Phenotypes in Male & Female First Degree Relatives of Women with PCOS. Andrea Dunaif, MD
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1 Phenotypes in Male & Female First Degree Relatives of Women with PCOS Andrea Dunaif, MD 1
2 ~7% Prevalence Anovulatory PCOS Leading Cause Hormonally-Related Infertility 4-Fold Increased Risk Type 2 Diabetes Mellitus ~80% Prevalence Obesity USA; 50% Elsewhere
3 Diagnostic Criteria PCOS NIH Rotterdam Hyperandrogenism Chronic Anovulation Exclusion Other Disorders + 2 of 3
4 PCOS Phenotypes According to Diagnostic Criteria Applied NIH ~7% Rotterdam 15% Hyperandrogenism Oligo-Amenorrhea PCOM
5 Diagnostic Criteria Metabolic Defects NIH Criteria Identify High Risk
6 Mendelian vs Complex Common Diseases/Traits Science 273: , 1996 Disease s PCOS 6 Type 2 diabetes 4 Obesity 4 Hypertension 4 Asthma 3
7 Non-Mendelian Familial Aggregation ~40% Sisters vs 7% Population Prevalence PCOS s = 5.7 ~ 70% Heritability Monozygotic Twins
8 If there is a genetic susceptibility to PCOS, are there phenotypes in firstdegree relatives?
9 Male Reproductive Phenotype? Brothers are Hyperandrogenemic 4,000 DHEAS P<0.01 ng/ml 3,000 2,000 1,000 0 Control PCOS Brothers Legro et al J Clin Endocrinol Metab 87:2134, 2002
10 AMH Levels Elevated in Male Relatives Fertil Steril 106:50, 2016
11 HOMAIR Insulin Resistance Aggregates PCOS Families * HOMAIR * Control n=125 PCOS n= Control n=125 HA n=40 *P< HOMAIR * HOMAIR * 0 Control n=60 Mother n=215 0 Control n=140 Sam et al. Diabetes Care 31:1237, 2008 Brother n=180
12 Increased T2D PCOS Families
13 100% 80% 60% Metabolic Syndrome Aggregates Sisters Unaffected vs Affected Ages yrs PCOS Families 60% * 100% 80% 60% Mothers NHANES III vs Mothers Ages yrs 62% 76% * 40% 29% 33% 40% 36% 33% 20% 0% 0% 0% 0% < >30 Sam et al, J Clin Endocrinol Metab 90: 4797, % 0% BMI (kg/m 2 ) 13% 7% < >30 * P<0.05 Sam et al, Proc Natl Acad Sci 103: , 2006
14 Increased MetS & Obesity Male Relatives Coviello et al. J Clin Endocrinol Metab 94:4361, 2009
15 Does PCOS have developmental origins?
16 Birthweight Does Not Differ PCOS & Relatives n=1038 J Clin Endocrinol Metab 95:789, 2010
17 Prenatally Androgenized Rhesus Phenocopy of PCOS David Abbott & Dan Dumesic
18 Does hyperandrogenemia resulting from genetic variation contribute to PCOS through epigenetic actions?
19 Analysis of control human fetal ovaries during the third trimester: morphology and immunohistochemical localization of P450c17. P450c17 Human Fetal Ovary Cole et al. J Clin Endocrinol Metab 91:3654, 2006
20 Cord Blood Androstenedione & Estradiol Decreased PCOS Female Offspring ,000 A'dione (ng/dl) p<0.05 Estradiol (pg/ml) 30,000 20,000 10,000 p< CONTROL PCOS n = 14 n = 17 0 CONTROL PCOS n = 12 n = 17 Anderson et al. J Clin Endocrinol Metab 95:2180, 2010
21 PCOS Daughters Testosterone & Insulin by Tanner Stage Sir-Petermann et al. J Clin Endocrinol Metab 94: 1923, 2009
22 Increased Total & Bioavailable Testosterone PCOS DaughtersTanner I-III Torchen et al. J Clin Endocrinol Metab 99:3855, 2014
23 PCOS Daughters β-cell Dysfunction Torchen et al. J Clin Endocrinol Metab 99:3855, 2014
24 PCOS Daughters At-Risk DI PCOS-d AIRg ( IU/ml) Increased Risk T2D Control Girls Sensitivity Index (min -1 /[mu/ml]) Torchen et al. J Clin Endocrinol Metab 99:3855, 2014
25 When do abnormalities in androgen metabolism begin in PCOS daughters?
26 Reproductive Phenotypes PCOS Daughters Minipuberty Adrenarche Puberty Menarche Adult Ovarian sex steroid production Adrenal androgen production Birth 8-12 years? Androstenedione Testosterone Estradiol Anderson et al. J Clin Endocrinol Metab 95:2180, 2010 Torchen et al. J Clin Endocrinol Metab 99:3855, 2014 & J Clin Endocrinol Metab 101:2069, 2016
27 Steroid Hormone Metabolites Increased 5α-Reductase Activity & Increased Glucocorticoid Metabolites CHOLESTEROL 3β-HSD 21-hydroxylase 11β-hydroxylase 18-hydroxylase 18-oxidase 5-PD 17α-hydroxylase PREG PROG DOC B 18OHB PD THDOC 5 THDOC* THB, 5 THB* THA, 5 THA* ALDO 5-PT 17,20-lyase 17PREG 17OHP S CORTISOL (F) PT 17HP THS THF, 5 THF*, β-cortols, α-cortols* 11β-HSD CORTISONE (E) THE β-cortolones, α-cortolones* DHEA D4 T DHT* DHEA 16OH-DHEA An* Et 17β-HSD Et 5α-reductase An* Torchen et al J Clin Endocrinol Metab 101:
28 Increased 5 α-reductase Activity PCOS Daughters1-3 yo Torchen et al J Clin Endocrinol Metab 101:
29 Reproductive Phenotypes PCOS Daughters Minipuberty Adrenarche Puberty Menarche Adult Ovarian sex steroid production Adrenal androgen production Birth years Androstenedione Estradiol 5α-Reductase Testosterone T DHT Anderson et al. J Clin Endocrinol Metab 95:2180, 2010 Torchen et al. J Clin Endocrinol Metab 99:3855, 2014 & J Clin Endocrinol Metab 101:2069, 2016
30 What are the genes involved in PCOS?
31 Published PCOS Loci
32 Polycystic Ovary Syndrome Consortium Boston Corrine Welt Richa Saxena DeCODE Unnur Strykarsdottir Estonia Reedik Magi Andres Salumets Rotterdam Joop Laven Andre Utterlinden GWAS Meta-Analysis 6 studies: NIH and/or Rotterdam diagnosis 4,890 cases: 20,405 controls 2,550,021 SNPs* Northwestern Chicago Andrea Dunaif Geoff Hayes Margrit Urbanek UK Oxford Stephen Franks Cecilia Lindgren Based on all SNPs λ GC Meta analysis Inverse-variance weighted fixed-effects meta-analysis 10,074 cases: 103,164 controls 10,637,747 SNPs* *SNP counts reflect markers passing N_studies>=3 and N_effective>50%
33 Polycystic Ovary Syndrome Biologic Pathways Implicated THADA INSR GnRH LH LHCGR FSHR FSHB Fibrillin-3 DENND1A RAD50 FSH Ovary E 2 T Insulin Resistance Function Unknown C9orf YAP1 RAB5B SUOX HMGA2 TOX3 SUMO1P1 ZNF217 NEIL2 DGK ERBB4 KRR1 Masculinization
34 European PCOS GWAS Meta Analysis by Diagnostic Criteria * * Meun C et al for PCOS Genetics Consortium. ASHG October, 2015, Baltimore, MD, abstract 933/T, Manuscript in Preparation.
35 Limitations of GWAS Biologic Validation Difficult Non-Coding Variants Typically <10% Heritability Explained
36 Case-Control Bioinformatic Pipeline
37 Bioinformatic Analysis Next Generation Sequencing Proofing for Typos Many Candidate Genes
38 Analytic Outcomes Same Gene Different Mutations Common Pathway Mutations Private Mutations My car won t start All roads lead to Rome Every family is unhappy in its own way
39 AMH Rare PAVs ~3% PCOS Decrease Bioactivity Lidija Gorsic PhD Candidate Gorsic et al. J Clin Endocrinol Metab 102:2862, 2017
40 Same Gene, Different PAVs AMH AMH
41 Fertil Steril 106:50, 2016 AMH PAVs Additional Phenotypes
42 Identifies Families at Risk Reproductive PCOS Hyperandrogenemia Sisters & Mothers Brothers Daughters premenarche Elevated AMH Sisters Brothers & Fathers Daughters premenarche Metabolic Metabolic Syndrome Sisters & Mothers Brothers & Fathers Overweight Brothers & Fathers T2D Mothers & Fathers Increased T2D Risk Sisters & Brothers Daughters premenarche
43 Polycystic Ovary Syndrome Biologic Pathways Implicated THADA INSR GnRH LH LHCGR FSHR FSHB Fibrillin-3 DENND1A RAD50 Rare Variants/Mutations AMH FSH Ovary DENND1A SRD5A2? E 2 T Insulin Resistance Function Unknown C9orf YAP1 RAB5B SUOX HMGA2 TOX3 SUMO1P1 ZNF217 NEIL2 DGK ERBB4 KRR1 Masculinization
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