The Effects of the SHBG Gene (TAAAA)n Pentanucleotıde Repeats Numbers on Serum SHBG and Lipid Levels in Men with Coronary Heart Disease

Abstract

Aim: One of the important regulators of the High-Density Lipoprotein Cholesterol (HDL-C) is sex hormones. Sex hormone binding globulin (SHBG) is a determining factor for the bioactive free sex hormones. Serum SHBG concentration is positively associated with HDL-C levels and under the genetic control. A (TAAAA)n pentanucleotide repeats polymorphism (rs35785886) was identified in Alu sequence in 5’ promotor of human SHBG gene. A correlation has been reported between repeat numbers and blood SHBG concentrations. In the present study, our aim was to investigate the (TAAAA)n pentanucleotide repeat polymorphism and its association with SHBG protein and HDL-C levels in Turkish men with Coronary Heart Disease (CHD).

Method: SHBG (TAAAA)n pentanucleotide repeat polymorphism was studied by polyacrylamide gel electrophoresis after polymerase chain reaction (PCR) in 75 men with CHD and 50 healthy men in Turkish population. Serum SHBG levels were measured by electro-chemiluminescence method.

Findings: The frequency of (TAAAA) six repeats allele was higher in controls (p=0.002, GR:0.293 (95% CI=0.133-0.649)). In control group without six repeats allele, serum triglyceride levels were higher than in controls with six repeats allele (p=0.048). While serum SHBG levels were higher in short repeat (≤ 8 repeats) allele carriers (p=0.006) in control group, serum SHBG levels were higher in patients with six repeat allele (p=0.027). HDL-C/LDL-C ratio (p=0.027) and mean systolic blood pressure (p=0.008) were observed higher in patients with 8 repeat allele compared to patients without 8 repeat allele. There was a significant decrease in serum SHBG by the smoking effect in long-repeat allele carriers in CHD group (p=0.024).

Conclusion: SHBG (TAAAA) 6 repeats-allele in CHD group and short repeats (≤ 8 repeats)  in control group were in a remarkable association with high SHBG levels. Our findings suggest that there is a positive association between SHBG levels and HDL-C levels in the CHD group and this association may be affected by the SHBG (TAAAA)n polymorphism and the effects of an interaction between repeat numbers and smoking.

Keywords

• Coronary heart disease,sex hormone binding globulin,TAAAA pentanucleotide repeat polymorphism

Koroner Kalp Hastası Erkeklerde SHBG Geni (TAAAA)n Pentanükleotid Tekrar Sayılarının Serum SHBG ve Lipid Düzeyleri Üzerine Etkisi

Abstract

Amaç: Yüksek yoğunluklu lipoprotein-kolesterol (HDL-K) seviyelerinin önemli düzenleyicilerinden biri cinsiyet hormonlarıdır. Cinsiyet hormon bağlayıcı globülin (SHBG), biyoaktif serbest cinsiyet hormonlarını belirleyen bir faktördür. Serum SHBG konsantrasyonu HDL-K düzeyleri ile pozitif ilişkilidir ve kısmen genetik kontrol altındadır. İnsan SHBG geninin 5’ promotöründe bir Alu dizisi içinde (TAAAA)n pentanükleotid tekrar polimorfizmi (rs35785886) tanımlanmıştır. Tekrar sayısı ve serum SHBG konsantrasyonları arasında korelasyon olduğu bildirilmiştir. Bu çalışmada koroner kalp hastalığı (KKH) olan Türk erkeklerinde SHBG geni pentanükleotid (TAAAA)n tekrar polimorfizminin serum SHBG proteini ve HDL-K düzeyleriyle ilişkisinin incelenmesi amaçlanmıştır.

Yöntem: SHBG geni (TAAAA)n pentanükleotid tekrar polimorfizmi 75 KKH erkek ve 50 sağlıklı erkekte polimeraz zincir reaksiyonu (PZR) sonrası Poliakrilamid jel elektroforezi yöntemiyle belirlenmiştir. Serum SHBG düzeyleri Elektrokemilüminesan metoduyla ölçülmüştür.

Bulgular: Kontrol grubunda 6 TAAAA tekrar allel frekansı KKH grubuna göre yüksektir (p=0,002 GR:0,293 (%95 GA= 0,133-0,649)). Kontrol grubunda 6 tekrar alleli taşımayanlarda serum trigliserid düzeyi 6 tekrar taşıyanlara göre yüksek gözlenmiştir (p=0,048). Kısa tekrar allellerini (≤ 8 tekrar) taşıyan kontrollerde serum SHBG düzeyi yüksek iken (p=0,006), hasta grubunda 6 tekrar taşıyan bireylerde serum SHBG düzeyi yüksektir (p=0,027). 8 tekrar alleli olan hastalarda 8 tekrar alleli bulunmayanlara göre HDL-K/LDL-K oranı (p=0,027) ve sistolik kan basıncı (p=0,008) düzeyleri düşük gözlenmiştir. KKH grubunda uzun tekrar alleli taşıyanlarda sigara etkisiyle birlikte serum SHBG seviyelerinde anlamlı bir düşüş belirlenmiştir (p=0,024).

Sonuç: KKH grubunda SHBG (TAAAA) 6 tekrar alleli ve kontrollerde ise kısa tekrarlar (≤ 8 tekrar) yüksek SHBG düzeyleriyle kayda değer bir ilişki içindedir. KKH grubumuzda SHBG düzeyleriyle HDL-K düzeyleri arasında pozitif ilişki bulunmuştur ve bu ilişkinin SHBG (TAAAA)n polimorfizminden ve tekrar sayısının sigara kullanımı ile birlikte olan etkisinden etkilenebileceği düşünülmüştür.

Keywords

• Koroner kalp hastalığı,cinsiyet hormonu bağlayıcı globülin,TAAAA pentanükleotid tekrar polimorfizmi

References

1. Hergenc G, Schulte H, Assmann G, von Eckardstein A. Associations of obesity markers, insulin, and sex hormones with HDL-cholesterol levels in Turkish and German individuals. Atherosclerosis. 1999;145: 147–156.
2. Mahley RW, Arslan P, Pekcan G, Pépin GM, Ağaçdiken A, Karaağoğlu N, Rakicioğlu N, Nursal B, Dayanikli P, Palaoğlu KE, Bersot TP. Plasma lipids in Turkish children: impact of puberty, socioeconomic status, and nutrition on plasma cholesterol and HDL. J Lipid Res. 2001; 42(12):1996-2006.
3. Yasui T, Uemura H, Irahara M, Arai M, Kojimahara N, Okabe R, Ishii Y, Tashiro S, Sato H. Associations of endogenous sex hormones and sex hormone-binding globulin with lipid profiles in aged Japanese men and women. Clin Chim Acta. 2008;398(1-2):43-7.
4. Vanbillemont G, Bogaert V, De Bacquer D, Lapauw B, Goemaere S, Toye K, Van Steen K, Taes Y, Kaufman JM. Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men. Clin Endocrinol (Oxf). 2009;70(2):303-10.
5. Avvakumov GV, Cherkasov A, Muller YA, Hammond GL. Structural analyses of sex hormone-binding globulin reveal novel ligands and function. Mol Cell Endocrinol. 2010;316(1):13-23.
6. Cousin P, Calemard-Michel L, Lejeune H, Raverot G, Yessaad N, Emptoz-Bonneton A, Morel Y, Pugeat M. Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women. J Clin Endocrinol Metab. 2004;89(2):917-24.
7. Pugeat M, Nader N, Hogeveen K, Raverot G, Déchaud H, Grenot C. Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Mol Cell Endocrinol. 2010;316(1):53-9.
8. Hoppé E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis. Joint Bone Spine. 2010;77(4):306-12.

9. Misao R, Nakanishi Y, Fujimoto J, Tamaya T. Expression of sex hormone-binding globulin exon VII splicing variant mRNA in human uterine myometrium and leiomyoma. J Steroid Biochem Mol Biol. 1997;63(4-6):269-74.
10. Liska F, Gösele C, Kren V, Hübner N, Krenová D. Molecular analysis of the sex hormone-binding globulin gene in the rat hypodactylous mutation (Hd). Folia Biol (Praha) 2004;50(2):63-8.
11. Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol Cell Endocrinol 2010;316(1):60-5.
12. Hogeveen KN, Talikka M, Hammond GL. Human Sex Hormone-binding Globulin Promoter Activity Is Influenced by a (TAAAA)n Repeat Element within an Alu Sequence. J Bıol Chem. 2001;276 (39): 36383–36390.
13. Thompson DJ, Healey CS, Baynes C, Kalmyrzaev B, Ahmed S, Dowsett M, Folkerd E, Luben RN, Cox D, Ballinger D, Pharoah PDP, Ponder BAJ, Dunning AM, Easton DF, and the SEARCH team. Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2008;17(12):3490-8.
14. Usdin K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 2008;18(7):1011-9.
15. Alevizaki M, Saltiki K, Xita N, Cimponeriu A, Stamatelopoulos K, Mantzou E, Doukas C, Georgiou I. The importance of the (TAAAA)n alleles at the SHBG gene promoter for the severity of coronary artery disease in postmenopausal women. Menopause. 2008;15(3):461-8.
16. Eriksson AL, Lorentzon M, Mellström D, Vandenput L, Swanson C, Andersson N, et al. SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density. J Clin Endocrinol Metab. 2006;91(12):5029-37.
17. Turk A, Kopp P, Colangelo LA, Urbanek M, Wood K, Liu K, Skinner HG, Gapstur SM. Associations of serum sex hormone binding globulin (SHBG) levels with SHBG gene polymorphisms in the CARDIA Male Hormone Study. Am J Epidemiol 2008;167(4):412-8.
18. Saltiki K, Stamatelopoulos K, Voidonikola P, Lazaros L, Mantzou E, Georgiou I, Anastasiou E, Papamichael C, Alevizaki M. Association of the SHBG gene promoter polymorphism with early markers of atherosclerosis in apparently healthy women. Atherosclerosis. 2011;219(1):205-10.
19. Jaquish CE, Mahaney MC, Blangero J, Haffner SM, Stern MP, MacCluer JW. Genetic correlations between lipoprotein phenotypes and indicators of sex hormone levels in Mexican Americans. Atherosclerosis. 1996 Apr 26;122(1):117-25.