Polycystic Ovary Syndrome - part 5 pps

Table 1 (Continued) Gene Chromosome location Polymorphism/ Allele Study Design Ethnicity Sample size Findings EPHX 1q42.12 H139R Haplotype D5S474 cc e Finnish Cauc. 112 PCOS/115 controls Positive haplotype only 145 FS 5p14 D5S623 D5S822 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Positive 33 FS 5p14 – D5S474 Mutation screen Chinese 64 PCOS no mutations 146 FS 5p14 D5S623 D5S822 Exon 6 SNP D5S474 Mutation Screen TDT a Linkage >90% US Cauc. >90% US Cauc. >90% US Cauc. 19 multiplex families 324 trios 75 ASPs Negative b 147 FS 5p14 D5S623 D5S822 cc e US Cauc 85 PCOS/87 controls Negative b 137 FSHR 2p21 – Mutation Screen Japanese 15 POF j /38 PCOS/3 controls Negative b 148 FSHR 2p21 2p21 Mutation screen cc e Singapore Chinese Singapore Chinese 16 POF j /124 PCOS124 PCOS/236 controls Negative b 149 Negative b 149 FSHR 2p21 D2S1352 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 FSHR 2p21 T307A N680S cc e Japanese 522 cohort Positive 150 FSH- 11p14.1 Exon 3 T/C Mutation screen cc e Singapore Chinese 135 PCOS/105 Controls Possibly associated with PCOS 151 GATA6 18q11.2 hCV7490431 hCV1892216 rs1941084 Mutation screen TDT a >90% US Cauc. >90% US Cauc. 15 PCOS/5 controls469 families Negative b 152 GDF9 5q23.3 – Mutation screen Japanese 15 POF j /38 PCOS/3 controls No polymor- phisms 153 BMP15 (GDF9B) Xq11.2 – Mutation screen Japanese 15 POF j /38 PCOS/3 controls No polymor- phisms 153 GnRH 8p21.2 – Mutation screen 80 PCOS No mutations in exons 154 GRL 5q32 Asn363Ser cc e US Cauc. 114 PCOS/92 controls Negative b 155 GSTM1 1p13.3 cc e South Indian 180 PCO f /72 controls Negative b 132 GST1 22q11.23 cc e South Indian 180 PCO f /72 controls Negative b 132 (Continued) Table 1 (Continued) Gene Chromosome location Polymorphism/ Allele Study Design Ethnicity Sample size Findings H6PD 1p36.22 R453Q cc e Spanish Cauc. 116 PCOS/76 controls Positive 156 HSD11B1 1q32.2 T1971G cc e Racially mixed 3551 population cohort Negative b 157 HSD11B1 1q32.2 83557insA cc e Spanish Cauc 116 PCOS/76 controls Negative b 156 HSD17B1 17q21.2 D17S934 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 HSD17B2 16q24.1 HSD17B2 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 HSD1B3 9q22 D9S1809 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 HSD17B3 9q22 Ser289Gly cc e US racially mixed 46 PCOS/32 controls Negative b 158 HSD17B5 10p15.1 G-71A cc e US racially mixed 121 PCOS/128 controls Positive 159 HSD3B1 1p31.1 D1S514 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 HSD3B2 1p31.1 D1S514 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 IGF1 12q23.2 IGF1 STRP TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 IGF1 12q23.2 IGF1 STRP cc e Spanish Cauc. 72 PCOS/42 controls Negative b 127 IGF1R 15q26.3 IGF1R TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 IGF1R 15q26.3 IGF1R cc e Spanish Cauc. 72 PCOS/42 controls Negative b 127 IGF2 11p15.5 Apa1 GA 3  UTR cc e Spanish Cauc. 72 PCOS/42 controls Positive 127 IGF2R 6q25.3 ACAA in/del 3  UTR cc e Spanish Cauc. 72 PCOS/42 controls Negative b 127 IGFBP1 7p13 D7S519 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 IGFBP3 7p13 D7S519 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 IL-6 G-174C cc e Austrian Cauc. 62 PCOS/94 controls Negative b161 INHA 2q35 D2S163 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 INHBA 7p14.1 INHBA STRP TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Not significant d 33 (Continued) Table 1 (Continued) Gene Chromosome location Polymorphism/ Allele Study Design Ethnicity Sample size Findings INHBB 2q14.2 D2S293 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Not significant d 33 Not significant d 33 INHC 12q13 D12S1691 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 INS 11p15.5 INS VNTR TDT a cc e >95% Cauc. 224 population cohort Positive paternal transmission of class III allele 61 INS 11p15.5 INS VNTR cc e TDT Linkage British Cauc.Racial MixedRacial Mixed 59 PCOS/52 controls17 multiplex families17 multiplex families Positive linkage & association with paternal transmission of class III allele 60 INS 11p15.5 INS VNTR TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 INS 11p15.5 INS VNTR cc e Spanish Cauc 96 HA h /38 controls Negative b 62 INS 11p15.5 INS VNTR cc e Czech Cauc. 38 PCOS/22 controls Negative b 63 INS 11p15.5 INS VNTR cc e TDT a Finish Cauc. British Cauc. British Cauc. 1589 pop. Cohort440 PCOS/1062 controls255 trios Negative b 64 INSR 19p13.3 INSR STRP TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Not significant d 33 INSR 19p13.3 H1058H C/T cc e US Cauc. 99 PCOS/136 controls Positive 161 Chr19p3.13 19p13.3 D19S884 TDT a Linkage >90% US Cauc. >90% US Cauc. 367 families 107 ASPs c Positive 33 94 Positive 94 Chr19p3.13 19p13.3 D19S884 cc e US Cauc. 85 PCOS/87 controls Positive 137 Chr19p3.13 19p13.3 D19S884 cc e Spanish CaucItalian Cauc. 50 PCOS/37 controls58 PCOS/29 controls Negative b 96 Negative b 96 INSL3 19p13.2 D19S212 D19S410 TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b33 Not significant d 33 IRS1 2q36.3 IRS1 STRP TDT a Linkage >90% US Cauc. >90% US Cauc. 150 families 39 ASPs c Negative b 33 Not significant d 33 IRS1 2q36.3 Gly972Arg Mutation screen cc e Cauc. Cauc. 28 PCOS53 PCOS/224 controls Positive association with fasting insulin levels 162 IRS1 2q36.3 Gly972Arg cc e Turkish Cauc. 60 PCOS/60 controls Positive 163 IRS1 2q36.3 Gly972Arg cc e Spanish Cauc. 103 cases/48 controls Negative b 164 (Continued) Table 1 (Continued) Gene Chromosome location Polymorphism/ Allele Study Design Ethnicity Sample size Findings IRS1 2q36.3 Gly972Arg cc e US Cauc. 109 cases/95 controls Negative b 142 IRS1 2q36.3 Gly972Arg cc e Chilean 146 PCOS/ 97controls Positive 165 IRS2 13q34 Gly1057Asp cc e Spanish Cauc. 103 cases/48 controls Negative b 164 IRS2 13q34 Gly1057Asp Mutation screen cc e Cauc. Cauc. 28 PCOS53 PCOS/224 controls Negative b 162 Negative b 164 LEP 7q32.1 D7S1875 TDT a Linkage US Cauc.US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 LEP 7q32.1 – Mutation screen cc e Finnish Cauc. Finnish Cauc. 38 PCOS38 PCOS/122 controls Negative b 166 LEPR 1p31 D1S198 TDT Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 LEPR 1p31 K109R Q223R K656N 3  UTR Mutation screen cc e Finnish Cauc.Finnish Cauc 38 PCOS38 PCOS/122 controls Negative b 166 Negative b 166 LEPR 1p31 Q223R cc e Turkish 56 PCOS/58 controls Negative b 167 LH- 19q13.33 Trp8ArgIle 15Thr cc e Finnish, Dutch, UK, and US Cauc. 363 PCOS/944 controls Positive for UK only 168 LH- 19q13.33 Exon 3 (Gly102Ser) cc e Korean 68 PCOS/59 controls Negative b 169 LHCGR 2p21 D2S1352 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 MADH4 18q21.1 D18S474 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 MIS 19p13.3 – Mutation screen Japanese 43 PCOS/20 controls Negative b 170 MC4R 18q21.32 D18S64 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 MMP1 11q22.2 –1607 GG/G cc e Austrian Cauc. 62 cases/94 controls Positive 171 MTHFR 1p36.22 C677T cc e Italian Cauc 70 PCOS/70 controls Negative b 172 PAI1 7q22.1 4G/5G promoter cc e Austrian Cauc. 106 PCOS/102 controls Negative b 173 PAI1 7q22.1 4G/5G promoter cc e Greek Cauc 98 PCOS/ 64 controls Positive 174 PAI1 7q22.1 4G/5G promoter cc e Spanish Cauc. 72 PCOS/42 controls Negative b 128 PC-1 6q23.2 K121Q cc e Finnish Cauc. 143 PCOS/115 controls Positive 175 PC-1 6q23.2 K121Q cc e Spanish Cauc. 72 PCOS/42 controls Negative b 128 POMC 2p23 D2S131 C-108T TDT Linkage US Cauc. US Cauc. 150 families 39 ASPs c Not significant d 33 Negative b 33 PON1 7q21.3 L55M N192R cc e Spanish Cauc. 72 PCOS/42 controls Positive C-108T only 128 (Continued) Table 1 (Continued) Gene Chromosome location Polymorphism/ Allele Study Design Ethnicity Sample size Findings PPARG 3p25.2 D3S1263 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 PPARG 3p25.2 Pro12Ala cc e Cauc. 102 cases/104 controls Negative b 176 PPARG 3p25.2 Pro12AlaExon 6C−→T cc e Italian Cauc. Italian Cauc. 120 PCOS/120 controls100 PCOS/100 controls Negative b 177 178 Positive 178 PPARG 3p25.2 Pro12Ala cc e Spanish Cauc. 72 PCOS/42 controls Negative b 128 PPARG 3p25.2 Pro12Ala cc e Finnish Cauc. 135 PCOS/115 controls Negative b 179 PTP1B 20q13.13 Ins/del 1484GC981T cc e Spanish Cauc. 72 PCOS/42 controls Negative b 128 RSTN 19p13.3 –420 C/G TDT a US Cauc. 258 families Negative b 180 SHBG 17p13.2 D17S1353 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 SHBG 17p13.2 Promoter (TAAAA) n cc e Greek Cauc. 185 PCOS/324 controls Positive 83 SORBS1 10q24.1 T228A cc e Spanish Cauc. 72 PCOS/42 controls Negative b 128 STAR 8p11.2 D8S1821 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 TNF 6p21.1 –C-850T promoter cc e Finnish Cauc 87 PCOS/155 controls Negative b 181 TNF 6p21.1 –308 promoter M196R cc e Australian Cauc. 84 PCOS + 38 PCO/136 controls Negative b 182 TNFRSF1B 1p36.22 G1663A 3  UTR T1668G 3  UTR T1690C 3  UTR cc e Spanish Cauc. Italian Cauc. 42 PCOS/36 controls64 PCOS/29 controls Positive M196R only 183 UCP-2 11q13 D11S911 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative 33 UCP-3 11q13 D11S911 TDT a Linkage US Cauc. US Cauc. 150 families 39 ASPs c Negative b 33 Negative b 33 a TDT Transmission Disequilibrium Test, family based test for association in the presence of linkage. b Negative absence of evidence for association. c ASPs Affected sib pairs. d Not significant nominal significant finding but not significant after correcting for multiple testing. e cc case control population based association study. f PCO polycystic ovarian morphology. g CAH congenital adrenal hyperplasia h PP premature pubarche. i HA hyperandrogenemia. j POF premature ovarian failure. [...]... of 141–209 repeats (49) The VNTR regulates transcription of the insulin gene (50 55 ) and is associated with hyperinsulinemia (55 ), susceptibility to T2DM (51 ,56 ,57 ), birth weight (57 ), fasting insulin levels (58 ), and the development of childhood (59 ) and juvenile obesity (58 ) In 1997, Waterworth et al (60) showed evidence for modest linkage between PCOS and the insulin gene VNTR in 17 families and... between PCOS and CYP11A [(33) and unpublished data] Gharani et al also found an association with allele 5 of D15S520, which is located in the promoter region of CYP11A although Urbanek et al could not provide replication for association at D15S520 (33) Two additional studies by Diamanti-Kandarakis et al ( 45) and Daneshmand et al (46) did show evidence for association between CYP11A promoter alleles and... allele at UCSNP-43 is associated with reduced muscle mRNA levels of calpain-10 and insulin resistance in non-diabetic Pima Indians Calpain-10 has also been found to play a role in insulin secretion and action As T2DM and insulin resistance are often associated with PCOS, calpain-10, therefore, is also a plausible candidate gene for PCOS Multiple studies have examined the contribution of calpain-10 to the... to show evidence for association between the D15S520 pentanucleotide repeat and PCOS More recently, Gaasenbeek et al (48) assessed the role of CYP11A in the etiology of PCOS using a large scale family- and population-based association study including 71 Genetic Analyses of PCOS 371 PCOS patients and 331 population controls from the United Kingdom and 52 7 symptomatic women and 1062 cohort controls from... 14 or 15 base pair repeats that are located in the 5 regulatory element of the insulin gene Alleles of the insulin gene VNTR are divided into three classes dependent on the number of repeats: class I with an average length of 26–63 repeats, class II with an average of 64–140 repeats, and class III with an average of 141–209 repeats (49) The VNTR regulates transcription of the insulin gene (50 55 ) and... variable number of tandem repeats (VNTR), calpain-10, sex hormone-binding globulin (SHBG), the androgen receptor (AR) and X-inactivation, and D19S884, a dinucleotide repeat marker mapping to chr19p13.2 4.1 CYP11A CYP11A is an ideal functional candidate gene for PCOS because it encodes the gene for the cytochrome p 450 side chain cleavage enzyme, the rate-limiting step in androgen biosynthesis In 1997,... role in the etiology of PCOS 72 Urbanek 4.3 Calpain-10 The cysteine protease caplain-10 (CAPN10) maps to chromosome 2q37.3 and is expressed in all adult and fetal tissues examined to date Calpain-10 was first identified as a susceptibility locus for T2DM in a genome-wide linkage scan for T2DM in Mexican Americans followed by positional cloning ( 65, 66), and it remains one of the few complex disease... three closely linked non-coding SNPs (UCSNP-43, -1 9, and -6 3) that conferred an increased risk for diabetes to individuals who were doubly heterozygous for the haplotypes (i.e., had the genotype 112/121) (66) These findings were replicated in populations of Northern European descent (66) but not in a study of British diabetes patients (67) or Samoans with T2DM (68) However, meta-analyses do support a... proliferator-activated receptor gamma (PPAR- ) Pro12Ala polymorphism, one of the few unambiguous type 2 diabetes susceptibility alleles identified to date, the more common proline residue is associated with approximately 1. 25 increased risk of developing T2DM and a population attributable risk for diabetes of 25% (41) However, owing to the small relative risk associated with this variant, it required a meta-analysis... be the case that CAG repeat length may be important only in a subset of PCOS patients with particularly high androgen levels As the AR receptor gene is X-linked and one copy of the X-chromosome is inactivated in women, the pattern of X-inactivation could influence AR activity and PCOS Hickey et al (86) compared X-inactivation and CAG repeat length in 83 fertile and 122 infertile Australian Caucasian . the insulin gene (50 55 ) and is associated with hyperinsulinemia (55 ), susceptibility to T2DM (51 ,56 ,57 ), birth weight (57 ), fasting insulin levels (58 ), and the development of childhood (59 ) and juvenile. PCOS /5 controls469 families Negative b  152  GDF9 5q23.3 – Mutation screen Japanese 15 POF j /38 PCOS/3 controls No polymor- phisms  153  BMP 15 (GDF9B) Xq11.2 – Mutation screen Japanese 15 POF j /38 PCOS/3 controls No polymor- phisms. Findings H6PD 1p36.22 R 453 Q cc e Spanish Cauc. 116 PCOS/76 controls Positive  156  HSD11B1 1q32.2 T1971G cc e Racially mixed 355 1 population cohort Negative b  157  HSD11B1 1q32.2 8 355 7insA cc e Spanish