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

Yıl 2017, Sayı: 3, 174 - 192, 30.12.2017

Öz

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.

Kaynakça

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Hoppé E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis. Joint Bone Spine. 2010;77(4):306-12.
  • 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.
  • 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.
  • Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol Cell Endocrinol 2010;316(1):60-5.
  • 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.
  • 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.
  • Usdin K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 2008;18(7):1011-9.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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

Yıl 2017, Sayı: 3, 174 - 192, 30.12.2017

Öz

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.

Kaynakça

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Hoppé E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis. Joint Bone Spine. 2010;77(4):306-12.
  • 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.
  • 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.
  • Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol Cell Endocrinol 2010;316(1):60-5.
  • 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.
  • 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.
  • Usdin K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 2008;18(7):1011-9.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Toplam 19 adet kaynakça vardır.

Ayrıntılar

Konular Klinik Tıp Bilimleri
Bölüm Makaleler
Yazarlar

Özlem Kurnaz Gömleksiz

Başak Akadam Teker Bu kişi benim

Zehra Buğra

Beyhan Ömer

Hülya Yılmaz Aydoğan

Yayımlanma Tarihi 30 Aralık 2017
Kabul Tarihi 24 Kasım 2017
Yayımlandığı Sayı Yıl 2017 Sayı: 3

Kaynak Göster

JAMA Kurnaz Gömleksiz Ö, Akadam Teker B, Buğra Z, Ömer B, Yılmaz Aydoğan H. The Effects of the SHBG Gene (TAAAA)n Pentanucleotıde Repeats Numbers on Serum SHBG and Lipid Levels in Men with Coronary Heart Disease. IGUSABDER. 2017;:174–192.

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