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Pii: s0015-0282(01)01691-0

Copyright 2001 American Society for Reproductive Medicine Printed on acid-free paper in U.S.A.
Apolipoprotein E alleles in women with
polycystic ovary syndrome

Seppo Heinonen, M.D.,a Seija Korhonen, M.D.,a Maritta Hippela¨inen, M.D.,aMikko Hiltunen, M.Sc.,b Arto Mannermaa, Ph.D.c and Seppo Saarikoski, M.D.a Kuopio University Hospital, Kuopio, Finland Objective: To investigate the frequency of apoE alleles among women with polycystic ovary syndrome.
Design: Retrospective case-control study.
Setting: University-based endocrinology/infertility clinic.
Patient(s): Healthy fertile women (n ϭ 91) and women with a diagnosis of polycystic ovary syndrome (n ϭ
Intervention(s): None.
Main Outcome Measure(s): The presence of the three most common apoE alleles (⑀2, ⑀3, and ⑀4)
determined by polymerase chain reaction–restriction fragment length polymorphism in the two groups and in
the general population in our area.
Result(s): The frequency of the apo ⑀4 allele was 17.2% among women with polycystic ovary syndrome and
was 18.7% among healthy fertile women, which is close to the rate in the general population in our area (19%).
None of the apoE genotypes (Fisher’s exact test; Pϭ.71) or alleles (Pϭ.78) was significantly overrepresented,
and the homozygous genotype ⑀4 was not associated with the clinical disease.
Conclusion(s): The observed profiles of allele and genotype frequencies confirm the equilibrium state
between apoE polymorphism and polycystic ovary syndrome and suggest that apoE does not play a major role
in the development of hyperlipidemia in the group of women with polycystic ovary syndrome. (Fertil Steril௡
2001;75:878 – 80. 2001 by American Society for Reproductive Medicine.)
Key Words: Apolipoprotein E, polycystic ovary syndrome, gene polymorphism
Polycystic ovary syndrome (PCOS) is asso- often found in this patient group. Accordingly, ciated with hyperinsulinemia and peripheral in- Talbott et al. (8) compared cardiovascular dis- sulin resistance, both of which have been linked to dyslipidemia (1, 2). Insulin resistance control subjects matched for body mass index appears to play a critical role in the pathophys- and documented higher levels of total choles- iology of PCOS, as evidenced by highly cor- terol, low-density lipoprotein C, and triglycer- related levels of ovarian vein androgens and ides and lower levels of high-density lipopro- insulin (3). When serum androgen concentra- tein C in the study group. This suggests that tions are reduced by means of a gonadotropin- releasing hormone agonist, insulin resistance remains in women with PCOS (4). On the other hand, suppression of serum insulin concentra- Apolipoprotein E (apoE) is an established and Gynecology, KuopioUniversity Hospital, 70211 tions by diazoxide reduces serum testosterone genetic marker for dyslipidemia and athero- sclerosis, and it plays an important role in lipid 17-172-486;
This suggests that the direction of causation metabolism (9). Cholesterol absorption effi- is from insulin to androgens, and collectively, ciency from the intestine increases, whereas these metabolic abnormalities result in varying bile acid secretion by the liver falls in the degrees of glucose intolerance, dyslipidemia, following allelic order: ⑀2 Ͻ ⑀3 Ͻ ⑀4 (10). The central obesity, and hypertension (6). However, aim of the current study was to investigate the von Eckardstein et al. (7) reported that dyslip- possible role of apoE in the dyslipidemia seen in PCOS by determining the frequencies of 0015-0282/01/$20.00PII S0015-0282(01)01691-0 with PCOS, independently of the excess weight apoE alleles and genotypes, using the polymer- Clinical characteristics of the PCOS women.
Apolipoprotein E genotype and allele frequencies in womenwith polycystic ovary syndrome; in healthy, fertile controls; Note: PCO ϭ polycystic ovary; BMI ϭ body mass index.
d Or free plasma testosterone Ͼ40 pmol/L, evaluated using SHBG.
Heinonen Apolipoprotein E and PCOS. Fertil Steril 2001. Heinonen Apolipoprotein E and PCOS. Fertil Steril 2001. ase chain reaction (PCR) combined with restriction fragment The clinical characteristics of the patients are presented in length polymorphism (RFLP) analysis.
Table 1. Serum concentrations of total cholesterol and tri-glycerides were above the normal range in 12% and 24%, MATERIALS AND METHODS
respectively, of the women with PCOS.
Written approval for the study was obtained from the Genomic deoxyribonucleic acid (DNA) was extracted Ethics Committee of Kuopio University Hospital, and the from peripheral blood lymphocytes using a standard phenol- protocol was approved by the investigation review board.
chloroform extraction method (13) and subjected to analysis Informed consent was obtained from all subjects and docu- by PCR and gel electrophoresis of the products. For detec- tion of ApoE alleles, polymerase chain reactions of genomicDNA and HhaI digestions of PCR products were carried out Information was collected retrospectively from 58 women as previously reported by Tsukamoto et al. (14). Each set of with PCOS seen in the endocrinology/infertility clinic at reactions was run with positive and negative controls and a Kuopio University Hospital and from 91 nonhirsute, fertile blank. From the PCR results, the genotypes and allele fre- control women with regular cycles and normal ovaries who quencies were calculated. Statistical analysis was conducted delivered at our institution between January 1999 and De- using Fisher’s exact test (run on SPSS, version 9.0, Chicago, cember 1999. In the study group, the indications for referral IL), and the level of statistical significance was defined as were menstrual cycle disturbances, infertility, and symptoms PϽ.05. ApoE genotypes were found to be in Hardy-Wein- berg equilibrium in both patient and control groups.
The diagnosis of PCOS was based on information ob- tained by clinical examination (hirsutism and ovulatory dis- orders with an intermenstrual interval of Ͼ36 days), obser-vation of polycystic ovaries in ultrasonography (11), The genotypes and frequencies of apoE alleles are pre- laboratory testing revealing androgen excess (serum total sented in Table 2. Population frequencies were derived from testosterone concentration Ͼ2.5 nmol/L), and an elevated the same geographical area, and they were based on more LH/FSH ratio (Ͼ2). In this study, PCOS was defined as the than 1,500 tested subjects in the general population. The presence of polycystic ovaries plus either of the classical distribution of apoE alleles and genotypes was equal in symptoms and either of the above-mentioned biochemical affected and unaffected cases (Pϭ.71 and Pϭ.78, respec- disturbances. Furthermore, we excluded other causes of tively). The frequency of the apo ⑀4 allele was 17.2% among anovulation and hirsutism, such as late-onset congenital ad- women with PCOS and was 18.7% among healthy fertile renal hyperplasia and prolactin and thyroid function abnor- women (nonsignificant), which in turn corresponded well malities. Hirsutism was defined by the presence of excessive with the population frequency (19%), as expected. None of body hair in an androgen-dependent pattern, with a modified the apoE genotypes was significantly overrepresented. Af- Ferriman-Gallwey score of 8 or more (12).
fected women were then divided into subgroups according to FERTILITY & STERILITY
the number of ⑀4 alleles: no ⑀4 allele (genotypes 2/3, 3/3), results of the current study suggest that there is no link one ⑀4 allele (genotypes 2/4, 3/4), and two ⑀4 alleles (geno- between apoE genotype and the hyperlipidemia seen in the type 4/4). The frequency of the 3/4 genotype, although group of patients with PCOS. Waterworth et al. reported that somewhat higher in affected women, was not significantly susceptibility to PCOS maps to a variable number of tandem different from that in the unaffected controls (Pϭ.43). Fur- repeats located upstream of the insulin gene, which also thermore, using the general population as a reference, the 3/4 supports the theory that PCOS is, in part, caused by an genotype was not associated with an increased risk of PCOS.
alteration in insulin production (17). The finding suggests Women having the ⑀4/4 genotype constituted 3.4% of all that there is a mechanistic link between type 2 diabetes and affected women and 7.7% of the control group. The clinical PCOS, which in turn would affect lipid metabolism and the course of PCOS as regards the severity of the disease (pa- risk of coronary disease. Overall, the altered pattern of sex tients with oligoamenorrhea of Ͼ3 months compared with hormones and insulin plays a major role in the dyslipidemia those with mild cycle abnormalities) among affected women associated with PCOS, and the role of the apoE genotype is having the ⑀4/4 genotype was comparable with that in the of minor importance. Exercise and weight loss are the ways remaining PCOS women having other genotypes. Collec- to reverse insulin resistance primarily and, secondarily, the tively, an equilibrium state between apoE alleles and geno- metabolic disturbances associated with it (18). The current types was established in both PCOS women and controls.
results do not affect the clinical management of plasma lipiddisturbances in PCOS but provide some evidence against DISCUSSION
familial hypercholesterolemia, which in turn is treated withlipid-lowering drugs in selected cases.
There is evidence that PCOS is clustered in families and is inherited as a complex trait, like osteoporosis or hyper- References
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families have revealed that even within individual PCOS 2. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for pedigrees, the clinical phenotype is very heterogeneous in coronary artery disease in lean and obese women with polycystic ovarysyndrome. Clin Endocrinol 1992;37:119 –25.
females, and in males, obligate carriers appear to have vary- 3. Nagamani M, Dinh TV, Kelver ME. Hyperinsulinemia in hyperthecosis ing degrees of premature male-pattern baldness (15). Family of the ovaries. Am J Obstet Gynecol 1986;154:384 –9.
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studies and studies among twins are valuable in identifying Persistence of insulin resistance in polycystic ovarian disease after susceptibility candidate genes that predispose women to inhibition of ovarian steroid secretion. Fertil Steril 1986;45:327–33.
5. Nestler JE, Barlascini CO, Matt DW, Steingold KA, Plymate SR, Clore JN, et al. Suppression of serum insulin by diazoxide reduces serumtestosterone levels in obese women with polycystic ovary syndrome.
New therapies may be designed based on knowledge of J Clin Endocrinol Metab 1989;68:1027–32.
gene function, and disease-associated genetic markers may 6. Reaven GM. Role of insulin resistance in human disease. Diabetes be used to identify women at high risk of developing the 7. von Eckardstein S, von Eckardstein A, Bender HG, Schulte H, Ass- disease. Finns, who are derived from a small group of mann G. Elevated low-density lipoprotein-cholesterol in women withpolycystic ovary syndrome. Gynaecol Endocrinol 1996;10:311– 8.
founders, are more genetically homogeneous than many 8. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K. Coronary other populations and are thus ideal for large-scale linkage heart disease risk factors in women with polycystic ovary syndrome.
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disequilibrium–mapping studies (16). Accordingly, familial 9. Ilveskoski E, Perola M, Lehtima¨ki T, Laippala P, Savolainen V, Paja- genetic predisposition can be investigated in association rinen J, et al. Age-dependent association of apolipoprotein E genotypewith coronary and aortic atherosclerosis in middle-aged men: an au- studies. Multiallele polymorphisms have been identified in topsy study. Circulation 1999;100:608 –13.
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in PCOS. In the current study, we used a multiallele poly- 11. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in morphism approach to evaluate whether this gene plays any women with anovulation and idiopathic hirsutism. BMJ 1986;293:355–9.
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women with PCOS than among healthy fertile women or the 14. Tsukamoto K, Watanabe T, Matsushima T, Kinoshita M, Kato H, general population. Accordingly, the results of the study Hashimoto Y, et al. Determination by PCR-RFLP of apoE genotype ina Japanese population. J Lab Clin Med 1993;121:598 – 602.
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disease heritage. Hum Mol Genet 1999;8:1913–23.
17. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, An association between apoE isoforms and plasma lipid Batty S, et al. Linkage and association of insulin gene VNTR regulatorypolymorphism with polycystic ovary syndrome. Lancet 1997;349:986 – levels has been reported in several populations, and the influence of PCOS on lipid metabolism is similar to the 18. Paquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic women before and after weight cholesterol-raising effect of the ⑀4 allele (8). However, the loss. J Clin Endocrinol Metab 1989;68:173–9.
Heinonen et al.


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