J Korean Endocr Soc.  2008 Oct;23(5):319-326. 10.3803/jkes.2008.23.5.319.

Calpain-10 Polymorphism in Korean Women with Polycystic Ovary Syndrome

• Lee HJ
• Pyun GW
• Byun EK
• Oh JY
• Oh JY
• Hong Y
• Sung YA
• Chung HW

• KMID: 1479224
• DOI: http://doi.org/10.3803/jkes.2008.23.5.319

Abstract

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenism and insulin resistance, and PCOS is known to be associated with an increased risk of type 2 diabetes mellitus (DM). PCOS has also been proposed to share a common genetic background with type 2 DM. The calpain 10 (CAPN10) gene is known to be associated with type 2 DM in several different population. We examined the association of CAPN10 gene polymorphisms and their influence on the metabolic abnormalities in Korean women who suffer with PCOS.
METHODS
One hundred sixty four women with PCOS and 325 control women were studied. The CAPN10 gene polymorphisms were genotyped by amplifying the genomic DNA. Anthropometric measures, a 75g oral glucose tolerance test and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique were performed.
RESULTS
The frequencies of CAPN10 UCSNP-43, UCSNP-19, UCSNP-63 and the haplotype combinations were not different between the women with PCOS and the control subjects. In the women with PCOS and who had the UCSNP-43 GA genotype, the post-load 90 minute plasma glucose level was significantly greater and the HDL cholesterol and insulin mediated glucose uptake were significantly lower compared to the women with PCOS and who had the GG genotype.
CONCLUSION
The CAPN10 UCSNP-43 genotype might be responsible for insulin resistance, yet further study is required to confirm the role of this genetic polymorphism in the development of PCOS and the presentation of its disease features.

Keyword

calpain 10; insulin resistance; polycystic ovary syndrome

MeSH Terms

Anovulation
Calpain
Cholesterol, HDL
Diabetes Mellitus, Type 2
DNA
Female
Genotype
Glucose
Glucose Tolerance Test
Haplotypes
Humans
Hyperandrogenism
Insulin
Insulin Resistance
Plasma
Polycystic Ovary Syndrome
Polymorphism, Genetic
Calpain
Cholesterol, HDL
DNA
Glucose
Insulin

Reference

1. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998. 95:14956–14960.

2. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997. 6:397–402.

3. Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994. 3:1873–1876.

4. Franks S. Polycystic ovary syndrome. N Engl J Med. 1995. 333:853–861.

5. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992. 41:1257–1266.

6. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995. 96:801–810.

7. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF 3rd, Spielman RS, Dunaif A. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999. 96:8573–8578.

8. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schröder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Lindner T, Mereu LE, Wang YQ, Xiang K, Yamagata K, Yang Y, Bell GI. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996. 13:161–166.

9. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet. 2000. 26:163–175.

10. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen GQ, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C. A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest. 2000. 106:R69–R73.

11. Sreenan SK, Zhou YP, Otani K, Hansen PA, Currie KP, Pan CY, Lee JP, Ostrega DM, Pugh W, Horikawa Y, Cox NJ, Hanis CL, Burant CF, Fox AP, Bell GI, Polonsky KS. Calpains play a role in insulin secretion and action. Diabetes. 2001. 50:2013–2020.

12. Escobar-Morreale HF, Peral B, Villuendas G, Calvo RM, Sancho J, San Millán JL. Common single nucleotide polymorphisms in intron 3 of the calpain-10 gene influence hirsutism. Fertil Steril. 2002. 77:581–587.

13. Ehrmann DA, Schwarz PE, Hara M, Tang X, Horikawa Y, Imperial J, Bell GI, Cox NJ. Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab. 2002. 87:1669–1673.

14. Gonzalez A, Abril E, Roca A, Aragón MJ, Figueroa MJ, Velarde P, Royo JL, Real LM, Ruiz A. Comment: CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002. 87:3971–3976.

15. Escobar-Morreale HF, Luque-Ramírez M, San Millán JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev. 2005. 26:251–282.

16. 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 Steril. 2004. 81:19–25.

17. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961. 21:1440–1447.

18. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999. 84:3666–3672.

19. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979. 237:E214–E223.

20. Crosignani PG, Nicolosi AE. Polycystic ovarian disease: heritability and heterogeneity. Hum Reprod Update. 2001. 7:3–7.

21. Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet. 2000. 26:151–157.

22. Patel YM, Lane MD. Role of calpain in adipocyte differentiation. Proc Natl Acad Sci U S A. 1999. 96:1279–1284.

23. Smith LK, Rice KM, Garner CW. The insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes is mediated by a calcium-dependent thiol protease. Mol Cell Endocrinol. 1996. 122:81–92.

24. Tsai HJ, Sun G, Weeks DE, Kaushal R, Wolujewicz M, McGarvey ST, Tufa J, Viali S, Deka R. Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. Am J Hum Genet. 2001. 69:1236–1244.

25. Evans JC, Frayling TM, Cassell PG, Saker PJ, Hitman GA, Walker M, Levy JC, O'Rahilly S, Rao PV, Bennett AJ, Jones EC, Menzel S, Prestwich P, Simecek N, Wishart M, Dhillon R, Fletcher C, Millward A, Demaine A, Wilkin T, Horikawa Y, Cox NJ, Bell GI, Ellard S, McCarthy MI, Hattersley AT. Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. Am J Hum Genet. 2001. 69:544–552.

26. Elbein SC, Chu W, Ren Q, Hemphill C, Schay J, Cox NJ, Hanis CL, Hasstedt SJ. Role of calpain-10 gene variants in familial type 2 diabetes in Caucasians. J Clin Endocrinol Metab. 2002. 87:650–654.

27. Fingerlin TE, Erdos MR, Watanabe RM, Wiles KR, Stringham HM, Mohlke KL, Silander K, Valle TT, Buchanan TA, Tuomilehto J, Bergman RN, Boehnke M, Collins FS. Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort. Diabetes. 2002. 51:1644–1648.

28. Lynn S, Evans JC, White C, Frayling TM, Hattersley AT, Turnbull DM, Horikawa Y, Cox NJ, Bell GI, Walker M. Variation in the calpain-10 gene affects blood glucose levels in the British population. Diabetes. 2002. 51:247–250.

29. Kang ES, Nam M, Kim HJ, Kim HJ, Myoung SM, Rhee Y, Ahn CW, Cha BS, Lee HC. Haplotype combination of Calpain-10 gene polymorphism is associated with metabolic syndrome in type 2 diabetes. Diabetes Res Clin Pract. 2006. 73:268–275.

30. Colilla S, Cox NJ, Ehrmann DA. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab. 2001. 86:2027–2031.

31. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med. 1995. 98:33S–39S.

32. McKeigue P, Wild S. Association of insulin gene VNTR polymorphism with polycystic ovary syndrome. Lancet. 1997. 349:1771–1772.

33. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet. 1997. 349:986–990.

34. Haddad L, Gharani N, Evans J, Cela E, Franks S, MaCarthy M. Linkage and association of variants of the diabetes susceptibility-gene NIDDM1 CAPN10 with polycystic ovarian syndrome in European parent-offspring trios. 82nd Annual Meeting of The Endocrine Society. 2000. Toronto, Ontario, Canada. 75.

35. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol. 1992. 167:1807–1812.