Skip to main content
SpringerLink
Log in

Identification of genetic variants for blood insulin level in sex-stratified Korean population and evaluation of the causal relationship between blood insulin level and polycystic ovary syndrome

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Background

Blood insulin level is an important risk factor for numerous disorders. Individual blood insulin level is known to be substantially influenced by genetic factors. Several genetic association studies identified a number of genetic variants for blood insulin level, but none of them was from a sex-stratified population.

Objective

This study aimed to identify male- and female-specific genetic variants related to blood insulin level and to evaluate the causal relationship between blood insulin level and polycystic ovary syndrome (PCOS) that is likely caused by high insulin in Korean women.

Methods

A genome-wide association study was conducted to identify genetic variants influencing blood insulin level in males (N = 4183) and females (N = 4659) in the Korean population. Two-sample Mendelian randomization (MR) analysis was used to investigate the causal effects of the insulin variants identified from GWAS on PCOS in Korean women. Genetic association data for PCOS were obtained from a PCOS study cohort (946 cases, 976 controls) in Ewha Womans University Hospital.

Results

GWAS linear regression analysis identified 13 female-specific SNPs and 13 male-specific SNPs showing suggestive associations (P < 10−5) with blood insulin level. The results from two-sample MR analysis using the GWAS variants for PCOS indicated that genetically determined insulin level was not associated with the risk of PCOS in Korean women.

Conclusion

This study identified sex-specific genetic variants showing associations with insulin for the first time in East Asian populations. In addition, MR analysis using variants discovered from Korean women revealed that genetically determined high level of insulin is not the cause of PCOS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ban M, McCauley JL, Zuvich R, Baker A, Bergamaschi L, Cox M, Kemppinen A, D’Alfonso S, Guerini FR, Lechner-Scott J et al (2010) A non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis. Genes Immun 11:660–664

    Article  CAS  Google Scholar 

  • Chen G, Bentley A, Adeyemo A, Shriner D, Zhou J, Doumatey A, Huang H, Ramos E, Erdos M, Gerry N et al (2012) Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans. Hum Mol Genet 21:4530–4536

    Article  CAS  Google Scholar 

  • Chen LY, Majerska J, Lingner J (2013) Molecular basis of telomere syndrome caused by CTC1 mutations. Genes Dev 27:2099–2108

    Article  CAS  Google Scholar 

  • Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M et al (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41:527–534

    Article  CAS  Google Scholar 

  • Consortium G, Laboratory DA, Coordinating Center-Analysis Working G, Statistical Methods groups-Analysis Working G, Enhancing Gg, Fund NIHC, Nih/Nci, Nih/Nhgri, Nih/Nimh, Nih/Nida et al (2017) Genetic effects on gene expression across human tissues. Nature 550:204–213

  • Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, Vrieze SI, Chew EY, Levy S, McGue M et al (2016) Next-generation genotype imputation service and methods. Nat Genet 48:1284–1287

    Article  CAS  Google Scholar 

  • Davey Smith G, Hemani G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23:R89-98

    Article  CAS  Google Scholar 

  • Davies NM, Holmes MV, Davey Smith G (2018) Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362:k601

    Article  Google Scholar 

  • Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030

    Article  CAS  Google Scholar 

  • El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G (2016) Poly cystic ovarian syndrome: an updated overview. Front Physiol 7:124

    Article  Google Scholar 

  • Engmann L, Jin S, Sun F, Legro RS, Polotsky AJ, Hansen KR, Coutifaris C, Diamond MP, Eisenberg E, Zhang H et al (2017) Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype. Am J Obstet Gynecol 216:493 e491-493 e413

    Article  Google Scholar 

  • Freeman MS, Mansfield MW, Barrett JH, Grant PJ (2002) Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 19:994–999

    Article  CAS  Google Scholar 

  • Gallagher MD, Chen-Plotkin AS (2018) The post-GWAS era: from association to function. Am J Hum Genet 102:717–730

    Article  CAS  Google Scholar 

  • Geer EB, Shen W (2009) Gender differences in insulin resistance, body composition, and energy balance. Gend Med 6(Suppl 1):60–75

    Article  Google Scholar 

  • Ghafouri-Fard S, Ghafouri-Fard S, Modarressi MH (2012) Expression of splice variants of cancer-testis genes ODF3 and ODF4 in the testis of a prostate cancer patient. Genet Mol Res 11:3642–3648

    Article  CAS  Google Scholar 

  • Goodarzi MO, Langefeld CD, Xiang AH, Chen YD, Guo X, Hanley AJ, Raffel LJ, Kandeel F, Nadler JL, Buchanan TA et al (2014) Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans. Obesity (silver Spring) 22:1157–1164

    Article  CAS  Google Scholar 

  • Guettier JM, Gorden P (2010) Insulin secretion and insulin-producing tumors. Expert Rev Endocrinol Metab 5:217–227

    Article  CAS  Google Scholar 

  • Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR (2012) Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 44:955–959

    Article  CAS  Google Scholar 

  • Hsing AW, Gao YT, Chua S Jr, Deng J, Stanczyk FZ (2003) Insulin resistance and prostate cancer risk. J Natl Cancer Inst 95:67–71

    Article  CAS  Google Scholar 

  • Huang JY, Bruno AM, Patel CA, Huynh AM, Philibert KD, Glucksman MJ, Marr RA (2008) Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40. Neuroscience 155:258–262

    Article  CAS  Google Scholar 

  • Iwase H, Kobayashi M, Nakajima M, Takatori T (2001) The ratio of insulin to C-peptide can be used to make a forensic diagnosis of exogenous insulin overdosage. Forensic Sci Int 115:123–127

    Article  CAS  Google Scholar 

  • Jung SY, Mancuso N, Yu H, Papp J, Sobel E, Zhang ZF (2019) Genome-wide meta-analysis of gene-environmental interaction for insulin resistance phenotypes and breast cancer risk in postmenopausal women. Cancer Prev Res (phila) 12:31–42

    Article  CAS  Google Scholar 

  • Lee H, Oh JY, Sung YA, Chung H, Kim HL, Kim GS, Cho YS, Kim JT (2015) Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum Reprod 30:723–731

    Article  CAS  Google Scholar 

  • Llorens C, Bernet GP, Ramasamy S, Feschotte C, Moya A (2012) On the transposon origins of mammalian SCAND3 and KRBA2, two zinc-finger genes carrying an integrase/transposase domain. Mob Genet Elem 2:205–210

    Article  Google Scholar 

  • Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913

    Article  CAS  Google Scholar 

  • Marshall JC, Dunaif A (2012) Should all women with PCOS be treated for insulin resistance? Fertil Steril 97:18–22

    Article  Google Scholar 

  • McArdle PF, Whitcomb BW, Tanner K, Mitchell BD, Shuldiner AR, Parsa A (2012) Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference. BMC Cardiovasc Disord 12:16

    Article  CAS  Google Scholar 

  • Palmer ND, Goodarzi MO, Langefeld CD, Wang N, Guo X, Taylor KD, Fingerlin TE, Norris JM, Buchanan TA, Xiang AH et al (2015) Genetic variants associated with quantitative glucose homeostasis traits translate to type 2 diabetes in Mexican Americans: the GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium. Diabetes 64:1853–1866

    Article  CAS  Google Scholar 

  • Pang SJ, Man QQ, Song S, Song PK, Liu Z, Li YQ, Jia SS, Wang JZ, Zhao WH, Zhang J (2018) Relationships of insulin action to age, gender, body mass index, and waist circumference present diversely in different glycemic statuses among Chinese population. J Diabetes Res 2018:1682959

    Article  Google Scholar 

  • Pierce BL, Burgess S (2013) Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol 178:1177–1184

    Article  Google Scholar 

  • Roberts CK, Hevener AL, Barnard RJ (2013) Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol 3:1–58

    PubMed  PubMed Central  Google Scholar 

  • Rojas J, Chavez M, Olivar L, Rojas M, Morillo J, Mejias J, Calvo M, Bermudez V (2014) Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med 2014:719050

    PubMed  PubMed Central  Google Scholar 

  • Saadah OI, Shaik NA, Banaganapalli B, Salama MA, Al-Harthi SE, Wang J, Shawoosh HA, Alghamdi SA, Bin-Taleb YY, Alhussaini BH et al (2015) Replication of GWAS coding SNPs implicates MMEL1 as a potential susceptibility locus among Saudi Arabian celiac disease patients. Dis Mark 2015:351673

    Google Scholar 

  • Saklayen MG (2018) The global epidemic of the metabolic syndrome. Curr Hypertens Rep 20:12

    Article  Google Scholar 

  • Shaaban Z, Khoradmehr A, Jafarzadeh Shirazi MR, Tamadon A (2019) Pathophysiological mechanisms of gonadotropins- and steroid hormones-related genes in etiology of polycystic ovary syndrome. Iran J Basic Med Sci 22:3–16

    PubMed  PubMed Central  Google Scholar 

  • Sonksen P, Sonksen J (2000) Insulin: understanding its action in health and disease. Br J Anaesth 85:69–79

    Article  CAS  Google Scholar 

  • Vigneri R, Sciacca L, Vigneri P (2020) Rethinking the relationship between insulin and cancer. Trends Endocrinol Metab 31:551–560

    Article  CAS  Google Scholar 

  • Yavorska OO, Burgess S (2017) MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol 46:1734–1739

    Article  Google Scholar 

  • Zheng J, Frysz M, Kemp JP, Evans DM, Davey Smith G, Tobias JH (2019) Use of Mendelian randomization to examine causal inference in osteoporosis. Front Endocrinol (lausanne) 10:807

    Article  Google Scholar 

Download references

Acknowledgements

All authors are grateful for bioresources from the National Biobank of Korea and the Centers for Disease Control and Prevention, Republic of Korea (KBN-2017-025).

Funding

This study was supported by a National Research Foundation of Korea (NRF) Grant (NRF-2020R1I1A2075302).

Author information

Authors and Affiliations

  1. Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea

    Woo Young Lim & Yoon Shin Cho

  2. Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea

    Hyejin Lee

Authors
  1. Woo Young Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyejin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoon Shin Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a significant contribution to the work reported. WYL contributed to manuscript preparation, construction of tables and figures, and statistical analysis. HL contributed to study design, data collection, and revision of manuscript. YSC contributed to study design, data collection and synthesis, manuscript preparation and revision, and submission of the manuscript.

Corresponding author

Correspondence to Yoon Shin Cho.

Ethics declarations

Conflict of interest

Woo Young Lim, Hyejin Lee, and Yoon Shin Cho declare that they have no conflicts of interest.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (HIRB-2020-033) of Hallym University. Informed consent was obtained from all subjects of the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

13258_2021_1134_MOESM1_ESM.pdf

Supplementary file1 Supplementary Figure 1. Regional association plots SNPs showing the evidence of association for blood insulin level in females (A to M) and males (N to Z) (PDF 1548 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lim, W.Y., Lee, H. & Cho, Y.S. Identification of genetic variants for blood insulin level in sex-stratified Korean population and evaluation of the causal relationship between blood insulin level and polycystic ovary syndrome. Genes Genom 43, 1105–1117 (2021). https://doi.org/10.1007/s13258-021-01134-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-021-01134-8

Keywords

Search

Navigation