Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The aim of this study was to investigate the association of oxidized low-density lipoprotein receptor 1 (OLR1) gene variations with the susceptibility of PCOS and to examine the relationship between the frequencies of OLR1 gene variations and atherosclerotic risk factors. Genomic DNA was extracted from blood samples collected from 49 patients with PCOS and 43 healthy controls. The variants in the OLR1 gene were identified using next-generation sequencing (NGS). Heterozygous rs11053646 (K167N), rs11611438, rs11611453, and rs35688880 genotype frequencies were significantly higher in the PCOS group than that of control group. Single nucleotide polymorphism (SNP) rs34163097 minor A allele increased the PCOS risk by ∼10-fold (p = 0.03). SNPs rs11053646, rs11611438, rs11611453, rs34163097, and rs35688880 were positively correlated with body mass index (BMI). The logistic regression model (area under the curve: 0.770, p = 0.000) further revealed a combination of 2-h plasma glucose (PG-2 h), dehydroepiandrosterone sulfate (DHEAS), and rs11053646 as predictors of PCOS phenotype. This is the first study reporting the NGS data of OLR1 gene variants which might be associated with the pathogenesis of PCOS and several atherosclerotic risk factors, particularly higher BMI and DHEAS. To fully understand the genetic basis of PCOS and the contribution of OLR1 gene variants to PCOS pathogenesis, additional large-scale studies are warranted.
AzzizRWoodsKSReynaR, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab2004; 89: 2745–2749.
2.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril2004; 81: 19–25.
3.
LegroRS.Polycystic ovary syndrome and cardiovascular disease: a premature association?Endocr Rev2003; 24: 302–312.
4.
RosenfieldRLEhrmannDA.The Pathogenesis of Polycystic Ovary Syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev2016; 37: 467–520.
5.
ShiYZhaoHShiY, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet2012; 44: 1020–1025.
6.
ChenZJZhaoHHeL, et alGenome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet2011; 43: 55–59.
7.
HayesMGUrbanekMEhrmannDA, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun2015; 6: 7502.
8.
ZeyaBArjumanAChandraNC.Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1): a chameleon receptor for oxidized LDL. Biochemistry2016; 55: 4437–4444.
PredazziIMNorataGDVecchioneL, et al. Association between OLR1 K167N SNP and intima media thickness of the common carotid artery in the general population. PLoS One. 2012; 7: e31086.
14.
TatsuguchiMFurutaniMHinagataJ, et al. Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction. Biochem Biophys Res Commun2003; 303: 247–250.
15.
PalmieriVOCoppolaBGrattaglianoI, et al. Oxidized LDL receptor 1 gene polymorphism in patients with metabolic syndrome. Eur J Clin Invest2013; 43: 41–48.
16.
SciacquaAPrestaIPerticoneM, et al. 3’-UTR OLR1/LOX-1 gene polymorphism and endothelial dysfunction: molecular and vascular data in never-treated hypertensive patients. Intern Emerg Med2014; 9: 273–281.
17.
HouXWWangLFWangN, et al. The G501C polymorphism of oxidized LDL receptor gene [OLR-1] is associated with susceptibility and serum C-reactive protein concentration in Chinese essential hypertensives. Clin Chim Acta2008; 388: 200–203.
18.
MussoGCassaderMDe MichieliF, et al. Effect of lectin-like oxidized LDL receptor-1 polymorphism on liver disease, glucose homeostasis, and postprandial lipoprotein metabolism in nonalcoholic steatohepatitis. Am J Clin Nutr2011; 94: 1033–1042.
19.
FerrimanDGallweyJD.Clinical assessment of body hair growth in women. J Clin Endocrinol Metab1961; 21: 1440–1447.
20.
WilliamsTMortadaRPorterS.Diagnosis and treatment of polycystic ovary syndrome. Am Family Physician2016; 94: 106–113.
21.
GarveyWTMechanickJIBrettEM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract2016; 22(Suppl 3): 1–203.
22.
MuniyappaRLeeSChenH, et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab2008; 294: E15–E26.
23.
AlbertiKGEckelRHGrundySM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation2009; 120: 1640–1645.
24.
MachielaMJChanockSJ.LDassoc: an online tool for interactively exploring genome-wide association study results and prioritizing variants for functional investigation. Bioinformatics2018; 34: 887–889.
25.
MohammadiM.Oxidative stress and polycystic ovary syndrome: a brief review. Int J Prev Med2019; 10: 86.
26.
MangoRClementiFBorgianiP, et al. Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. J Med Genet2003; 40:933–936.
27.
GuYLiuZLiL, et al. OLR1, PON1 and MTHFR gene polymorphisms, conventional risk factors and the severity of coronary atherosclerosis in a Chinese Han population. Cell Physiol Biochem2013; 31: 143–152.
28.
KurnazOAydoganHYIsbirCS, et al. Is LOX-1 K167N polymorphism protective for coronary artery disease?In Vivo2009; 23: 969–973.
29.
KnowlesJWAssimesTLBoerwinkleE, et al. Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLR1) with CAD. BMC Med Genet2008; 9: 23.
30.
TrabettiEBiscuolaMCavallariU, et al. On the association of the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction or coronary artery disease. Eur J Hum Genet2006; 14: 127–130.
31.
OhmoriRMomiyamaYNaganoM, et al. An oxidized low-density lipoprotein receptor gene variant is inversely associated with the severity of coronary artery disease. Clin Cardiol2004; 27: 641–644.
32.
ChenQReisSEKammererC, et al. Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. Circulation2003; 107: 3146–3151.
33.
DadachanjiRPatilAMukherjeeS.Investigating oxidized LDL receptor 1 (OLR1) polymorphisms as putative genetic markers for polycystic ovary syndrome. Meta Gene2021; 27: 100829.
34.
Behboudi-GandevaniSRamezaniTehrani FHosseinpanahF, et al. Cardiometabolic risks in polycystic ovary syndrome: long-term population-based follow-up study. Fertil Steril2018; 110: 1377–1386.
35.
VrbikovaJCifkovaRJirkovskaA, et al. Cardiovascular risk factors in young Czech females with polycystic ovary syndrome. Hum Reprod2003; 18: 980–984.
36.
EltingMWKorsenTJBezemerPD, et al. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod2001; 16: 556–560.
37.
RandevaHSTanBKWeickertMO, et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev2012; 33: 812–841.
38.
ZhangJBaoYZhouX, et al. Polycystic ovary syndrome and mitochondrial dysfunction. Reprod Biol Endocrinol2019; 17: 67.
39.
YanMMehtaJLHuC.LOX-1 and obesity. Cardiovasc Drugs Ther2011; 25: 469–476.
40.
O’ReillyMWTaylorAECrabtreeNJ, et al. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab2014; 99: 1027–1036.
41.
PinolaPPiltonenTTPuurunenJ, et al. Androgen profile through life in women with polycystic ovary syndrome: a nordic multicenter collaboration study. J Clin Endocrinol Metab2015; 100: 3400–3407.
42.
KhorshidiAAzamiMTardehS, et al. The prevalence of metabolic syndrome in patients with polycystic ovary syndrome: a systematic review and meta-analysis. Diabetes Metab Syndr2019; 13: 2747–2753.
43.
JamatiaELaliPKonerBC, et al. OLR1 Gene polymorphism and oxidized LDL levels in metabolic syndrome in Indian population. Indian J Endocrinol Metab2018; 22: 530–534.
44.
LegroRSKunselmanARDodsonWC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab1999; 84: 165–169.
45.
DeUgarteCMBartolucciAAAzzizR.Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril2005; 83: 1454–1460.
46.
Cree-GreenMRahatHNewcomerBR, et al. Insulin resistance, hyperinsulinemia, and mitochondria dysfunction in Nonobese Girls With polycystic ovarian syndrome. J Endocr Soc2017; 1:931–944.
47.
ChangRJNakamuraRMJuddHL, et al. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab1983; 57: 356–359.
48.
RosenzweigJLBakrisGLBerglundLF, et al. Primary prevention of ASCVD and T2DM in patients at metabolic risk: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab2019; 104: 3939–3985.
49.
ChorevMCarmelL.The function of introns. Front Genet2012; 3: 55.
50.
BaralleDBaralleM.Splicing in action: assessing disease causing sequence changes. J Med Genet2005; 42: 737–748.
51.
AnnaAMonikaG.Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet2018; 59: 253–268.
52.
ShawDJSeeseRPonnambalamS, et al. The role of lectin-like oxidised low-density lipoprotein receptor-1 in vascular pathology. Diab Vasc Dis Res2014; 11: 410–418.
53.
MangoRBioccaSdel VecchioF, et al. In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ Res2005; 97: 152–158.
54.
BioccaSFilesiIMangoR, et al. The splice variant LOXIN inhibits LOX-1 receptor function through hetero-oligomerization. J Mol Cell Cardiol2008; 44: 561–570.
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