationship between described alterations in protein expression among women with preeclampsia might be attributed to those polymorphisms. We hypothesized that polymorphisms within the interleukin-1ß cluster are associated with the development of preeclampsia.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
This study was approved by the internal review board at Baylor College of Medicine. Between June 1997 and April 2000, Hispanic women admitted to labor and delivery at Ben Taub General Hospital were selected randomly for participation. Ethnicity was determined by analysis of country of origin of parents through direct questioning or review of medical records. All women were of Hispanic ancestry (Mexico: n = 107, El Salvador: n = 2, Honduras: n = 4, Guatemala: n = 3). Preeclampsia was defined according to criteria of the Working Group Report on High Blood Pressure in Pregnancy as increased blood pressure (BP) accompanied by proteinuria.1 Blood pressure was considered elevated when systolic BP was at least 140/90 mmHg at admission. If BP was less than 140/90, an elevation 30 mmHg or greater systolic or 15 mmHg or greater diastolic from values before 20 weeks’ gestation was used as an inclusion criterion. Proteinuria was defined as one 24-hour urine collection with a total protein excretion of at least 300 mg. If a 24-hour urine specimen was unavailable, a urine dipstick value of 1+ (30 mg/dL) or greater at admission was used as an inclusion criterion. Women with hypertension and proteinuria were excluded from analysis if those findings were present before 20 weeks, or if they had other significant medical conditions that could cause proteinuria and hypertension.

Controls were at least gravida 2 with one prior term delivery and at term with no history of preeclampsia. Because some women in the preeclampsia group had prior normal pregnancies, we selected our controls so that women had at least two normal pregnancies, including the current one. Controls were healthy with no histories of essential hypertension, chronic renal disease, diabetes, platelet disorders, or autoimmune conditions. Controls were carrying singleton pregnancies and delivered live fetuses.

Staff nurses in the clinics, the obstetrics triage area, and on labor and delivery measured BP at admission. Care providers were unaware of women’s participation in the study. Urine protein dipstick analysis (Multistix 10 SG, Bayer Corp., Elkhart, IN) was done by the same staff nurses. Serum analytes and complete blood counts were done in the clinical laboratories at Ben Taub General Hospital. Patients’ hemoglobin, hematocrit, platelet counts, alanine aminotransferase, aspartate aminotransferase, uric acid, blood urea nitrogen, and serum creatinine were measured.

DNA was extracted from blood using the Puregene System (Gentra Systems, Research Triangle Park, NC) and stored at 4C until analyzed. A transition from cytosine to thymine at position -511 in the interleukin-1ß gene promoter was searched for using a polymerase chain reaction (PCR) strategy as published previously.18 For interleukin-1ß gene exon 5, PCR amplification was followed by restriction fragment length polymorphism analysis as previously described.17,23 For interleukin-1 receptor antagonist gene intron 2, PCR amplification with oligonucleotide primers flanking the 86-bp repeat region in intron 2 of the interleukin-1 receptor antagonist gene was done.19 All PCR primers used to genotype women are shown in Table 1Go.


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  		Table 1. Polymerase Chain Reaction Primer Sequences
 
The statistical software package SigmaStat 2.0 (Jandel Scientific, San Rafael, CA) was used for statistical analysis. Clinical data were collected from medical records. We compared clinical data by each polymorphism separately and by all three polymorphisms combined, women with at least three mutant alleles in the cluster versus all others. Where appropriate, {chi}2 analysis, Student t test, or Mann-Whitney rank-sum test were done. Normality was evaluated by Kolmogorov-Smirnov normality test and was assessed with P < .05. Bonferroni correction was applied when multiple comparisons were done. We calculated the power to detect a difference between preeclamptic and control women for the interleukin-1ß promoter, interleukin-1ß exon 5, and interleukin-1 receptor antagonist polymorphisms separately. We used data from Table 2Go. For the first two comparisons, we used a total of 110 women (220 alleles) and for the third comparison 101 women (202 alleles). We achieved powers of 21%, 15.9%, and 30.9%, respectively. We calculated the necessary sample to achieve a power of 80% and an {alpha} of .05 using the Yates correction factor. We considered P < .05 statistically significant.


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  		Table 2. Allelic Frequencies of Interleukin-1ß Promoter, Interleukin-1ß Exon 5, and Interleukin-1 Receptor Antagonist Genes
 

   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
Demographic data from women with preeclampsia and controls are in Table 3Go. The observation of higher gravidity and parity in controls was consistent with inclusion criteria. Preeclamptic women were admitted at earlier gestational ages, consistent with the expected clinical course for them. Ten women with preeclampsia had histories of it. There was one twin pregnancy among women with preeclampsia. Genotyping data for all three investigated polymorphisms was available for 59 women with preeclampsia and 38 controls. Among 116 women who participated, genotyping data were only available for 110, 110, and 101 women for the interleukin-1ß promoter, interleukin-1ß exon 5, and interleukin-1 receptor antagonist polymorphisms, respectively. For six women, DNA could not be extracted from blood, for nine, the PCR was unsuccessful after repeated attempts.


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  		Table 3. Demographic Data
 
Frequencies of each allele of the interleukin-1ß gene promoter, interleukin-1ß gene exon 5, and the interleukin-1 receptor antagonist gene for women with preeclampsia and controls, and odds ratios (ORs) and 95% confidence intervals (CIs) are given in Table 2Go. Although not statistically significant, the IV allele of the interleukin-1 receptor antagonist gene was only in women with preeclampsia (three of 62). Table 4Go shows the number of women with preeclampsia and controls with zero, one, two, three, and four mutant alleles, respectively. This table shows a clear distinction in frequency of women with two or fewer polymorphisms in the interleukin-1ß gene cluster compared with those with at least three polymorphisms. Presence of at least three polymorphisms in the interleukin-1ß cluster was not associated with occurrence of preeclampsia (P = .98).


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  		Table 4. Number of Mutant Alleles in the Interleukin-1ß Gene Cluster
 
The frequency of mutant interleukin-1 receptor antagonist alleles in our population (8.9%) was significantly lower (P < .001) than that published for white women (26–29%).19,24 The frequency for the interleukin-1ß exon 5 polymorphism in our population (14.1%) was in accordance with published data (20%).23,24 The frequency of the interleukin-1ß gene promoter polymorphism we observed (65.5%) was significantly increased (P < .001) compared with published reports for whites (40.3%).24 Others reported cosegregation of interleukin-1 receptor antagonist gene polymorphisms with mutant alleles of the interleukin-1ß (-511C/T) polymorphism (allele T) or no E2 allele.22 All 13 women with mutant interleukin-1 receptor antagonist alleles (seven with preeclampsia, six controls) in our series had the T allele (n = 11) or no E2 allele (n = 10).

Women with preeclampsia who also had polymorphisms of interleukin-1 receptor antagonist gene had higher mean systolic BP at diagnosis (178 ± 33.4 mmHg versus 159 ± 19.5 mmHg, P = .039). No significant associations between the other polymorphisms and BP were found. Four women had four, and four women had three mutant alleles in the interleukin-1ß gene cluster (Table 3Go). Women with at least three mutant alleles had higher systolic BP (182 ± 30 mmHg versus 160 ± 20.5 mmHg, P = .009), elevated alanine aminotransferase (67 [10–1024] versus 20 [3–407] IU/L, P = .04), and elevated aspartate aminotransferase (119 [25–2239] versus 24 [4–489] IU/L, P = .002) compared with the other women with preeclampsia. Blood pressure at admission in controls was independent of any polymorphism investigated. No significant association between polymorphism and clinical parameters was found.


   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
This gene cluster on chromosome 2 is believed to have arisen as a result of gene duplication, so homologies between the interleukin-1ß and interleukin-1 receptor antagonist genes are relatively high.25 The interleukin-1ß and interleukin-1 receptor antagonist genes are in order upstream of the interleukin-1{alpha} gene.16 An interregulatory relationship between polymorphisms within the interleukin-1ß and interleukin-1 receptor antagonist genes was proposed.21 It was suggested that interleukin-1ß gene polymorphisms lead to upregulation of interleukin-1 receptor antagonist in the presence of an interleukin-1 receptor antagonist gene polymorphism.21 We identified very few women with preeclampsia who also had interleukin-1 receptor antagonist gene polymorphisms (n = 8). The interleukin-1ß exon 5 gene polymorphism (E2) was identified in 15 women with preeclampsia. Among those, one showed an interleukin-1 receptor antagonist gene polymorphism. The interleukin-1ß gene promoter polymorphism -511 C/T was the most commonly seen (89% of women with preeclampsia). We could find no evidence to suggest linkage desequilibrium between polymorphisms within the interleukin-1ß and interleukin-1 receptor antagonist genes. Fisher exact test for alleles within the interleukin-1ß gene (data not shown) did not support linkage desequilibrium. In vitro data shows that each of the interleukin-1ß gene polymorphisms we tested are associated with increased interleukin-1ß production.17,20,22 Those polymorphisms are regulatory and associated with enhanced protein expression. Given the proinflammatory nature of interleukin-1ß, those polymorphisms are clearly candidates for genes that contribute to the preeclampsia phenotype.

Hispanics account for 11.8% of the United States population. However, there are few studies that address preeclampsia among ethnic-specific groups, especially Hispanic women. Angiotensinogen polymorphism (M235T) is associated with preeclampsia among non-Hispanics,3 and its frequency among Hispanics is high, which limits its predictive value.26,27 Recently, factor V Leiden mutation-associated activated protein C resistance was found higher in Hispanic women compared with other cohorts.28 We also identified a greater frequency of interleukin-1ß gene promoter polymorphisms (-511C/T) among Hispanic women and a much lower frequency of interleukin-1 receptor antagonist gene polymorphisms compared with reports on other racial-ethnic groups. We explored those relationships and evaluated the polymorphisms for an association with preeclampsia. No association between any of the three investigated polymorphisms could be found. Although no association between the polymorphisms and preeclampsia was identified, women with preeclampsia and an interleukin-1 receptor antagonist gene polymorphism had higher systolic BP at admission.

Our data showed no evidence of linkage disequilibrium (nonrandom assortment), so we attempted to evaluate genetic burden or contribution of multiple genes and their polymorphisms to preeclampsia, a likely polygenic disorder. Overexpression or underexpression of genes from polymorphisms could result in a greater disease risk. When all polymorphisms were evaluated in aggregate, the relationship with systolic BP was stronger for women with preeclampsia. Our data and that previously reported might suggest that interleukin-1 receptor antagonist gene polymorphisms are permissive in upregulation of proteins produced by that gene cluster, and physiologic effects result from those regulatory events.21 Those effects were not limited to higher systolic BP, but also included increased liver function parameters (alanine aminotransferase and aspartate aminotransferase).

We recognize the limited power of our study to definitively exclude any polymorphisms we evaluated with onset of preeclampsia in our population. To detect a difference for each polymorphism with a power of 80% and an alpha of .05 we would have needed to enroll 344, 556, and 154 preeclamptic and control women in each group, respectively. However, even with greater numbers, our data suggest a positive predictive value of no more than 9% and an attributable risk of no more than 9% for the interleukin-1 receptor antagonist gene polymorphisms.27 If allelic variation within inflammatory mediators is a consideration in the pathogenesis of preeclampsia, then genes regulating proteins other than interleukin-1ß and interleukin-1 receptor antagonist should be considered.


   Footnotes
 
This work was supported in part by the Erwin-Schroedinger-Auslandsstipendium J1839-MED with funding by the Fonds zur Foerderung der Wissenschaftlichen Forschung (to LAH).

PII S0029-7844(00)01128-0

Received September 8, 2000. Received in revised form December 6, 2000. Accepted January 12, 2001.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
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1. United States Department of Health and Human Services. NIH Publication No. 91, National high blood pressure education programme working group report on high blood pressure in pregnancy. Bethesda, MD: United States Department of Health and Human Services, 1991.

2. Morgan T, Ward K. New insights into the genetics of preeclampsia. Semin Perinatol 1999;23:14–23.[Medline]

3. Ward K, Hata A, Jeunemaitre X, Helin C, Nelson L, Namikawa C, et al. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet 1993;4:59–61.[Medline]

4. Chen G, Wilson R, Wang SH, Zheng HZ, Walker JJ, McKillop JH. Tumour necrosis factor-alpha (TNF-alpha) gene polymorphism and expression in pre-eclampsia. Clin Exp Immunol 1996;104: 154–9.[Medline]

5. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Paladini D, Martinelli P, et al. Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77:1052–4.[Medline]

6. Laivuori H, Kaaja R, Ylikorkala O, Hiltunen T, Kontula K. 677 C-->T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia. Obstet Gynecol 2000;96:277–80.[Abstract/Free Full Text]

7. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol 1997;37:240–9.

8. Redman CW, Sacks GP, Sargent IL. Preeclampsia: An excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999;180:499–506.[Medline]

9. Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol 1998;16:457–99.[Medline]

10. Arend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest 1991;88:1445–51.

11. Eisenberg SP, Brewer MT, Verderber E, Heimdal P, Brandhuber BJ, Thompson RC. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: Evolution of a cytokine control mechanism. Proc Natl Acad Sci USA 1991;88:5232–6.[Abstract/Free Full Text]

12. Rinehart BK, Terrone DA, Lagoo-Deenadayalan S, Barber WH, Hale EA, Martin JN, Jr, et al. Expression of the placental cytokines tumor necrosis factor alpha, interleukin 1beta, and interleukin 10 is increased in preeclampsia. Am J Obstet Gynecol 1999;181:915–20.[Medline]

13. Greer IA, Lyall F, Perera T, Boswell F, Macara LM. Increased concentrations of cytokines interleukin-6 and interleukin-1 receptor antagonist in plasma of women with preeclampsia: A mechanism for endothelial dysfunction? Obstet Gynecol 1994;84:937–40.[Abstract/Free Full Text]

14. Kimya Y, Akdis C, Cengiz C, Ozan H, Tatlikazan S, Uncu G, et al. Plasma interleukin-1alpha, interleukin-1beta and interleukin-1 receptor antagonist levels in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 1997;73:17–21.[Medline]

15. Heyl W, Handt S, Reister F, Gehlen J, Schroder W, Mittermayer C, et al. Elevated soluble adhesion molecules in women with preeclampsia. Do cytokines like tumour necrosis factor-alpha and interleukin-1beta cause endothelial activation. Eur J Obstet Gynecol Reprod Biol 1999;86:35–41.[Medline]

16. Nicklin MJ, Weith A, Duff GW. A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics 1994;19: 382–4.[Medline]

17. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 1992;22:396–402.[Medline]

18. di Giovine FS, Takhsh E, Blakemore AI, Duff GW. Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Hum Mol Genet 1992;1:450.[Free Full Text]

19. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993;91:403–4.[Medline]

20. Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: Inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol 1995;99:303–10.[Medline]

21. Hurme M, Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are coordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 1998;28:2598–602.[Medline]

22. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 1998;47:195–8.[Medline]

23. Bioque G, Crusius JB, Koutroubakis I, Bouma G, Kostense PJ, Meuwissen SG, et al. Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease. Clin Exp Immunol 1995;102:379–83.[Medline]

24. Cantagrel A, Navaux F, Loubet-Lescoulie P, Nourhashemi F, Enault G, Abbal M, et al. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: Relationship to occurrence and severity of rheumatoid arthritis. Arthritis Rheum 1999;42:1093–100.[Medline]

25. Dinarello CA. The interleukin-1 family: 10 years of discovery. FASEB J 1994;8:1314–25.[Abstract]

26. Fardella CE, Claverie X, Vignolo P, Montero J, Villarroel L. T235 variant of the angiotensinogen gene and blood pressure in the Chilean population. J Hypertens 1998;16:829–33.[Medline]

27. Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000;343:141–4.[Free Full Text]

28. Fassett MJ, Bohn YC, Kuo J, Wing DA. Longitudinal evaluation of activated protein C resistance among normal pregnancies of Hispanic women. Am J Obstet Gynecol 2000;182:1433–6.[Medline]




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