Supplementary Table 1 Studies of candidate genes for PCOS
advertisement
Supplementary Table 1 Studies of candidate genes for polycystic ovary syndrome; all have been evaluated at the DNA level. Gene or chromosome Chromo some location Polymorphism or allele Study design Ethnicity Sample size Findings ACVRL1 12q13.13 D12S347 TDT Linkage 150 Families 39 ASPs Negative23 Negative23 ACVR2A 2q22.3 D2S2335 TDT Linkage 150 Families 39 ASPs Negative23 Not significant23 ACVR2B 3p22.2 D3S1298 TDT Linkage 150 Families 39 ASPs Negative23 Negative23 ADIPOQ 3q27.3 None CC >90% US white >90% US white >90% US white >90% US white >90% US white >90% US white Finnish white 143 Cases/245 controls Negative79 ADIPOQ 3q27.3 G45T T276G CC Spanish white 72 PCOS/42 controls Negative80 ADRB3 8p12 Y64R CC Chilean 106 Cases/82 controls Negative81 AGT 1q24.2 M235T CC Italian white 95 Cases/64 controls Positive82 APOE 19q13.32 CC Finnish white 58 PCOS/91 controls Negative83 AR Xq11.2 epsilon2 epsilon3 epsilon4 (CAG)n TDT Linkage 150 Families 39 ASPs Negative23 Not significant23 AR Xq11.2 (CAG)n CC >90% US white >90% US white US Hispanic 110 Infertility patients AR Xq11.2 (CAG)n CC Chinese, Asian Indian 91 PCOS/112 controls AR Xq11.2 (CAG)n CC 205 PCOS/831 controls AR Xq11.2 (CAG)n CC Australian white Finnish white No association with measures of hyperandrogenism71 Shorter repeats associated with lower androgen levels72 Longer repeats associated with PCOS74 Negative70 CAPN10 2q37.3 SNP-43 SNP-19 SNP-63 CC African American US white 57 African American PCOS 124 Caucasian PCOS CAPN10 2q37.3 SNP-44 SNP-43 SNP-19 SNP-63 TDT CC White 146 Trios 331 PCOS/525 controls CAPN10 2q37.3 CC Spanish white 148 PCOS/93 controls Positive SNP-44 only84,85 CYP1A 15q24.1 SNP-44 SNP-43 SNP-19 SNP-63 T6235C CC South Indian 180 PCOS/72 controls Positive86 CYP11A 15q23 D15S519 Linkage CC 15q23 D15S519 CC 20 Multiplex families 97 PCOS/51 PCO/59 controls 80 PCOS/90 controls Positive33 Positive33 CYP11A European and Asian European Greek white 106 Cases/112 controls Positive association elevated insulin levels in OGTT in African American women48 Negative49 Positive34 92 Hirsuite women/33 controls 150 Families 39 ASPs Negative36 1,599 Population cohort 440 PCOS/1,062 controls 255 Trios 69 PCOS/63 CAH/124 controls Not significant37 CYP11A 15q23 D15S519 CC Spanish white CYP11A 15q23 D15S519 D15S520 TDT Linkage CYP11A 15q23 D15S520 P4 repeat CC TDT >90% US white >90% US white Finnish white British white British white CYP17 10q24.3 –34 promoter CC British white CYP17 10q24.3 –34 promoter CC White Asian CYP17 10q24.3 –34 promoter CC Polish white 55 PCOS/56 controls Negative89 CYP17 10q24.3 –34 promoter CC Greek white 50 PCOS/50 controls Possible increased risk with C/C genotype90 CYP17 10q24.3 D10S192 CC US white 85 PCOS/87 controls Negative91 CYP17 10q24.3 D10S192 TDT Linkage 150 Families 39 ASPs Not significant23 Negative23 CYP17 10q24.3 –34 promoter CC >90% US white >90% US white US white 259 PCOS/161 controls Negative92 CYP19 15q21 CYP19 CC US white 85 PCOS/87 controls Negative91 CYP19 15q21 CYP19 TDT Linkage 150 Families 39 ASPs Not significant23 Negative23 CYP19 15q21 rs12907866 rs2414096 SNP-60 rs4646 Haplotype CC >90% US white >90% US white Spanish white 186 postpartum/71 Positive for rs241096 and haplotype93 Negative87 Negative88 controls UK (97% white) Negative23 Not significant23 Positive for rs24109693 224 Women 25 PCOS/50 controls Negative94 30 hyperandrogenic girls/14 controls 109 PCOS/95 controls Increased heterozygosity in symptomatic hyperandrogenism95 Negative96 US white 152 PCOS/96 controls Negative97 CC US Hispanic 180 Women Y113H H139R Haplotype CC Finnish white 112 PCOS/115 controls Positive association with irregular menses98 Positive haplotype only99 D5S474 D5S623 D5S822 TDT Linkage >90% US white >90% US white 150 Families 39 ASPs Negative23 Positive23 CYP19 15q21 None Mutation screen MexicanMestizo CYP21 6p21.1 V281L CC CYP21 6p21.1 CC US white DRD3 3q13.31 P30L Intron 2 I172N V281L Q318X R354W P453S MscI CC DRD3 3q13.31 MscI EPHX1 1q42.12 FST 5q11.2 Chinese 64 PCOS No mutations100 >90% US white >90% US white >90% US white US white 19 Multiplex families 324 Trios 75 ASPs Negative101 85 PCOS/87 controls Negative91 Japanese 15 POF/38 PCOS/3 controls 16 POF/124 PCOS 124 PCOS/236 controls Negative102 150 Families 39 ASPs Negative23 Negative23 522 Cohort Positive104 Singapore Chinese 135 PCOS/105 controls Possibly associated with PCOS105 >90% US white >90% US white Japanese 15 PCOS/5 controls 469 Families Negative106 No polymorphisms107 NA 15 POF/38 PCOS/3 controls 15 POF/38 PCOS/3 controls 80 PCOS US white 114 PCOS/92 controls Negative109 CC South Indian 180 PCOS/72 controls Negative86 None CC South Indian 180 PCOS/72 controls Negative86 1p36.22 R453Q CC Spanish white 116 PCOS/76 controls Positive110 HSD11B1 1q32.2 T1971G CC Racially mixed 3,551 Population cohort Negative111 HSD11B1 1q32.2 83557insA CC Spanish white 116 PCOS/76 controls Negative110 HSD17B 17q21.2 D17S934 TDT Linkage 150 Families 39 ASPs Negative23 Negative23 HSD17B2 16q24.1 HSD17B2 TDT Linkage 150 Families 39 ASPs Not significant23 Negative23 HSD17B3 9q22 D9S1809 TDT Linkage 150 Families 39 ASPs Negative23 Negative23 HSD17B3 9q22 Ser289Gly CC >90% US white >90% US white >90% US white >90% US white >90% US white >90% US white US racially mixed 46 PCOS/32 controls Negative112 HSD17B5 10p15.1 G→71A CC 121 PCOS/128 controls Positive113 HSD3B1 1p31.1 D1S514 TDT Linkage US racially mixed >90% US white >90% US 150 Families 39 ASPs Negative23 Negative23 FST 5q11.2 None FST 5q11.2 D5S474 D5S623 D5S822 Exon 6 SNP FST 5p14 FSHR 2p21 D5S474 D5S623 D5S822 None FSHR 2p21 2p21 FSHR 2p21 D2S1352 TDT Linkage FSHR 2p21 T307A N680S CC FSHB 11p14.1 Exon 3 T/C GATA6 18q11.2 hCV7490431 hCV1892216 rs1941084 Mutation screen CC Mutation screen TDT GDF9 5q23.3 None BMP15 (GDF9B) Xq11.2 None GNRH 8p21.2 None GRL 5q32 Asn363Ser Mutation screen Mutation screen Mutation screen CC GSTM1 1p13.3 None GST1 22q11.23 H6PD Mutation screen Mutation screen TDT Linkage CC Mutation screen Mutation screen CC Singapore Chinese Singapore Chinese >90% US white >90% US white Japanese Japanese Negative103 Negative103 No polymorphisms107 No mutations in exons108 white >90% US white >90% US white >90% US white >90% US white Spanish white 150 Families 39 ASPs Negative23 Negative23 150 Families 39 ASPs Negative23 Negative23 72 PCOS/42 controls Negative80 150 Families 39 ASPs Negative23 Negative23 CC >90% US white >90% US white Spanish white 72 PCOS/42 controls Negative80 Apa1 GA 3 UTR CC Spanish white 72 PCOS/42 controls Positive80 6q25.3 ACAA in/del 3 UTR CC Spanish white 72 PCOS/42 controls Negative80 IGFBP1 7p13 D7S519 TDT Linkage 150 Families 39 ASPs Not significant23 Negative23 IGFBP3 7p13 D7S519 TDT Linkage 150 Families 39 ASPs Not significant23 Negative23 G→174C CC >90% US white >90% US white >90% US white >90% US white Austrian white 62 PCOS/94 controls Negative114 >90% US white >90% US white >90% US white >90% US white >90% US white >90% US white >90% US white >90% US white >95% white 150 Families 39 ASPs Negative23 Negative23 150 Families 39 ASPs Negative23 Not significant23 150 Families 39 ASPs Not significant23 Not significant23 150 Families 39 ASPs Not significant23 Negative23 224 Population cohort Positive paternal transmission of class III allele41 Positive linkage and association with paternal transmission of class III allele40 Negative23 Negative23 HSD3B2 1p31.1 D1S514 TDT Linkage IGF1 12q23.2 IGF1 STRP TDT Linkage IGF1 12q23.2 IGF1 STRP CC IGF1R 15q26.3 IGF1R TDT Linkage IGF1R 15q26.3 IGF1R IGF2 11p15.5 IGF2R IL6 INHA 2q35 D2S163 TDT Linkage INHBA 7p14.1 INHBA STRP TDT Linkage INHBB 2q14.2 D2S293 TDT Linkage INHBC 12q13 D12S1691 TDT Linkage INS 11p15.5 INS VNTR TDT CC INS 11p15.5 INS VNTR CC TDT Linkage British white Racially mixed Racially mixed 59 PCOS/52 controls 17 Multiplex families 17 Multiplex families INS 11p15.5 INS VNTR TDT Linkage 150 Families 39 ASPs INS 11p15.5 INS VNTR CC >90% US white >90% US white Spanish white 96 hyperandrogenics/38 controls Negative42 INS 11p15.5 INS VNTR CC Czech white 38 PCOS/22 controls Negative115 INS 11p15.5 INS VNTR CC TDT Finnish white British white British white Negative43 INSR 19p13.2 INSR STRP TDT Linkage INSR 19p13.2 H1058H C/T CC >90% US white >90% US white US white 1,599 Population cohort 440 PCOS/1,062 controls 255 Trios 150 Families 39 ASPs 99 PCOS/136 controls Positive116 Chr19p3.13 19p13.2 D19S884 TDT Linkage 367 Families 107 ASPs Positive23,50 Positive50 Chr19p3.13 19p13.2 D19S884 CC >90% US white >90% US white US white 85 PCOS/87 controls Positive91 Chr19p3.13 19p13.9 D19S884 CC Spanish white Italian white 50 PCOS/37 controls 58 PCOS/29 controls Negative52 Negative52 INSL3 19p13.2 D19S212 D19S410 TDT Linkage 150 Families 39 ASPs Negative23 Not significant23 IRS1 2q36.3 IRS1 STRP TDT Linkage 150 Families 39 ASPs Negative23 Not significant23 IRS1 2q36.3 Gly972Arg 28 PCOS 53 PCOS/224 controls Positive association with fasting insulin levels117 IRS1 2q36.3 Gly972Arg Mutation screen CC CC >90% US white >90% US white >90% US white >90% US white White White Turkish white 60 PCOS/60 controls Positive118 IRS1 2q36.3 Gly972Arg CC Spanish white 103 Cases/48 controls Negative119 IRS1 2q36.3 Gly972Arg CC US white 109 Cases/95 controls Negative96 IRS1 2q36.3 Gly972Arg CC Chilean 146 PCOS/97 controls Positive120 IRS2 13q34 Gly1057Asp CC Spanish white 103 Cases/48 controls Negative119 IRS2 13q34 Gly1057Asp Mutation screen CC White White 28 PCOS 53 PCOS/224 controls Negative117 Negative117 LHB 19q13.33 Trp8Arg Ile15Thr CC Finnish, Dutch, UK, and US white 363 PCOS/944 controls Positive for UK only121 LHB 19q13.33 Exon 3 (Gly102Ser) CC Korean 68 PCOS/59 controls Negative122 LHCGR 2p21 D2S1352 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 SMAD4 18q21.1 D18S474 TDT Linkage US white US white 150 Families 39 ASPs Not significant23 Negative23 AMH 19p13.3 None Mutation screen Japanese 43 PCOS/20 controls Negative123 Negative23 Not significant23 MC4R 18q21.32 D18S64 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 MMP1 11q22.2 –1607 GG/G CC Austrian white 62 Cases/94 controls Positive124 MTHFR 1p36.22 C677T CC Italian white 70 PCOS/70 controls Negative125 LEP 7q32.1 D7S1875 TDT Linkage US white US white 150 Families 39 ASPs Not significant23 Negative23 LEP 7q32.1 None LEPR 1p31 D1S198 Mutation screen CC TDT Linkage LEPR 1p31 LEPR 1p31 K109R Q223R K656N 3 UTR Q223R PAI1 7q22.1 PAI1 Negative126 US white US white 150 Families 39 ASPs Negative23 Negative23 Mutation screen CC Finnish white Finnish white 38 PCOS 38 PCOS/122 controls Negative126 Negative126 CC Turkish 56 PCOS/58 controls Negative127 4G/5G promoter CC Austrian white 106 PCOS/102 controls Negative128 7q22.1 4G/5G promoter CC Greek white 98 PCOS/64 controls Positive129 PAI1 7q22.1 4G/5G promoter CC Spanish white 72 PCOS/42 controls Negative80 ENPP1 6q23.2 K121Q CC Finnish white 143 PCOS/115 controls Positive130 ENPP11 6q23.2 K121Q CC Spanish white 72 PCOS/42 controls Negative80 POMC 2p23 D2S131 TDT Linkage US white US white 150 Families 39 ASPs Not significant23 Negative23 PON1 7q21.3 CC Spanish white 72 PCOS/42 controls Positive C–108T only80 PPARG 3p25.2 C→108T L55M N192R D3S1263 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 PPARG 3p25.2 Pro12Ala CC White 102 Cases/104 controls Negative131 PPARG 3p25.2 Pro12Ala Exon 6 CT CC Italian white Italian white 120 PCOS/120 controls 100 PCOS/100 controls Negative132,133 Positive133 PPARG 3p25.2 Pro12Ala CC Spanish white 72 PCOS/42 controls Negative80 PPARG 3p25.2 Pro12Ala CC Finnish white 135 PCOS/115 controls Negative134 PTP1B 20q13.13 Ins/del 1484G C981T CC Spanish white 72 PCOS/42 controls Negative80 RSTN 19p13.3 –420 C/G TDT US white 258 Families Negative135 SHBG 17p13.2 D17S1353 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 SHBG 17p13.2 Promoter (TAAAA)n CC Greek white 185 PCOS/324 controls Positive136 SORBS1 10q24.1 T228A CC Spanish white 72 PCOS/42 controls Negative80 STAR 8p11.2 D8S1821 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 TNF 6p21.1 –C→850T promoter CC Finnish white 87 PCOS/155 controls Negative137 TNF 6p21.1 –308 promoter CC Australian white 84 PCOS + 38 PCO/136 controls Negative138 TNFRSF1B 1p36.22 CC Spanish white Italian white 42 PCOS/36 controls 64 PCOS/29 controls Positive M196R only139 UCP2 11q13 M196R G1663A 3 UTR T1668G 3 UTR T1690C 3 UTR D11S911 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 UCP3 11q13 D11S911 TDT Linkage US white US white 150 Families 39 ASPs Negative23 Negative23 Abbreviations: ASP, affected sibling pair; (CAG)n, CAG repeats; CAH, congenital adrenal hyperplasia; CC, case–control; NA, not available; OGTT, oral glucose tolerance test; PCO, polycystic ovary; PCOS, patients with polycystic ovary syndrome; POF, premature ovarian failure; SNP, single-nucleotide polymorphism; TDT, terminal deoxnucleotidyl transferase. References 1. Diamanti-Kandarakis E et al. (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84: 4006–4011 2. Knochenhauer ES et al. (1998) Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83: 3078–3082 3. Sam S and Dunaif A (2003) Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 14: 365–370 4. Yildiz BO et al. (2003) Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: 2031–2036 5. Sam S et al. (2005) Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 4797–4802 6. Sir-Petermann T et al. (2002) Prevalence of type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome. Diabetologia 45: 959–964 7. Yilmaz M et al. (2005) Glucose intolerance, insulin resistance and cardiovascular risk factors in first degree relatives of women with polycystic ovary syndrome. Hum Reprod (Oxf) 20: 2414–2420 8. Kiddy DS et al. (1992) Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 36: 105–111 9. Norman RJ et al. (2004) Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 10: 267–280 10. Moran LJ et al. (2004) Short term energy restriction (using meal replacements) improves reproductive parameters in polycystic ovary syndrome. Asia Pacific J Clin Nutr 13 (Suppl): S88 11. Moran L and Norman RJ (2004) Understanding and managing disturbances in insulin metabolism and body weight in women with polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 18: 719–736 12. Norman RJ et al. (2002) The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 13: 251–257 13. Cooper HE et al. (1968) Hereditary factors in Stein-Leventhal syndrome. Am J Obstet Gynecol 100: 371–387 14. Givens JR (1988) Familial polycystic ovarian disease. Endocrinol Metab Clin N Am 17: 771– 783 15. Hague W et al. (1988) Familial polycystic ovaries: a genetic disease. Clin Endocrinol 29: 593–605 16. Ferriman D and Purdie AW (1979) The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clin Endocrinol 11: 291–300 17. Carey AH et al. (1993) Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol 38: 653–658 18. Legro RS et al. (1998) Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 95: 14956–14960 19. Kahsar-Miller M and Azziz R (1999) Heritability and the risk of developing androgen excess. J Steroid Biochem Mol Biol 69: 261–268 20. Jahanfar S et al. (1997) A twin study of polycystic ovary syndrome and lipids. Gynecol Endocrinol 11: 111–117 21. Kahsar-Miller MD et al. (2001) Prevalence of polycystic ovary syndrome (PCOS) in first degree relatives of patients with PCOS. Fertil Steril 75: 53–58 22. Vink J et al. (2005) Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 91: 2100–2104 23. Urbanek M et al. (1999) Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A 96: 8573–8578 24. Escobar-Morreale HF et al. (2005) The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 26: 251–282 25. Newton-Cheh C and Hirschhorn JN (2005) Genetic association studies of complex traits: design and analysis issues. Mutat Res 573: 54–69 26. Hirschhorn JN (2005) Genetic approaches to studying common diseases and complex traits. Pediatr Res 57: 74R–77R 27. Hirschhorn JN and Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6: 95–108 28. Hattersley AT and McCarthy MI (2005) What makes a good genetic association study? Lancet 366: 1315–1323 29. Zawadzki JK and Dunaif A (1992) Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Polycystic Ovary Syndrome, 377–384 (Eds Dunaif A et al.) Boston: Blackwell Scientific 30. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19: 41–47 31. Altshuler D et al. (2000) The common PPAR[gamma] Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26: 76–80 32. Grant SF et al. (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38: 320–323 33. Gharani N et al. (1997) Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6: 397–402 34. Diamanti-Kandarakis E et al. (2000) Microsatellite polymorphism (tttta)(n) at -528 base pairs of gene CYP11[alpha] influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil Steril 73: 735–741 35. Daneshmand S et al. (2002) Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17[alpha]hydroxylase/C(17-20) lyase promoters. Fertil Steril 77: 274–280 36. San Millan JL et al. (2001) Role of the pentanucleotide (tttta)(n) polymorphism in the promoter of the CYP11[alpha] gene in the pathogenesis of hirsutism. Fertil Steril 75: 797–802 37. Gaasenbeek M et al. (2004) Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J Clin Endocrinol Metab 89: 2408–2413 38. Bell GI et al. (1982) The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295: 31–35 39. Pugliese A and Miceli D (2002) The insulin gene in diabetes. Diabetes Metab Res Rev 18: 13–25 40. Waterworth DM et al. (1997) Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349: 986–990 41. Michelmore K et al. (2001) Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight. Clin Endocrinol (Oxf) 55: 439–446 42. Calvo RM et al. (2002) Insulin gene variable number of tandem repeats regulatory polymorphism is not associated with hyperandrogenism in Spanish women. Fertil Steril 77: 666–668 43. Powell BL et al. (2005) Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits. J Clin Endocrinol Metab 90: 2988–2993 44. Hanis CL et al. (1996) A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13: 161–166 45. Horikawa Y et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26: 163–175 46. Evans JC et al. (2001) Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. Am J Hum Genet 69: 544–552 47. Tsai HJ et al. (2001) Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. Am J Hum Genet 69: 1236–1244 48. Ehrmann DA et al. (2002) Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 87: 1669–1673 49. Haddad L et al. (2002) Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome. J Clin Endocrinol Metab 87: 2606–2610 50. Urbanek M et al. (2005) Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J Clin Endocrinol Metab 90: 6623–6629 51. Tucci S et al. (2001) Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor locus. J Clin Endocrinol Metab 86: 446–449 52. Villuendas G et al. (2003) Association between the D19S884 marker at the insulin receptor gene locus and polycystic ovary syndrome. Fertil Steril 79: 219–220 53. Hata R et al. (2000)Association of functional microsatellites in the human type I collagen [alpha]2 chain (COL1A2) gene with systemic sclerosis. Biochem Biophys Res Commun 272: 36–40 54. Fenech AG et al. (2004) Novel polymorphisms influencing transcription of the human CHRM2 gene in airway smooth muscle. Am J Respir Cell Mol Biol 30: 678–686 55. Huang TS et al. (2003) Shortening of microsatellite deoxy(CA) repeats involved in GL331- induced down-regulation of matrix metalloproteinase-9 gene expression. Biochem Biophys Res Commun 300: 901–907 56. Gabellini N (2001) A polymorphic GT repeat from the human cardiac Na +Ca2+ exchanger intron 2 activates splicing. Eur J Biochem 268: 1076–1083 57. Hui J et al. (2003) HnRNP L stimulates splicing of the eNOS gene by binding to variable- length CA repeats. Nat Struct Biol 10: 33–37 58. Abbott DH et al. (2002) Developmental origin of polycystic ovary syndrome—a hypothesis. J Endocrinol 174: 1–5 59. Abbott DH et al. (2005) Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update 11: 357–374 60. Foecking EM et al. (2005) Neuroendocrine consequences of prenatal androgen exposure in the female rat: absence of luteinizing hormone surges, suppression of progesterone receptor gene expression, and acceleration of the gonadotropin-releasing hormone pulse generator. Biol Reprod 72: 1475–1483 61. de Zegher F et al. (2006) Prenatal growth restraint followed by catch-up of weight: a hyperinsulinemic pathway to polycystic ovary syndrome. Fertil Steril 86: S4 62. Ibanez L et al. (2002) Reduced ovulation rate in adolescent girls born small for gestational age. J Clin Endocrinol Metab 87: 3391–3393 63. Ibanez L et al. (2002) Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism. J Clin Endocrinol Metab 87: 5702–5705 64. Ibanez L et al. (2001) Polycystic ovary syndrome after precocious pubarche: ontogeny of the low birthweight effect. Clin Endocrinol 55: 667–672 65. Ibanez L et al. (2006) Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational age children. J Clin Endocrinol Metab 91: 2153–2158 66. Hickey TE et al. (2006) Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome. J Clin Endocrinol Metab 91: 2789–2791 67. Mhatre AN et al. (1993) Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet 5: 184–188 68. Tut TG et al. (1997) Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab 82: 3777–3782 69. Jakubiczka S et al. (1997) Mutations of the androgen receptor gene in patients with complete androgen insensitivity. Hum Mutat 9: 57–61 70. Jèaèaskelèainen et al. (2005) Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 83: 1724–1728 71. Legro R et al. (1994) Size polymorphisms of the androgen receptor among female Hispanics and correlation with androgenic characteristics. Obstet Gynecol 83: 701–706 72. Mifsud A et al. (2000) Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 85: 3484–3488 73. Mohlig M et al. (2006) The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome. Eur J Endocrinol 155: 127–130 74. Hickey T et al. (2002) The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab 87: 161–165 75. The International HapMap Consortium (2003) The International HapMap Project. Nature 426: 789–796 76. Altshuler D et al. (2005) A haplotype map of the human genome. Nature 437: 1299–1320 77. Pasternack JJ (1999) Discovering human disease genes. In An Introduction to Human Molecular Genetics, 218–219 (Ed Pasternack JJ) Bethesda, MD: Fitzgerald Science Press 78. Metzker ML (2005) Emerging technologies in DNA sequencing. Genome Res 15: 1767–1776 79. Heinonen S et al. (2005) Associations between two single nucleotide polymorphisms in the adiponectin gene and polycystic ovary syndrome. Gynecol Endocrinol 21: 165–169 80. San Millan JL et al. (2004) Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab 89: 2640–2646 81. Perez-Bravo F et al. (2005) Tryptophan 64 arginine polymorphism of [beta]-3-adrenergic receptor in Chilean women with polycystic ovary syndrome. Clin Endocrinol 62: 126–131 82. Zulian E et al. (2005) The M235T polymorphism of the angiotensinogen gene in women with polycystic ovary syndrome. Fertil Steril 84: 1520–1521 83. Heinonen S et al. (2001) Apolipoprotein E alleles in women with polycystic ovary syndrome. Fertil Steril 75: 878–880 84. Gonzalez A et al. (2003) Specific CAPN10 gene haplotypes influence the clinical profile of polycystic ovary patients. J Clin Endocrinol Metab 88: 5529–5536 85. Gonzalez A et al. (2002) CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab 87: 3971–3976 86. Babu KA et al. (2004) CYP1A1, GSTM1 and GSTT1 genetic polymorphism is associated with susceptibility to polycystic ovaries in South Indian women. Reprod Biomed Online 9: 194–200 87. Techatraisak K et al. (1997) Frequency of a polymorphism in the regulatory region of the 17 [alpha]-hydroxylase-17,20-lyase (CYP17) gene in hyperandrogenic states. Clin Endocrinol 46: 131– 134 88. Gharani N et al. (1996) 5 Polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries. J Clin Endocrinol Metab 81: 4174 89. Marszalek B et al. (2001) Investigations on the genetic polymorphism in the region of CYP17 gene encoding 5-UTR in patients with polycystic ovarian syndrome. Gynecol Endocrinol 15: 123–128 90. Diamanti-Kandarakis E et al. (1999) Polymorphism TC (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome. Fertil Steril 71: 431–435 91. Tucci S et al. (2001) Evidence for association of polycystic ovary syndrome in Caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab 86: 446–449 92. Kahsar-Miller M et al. (2004) Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. Fertil Steril 82: 973– 975 93. Petry CJ et al. (2005) Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Hum Reprod 20: 1837–1843 94. Sèoderlund D et al. (2005) No evidence of mutations in the P450 aromatase gene in patients with polycystic ovary syndrome. Hum Reprod (Oxf) 20: 965–969 95. Witchel SF and Aston CE (2000) The role of heterozygosity for CYP21 in the polycystic ovary syndrome. J Pediatr Endocrinol Metab 13: 1315–1317 96. Witchel SF et al. (2005) Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertil Steril 83: 371–375 97. Kahsar-Miller M et al. (1999) Dopamine D3 receptor polymorphism is not associated with the polycystic ovary syndrome. Fertil Steril 71: 436–438 98. Legro R et al. (1995) A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics. Fertil Steril 63: 779–784 99. Korhonen S et al. (2003) Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are associated with polycystic ovary syndrome. Fertil Steril 79: 1353–1357 100. Liao WX et al. (1999) Preliminary investigation of follistatin gene mutations in women with polycystic ovary syndrome. Mol Hum Reprod 6: 587–590 101. Urbanek M et al. (2000) Allelic variants of the follistatin gene in polycystic ovary syndrome. J Clin Endocrinol Metab 85: 4455–4461 102. Takakura K et al. (2001) Follicle-stimulating hormone receptor gene mutations are rare in Japanese women with premature ovarian failure and polycystic ovary syndrome. Fertil Steril 75: 207– 209 103. Tong Y et al. (2001) Absence of mutations in the coding regions of follicle-stimulating hormone receptor gene in Singapore Chinese women with premature ovarian failure and polycystic ovary syndrome. Horm Metab Res 33: 221–226 104. Sudo S et al. (2002) Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod 8: 893–899 105. Tong Y et al. (2000) Association of AccI polymorphism in the follicle-stimulating hormone [beta] gene with polycystic ovary syndrome. Fertil Steril 74: 1233–1236 106. Ho CK et al. (2005) Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 90: 6596–6602 107. Takebayashi K et al. (2000) Mutation analysis of the growth differentiation factor-9 and -9B genes in patients with premature ovarian failure and polycystic ovary syndrome. Fertil Steril 74: 976– 979 108. Cohen DP et al. (1999) Molecular analysis of the gonadotropin-releasing hormone receptor in patients with polycystic ovary syndrome. Fertil Steril 72: 360–363 109. Kahsar-Miller M et al. (2000) A variant of the glucocorticoid receptor gene is not associated with adrenal androgen excess in women with polycystic ovary syndrome. Fertil Steril 74: 1237–1240 110. San Millâan JL et al. (2005) A study of the hexose-6-phosphate dehydrogenase gene R453Q and 11[beta]-hydroxysteroid dehydrogenase type 1 gene 83557insA polymorphisms in the polycystic ovary syndrome. J Clin Endocrinol Metab 90: 4157–4162 111. White PC (2005) Genotypes at 11[beta]-hydroxysteroid dehydrogenase type 11B1 and hexose-6-phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample. J Clin Endocrinol Metab 90: 5880–5883 112. Moghrabi N et al. (1998) Deleterious missense mutations and silent polymorphism in the human 17[beta]-hydroxysteroid dehydrogenase 3 gene (HSD17B3). J Clin Endocrinol Metab 83: 2855–2860 113. Qin K et al. (2006) Identification of a functional polymorphism of the human type 5 17[beta]- hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J Clin Endocrinol Metab 91: 270–276 114. Walch K et al. (2004) A common interleukin-6 gene promoter polymorphism influences the clinical characteristics of women with polycystic ovary syndrome. Fertil Steril 81: 1638–1641 115. Vankova M et al. (2002) Association of insulin gene VNTR polymorphism with polycystic ovary syndrome. Ann N Y Acad Sci 967: 558–565 116. Siegel S et al. (2002) A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertil Steril 78: 1240–1243 117. El Mkadem SA et al. (2001) Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. Diabetes 50: 2164–2168 118. Dilek S et al. (2005) Association of Gly972Arg variant of insulin receptor substrate-1 with metabolic features in women with polycystic ovary syndrome. Fertil Steril 84: 407–412 119. Villuendas G et al. (2005) Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls. Hum Reprod (Oxf) 20: 3184–3191 120. Sir-Petermann T et al. (2001) G972R polymorphism of IRS-1 in women with polycystic ovary syndrome. Diabetologia 44: 1200–1201 121. Tapanainen JS et al. (1999) A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone. J Clin Endocrinol Metab 84: 1711–1715 122. Kim NK et al. (2001) The luteinizing hormone [beta]-subunit exon 3 (Gly102Ser) gene mutation is rare in Korean women with endometriosis and polycystic ovary syndrome. Fertil Steril 75: 1238–1239 123. Wang HQ et al. (2002) Mutational analysis of the mèullerian-inhibiting substance gene and its receptor gene in Japanese women with polycystic ovary syndrome and premature ovarian failure. Fertil Steril 78: 1329–1330 124. Walch K et al. (2005) A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the presence of polycystic ovary syndrome in Caucasian women. Fertil Steril 83: 1565– 1567 125. Orio F Jr et al. (2003) Homocysteine levels and C677T polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: 673–679 126. Oksanen L et al. (2000) No evidence for mutations of the leptin or leptin receptor genes in women with polycystic ovary syndrome. Mol Hum Reprod 6: 873–876 127. Erel CT et al. (2002) Leptin receptor variant in women with polycystic ovary syndrome. Fertil Steril 78: 1334–1335 128. Walch K et al. (2005) A polymorphism of the plasminogen activator inhibitor-1 gene promoter and the polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 123: 77–81 129. Diamanti-Kandarakis E et al. (2004) The prevalence of 4G5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in polycystic ovarian syndrome and its association with plasma PAI1 levels. Eur J Endocrinol 150: 793–798 130. Heinonen S et al. (2004) The 121Q allele of the plasma cell membrane glycoprotein 1 gene predisposes to polycystic ovary syndrome. Fertil Steril 82: 743–745 131. Hahn S et al. (2005) The peroxisome proliferator activated receptor [gamma] Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome. Clin Endocrinol 62: 573–579 132. Orio F Jr et al. (2004) Lack of an association between peroxisome proliferator-activated receptor-[gamma] gene Pro12Ala polymorphism and adiponectin levels in the polycystic ovary syndrome. J Clin Endocrinol Metab 89: 5110–5115 133. Orio F Jr et al. (2003) Exon 6 and 2 peroxisome proliferator-activated receptor-[gamma] polymorphisms in polycystic ovary syndrome. J Clin Endocrinol Metab 88: 5887–5892 134. Korhonen S et al. (2003) Polymorphism in the peroxisome proliferator-activated receptor- [gamma] gene in women with polycystic ovary syndrome. Hum Reprod 18: 540–543 135. Urbanek M et al. (2003) Variation in resistin gene promoter not associated with polycystic ovary syndrome. Diabetes 52: 214–217 136. Xita N et al. (2003) Association of the (TAAAA)n repeat polymorphism in the sex hormone- binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. J Clin Endocrinol Metab 88: 5976–5980 137. Korhonen S et al. (2002) Lack of association between C-850T polymorphism of the gene encoding tumor necrosis factor-[alpha] and polycystic ovary syndrome. Gynecol Endocrinol 16: 271– 274 138. Milner CR et al. (1999) No association between the -308 polymorphism in the tumour necrosis factor [alpha] (TNF[alpha]) promoter region and polycystic ovaries. Mol Hum Reprod 5: 5–9 139. Peral B et al. (2002) Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab 87: 3977–3983
