PCO and its genetics

 

 

PCOS is the most   common female   endocrine    disorder   affecting some  5-15% of all women   in their reproductive    years. It is   a notoriously   heterogeneous   syndrome which runs within families. It has  a high degree of heritability and   is currently  looked upon as being  a complex   genetic  disorder.

Several hundreds   of candidate   genes have been studied however the    majority of these genetic   variants have not   been replicated in sufficiently large case control studies .

 

Genetic   variants   in the fibrillin  gene  , the Androgen  receptor, FTO  gene the insulin   receptor , the FSHR    gene, the  TNF    alpha gene    and some variants   in the lL-6   gene do confer  a certain  risk for   PCOS   and have been   replicated in sufficiently large studies or meta analyses.

More recently, GWAS   has identified up to 20  genetic   variants genes  involved    in neuroendocrine, metabolic and reproductive pathways. These studies   also provided   evidence   for shared biologic pathways between PCOS   and a number   of metabolic   disorders menopause ,  depression and   male- pattern balding and a putative  male phenotype.

 

There is   not much   of overlap between GWAS   findings and most functional    molecular studies. However   most of the   identified SNPs seem to paly  a role in a pathway  responsible for trafficking   and recycling   of large  protein  transmembrane    receptors.

 

Moreover   some promising SNPs   involved   in  gonadotropin  action have been   identified  which do  not only constitute   risk factors    for PCOS   but also  seem  to influence  response to ovulation   induction  treatment.

Lastly    but not least evidence   is accumulating   that epigenetic   mechanisms  might   as well play a role in  the pathogenesis of PCOS   either    during   fetal  programming or in later life via factors as obesity  and diet composition .

In conclusion   genetic studies   have shown   that neuroendocrine, metabolic   and reproductive pathways   are involved   in the pathogenesis      of PCOS.  Genetic   findings     are strikingly   consistent    between different   PCOS   phenotypes. There is genetic      evidence    for shared biologic pathways    between PCOS  and a  number   of metabolic disorders, menopause, depression  and   male- pattern   balding , the putative male  phenotype.

Introduction

What are the diseases or syndromes associated with long standing PCO?? The syndrome  is also associated  with other  distressing  phenomena   such as depression , negative self esteem and metabolic   dysfunction  characterized  by insulin resistance  and compensatory  hyperinsulinaemia.

PCOS  increases  the risk for type   2 diabetes   mellitus,   gestational    diabetes  and other pregnancy  related   complications.

 Women   with PCOS    also more   often have hypertension .Finally, if  left  untreated , due to unopposed  estrogen exposure   women  with PCOS   are at an increased risk to develop  endometrial   cancer. Phenotypes of PCO may change!!!! The    PCOS   phenotype might change with   increasing   age or  changes  in body mass.

        

Heritability of PCO & Candidate genes??

PCOS  seems to  run within families and  although  50%  of all sisters  were  unaffected only 25%   had a similar   phenotype   compared  to the proband  whereas  the remaining 25% suffered from  hyperandrogenemia   .

In subsequent   studies  it was   shown that brothers  of women with  PCOS   have dyslipidemia as well as     evidence    for insulin resistance similar   to that of   their proband sisters  with  PCOS.

 More  recently   evidence emerged   indicating   clustering of metabolic syndrome , hypertension and dyslipidemia in mothers  , fathers   sisters,  and brothers  of women   with PCOS.

Twin studies revealed    similar results indicating a familial   component   in PCOS  is due to genetic  factors. The resemblance in monozygotic twin   sisters   for PCOS   was about   twice as large  as in dizygotic twin  pairs   indicating a high degree of heritability.

 

PCO and its Candidate  gene  studies –What informations we have with us??

In PCOS  candidate  genes have been  studies that were   involved in the     biosynthesis   and trafficking of androgens, genes   related  to metabolic   aspects of PCOS   and genes  correlated  with inflammatory   cytokines. Currently more than 200 studies    have been reporting    on SNP( single   nucleotide polymorphisms)   in genes   involved  in these pathways.

Numerous  studies have  been reporting  on other  SNPs  in genes  that are  associated  with either   the risk of    having PCOS   or one of its  characteristic  features.

However   the majority   of these    studies are small and lack proper    replication   studies   and should   therefore  be interpreted with caution.

A potential  association    of the D195884  marker in the fibrillin gene    with PCOS   in Chinese    women  was found . A meta  analysis    identified that   allele 8 may    increase  a women ‘s    susceptibility     to PCOS  .

Genes   involved in androgen metabolism have been   studied extensively .  Two  SNPs   in the promotor region   of the genes   encoding  for CYP17A1 and CYP11A1     were associated   with serum     androgen levels  in a subset   of Indian   women. However a recent metaanalysis  failed to verify  this relationship .

 

The    androgen receptor    has also  been studied in relation to PCOS     susceptibility    and the associated   hyperandrogenism. However     a recent meta   analysis   including 1536   PCOS  patients and 1807   controls   revealed  that the   lengths  of CAG  repeats    in the AR contributed  to hyperandrogenism  in PCOS.

In  a recent   meta analysis   including  12 studies    only one  single  nucleotide   polymorphism  in the “Fat  Mass    and Obesity  associated gene”--  did   significantly increase  the risk of PCOS  in women. However , two other   SNP’s    were associated  with PCOS   only in a  recessive  model.

 

Given the increased risk for type 2 diabetes   and the insulin resistance   frequently encountered in women   with PCOS into account the insulin  receptor  gene also   has been   studied   frequently . In a   recent meta    analysis a total of 20 case control studies including  23, 845   controls and  17, 460   PCOS cases were   analyzed   and only 17  SNPs    were found to be associated   with PCOS.

 

Further   subgroup   stratification  by ethnicity  and weight  did not lead     to discovery of significant correlation. Only   one other SNP  e.g.  2059807   was associated  with PCOS.  The current   meta analysis suggests no significant correlation between  both SNPs  rs1799817/rs2059807  was associated with PCOS.

Insulin  receptor   substrates  although significantly  associate   with PCOS in Japanese and Greek  population    a recent  meta analysis  of 11   studies   did not  reveal   a significant    association    between   IRS 1 SNPs   and the     risk to develop   PCOS.

A recent   meta analysis   revealed   no significant   association    between  INS  VNTR  polymorphisms and the risk   of PCOS   in the overall   population .

There  are    several  FSH   receptor  polymorphisms   located  in the FSHR  gene. The two  most common    are the Thr307 Ala and  Asn680Ser   polymorphisms.

A total   of 11 studies were  included  in a recent metaanalysis . The Asn680Ser   variant is significantly associated  with treatment    outcome  and pregnancy rates  in ovulation   induction . no  significant   association  were found  between  Thr30 7Ala   and PCOS.

More recently based  on the fact  that AMH  serum  levels  are increased  in women   with PCOS   SNPs in the AMH  gene as well as  in the AMH   Type  ll Receptor   gene have   been studied. Neither SNPs    in the    AMH  gene  nor those in the   AMHR2  did  confer a  heightened   risk   for PCOS. The results  of a meta  analysis     including  13 studies , assessing the role of    different TNF  alpha SNPs     and PCOS  susceptibility   suggests   a positive   associations   between  one TNF alpha SNP and the risk of PCOS. However no association were    detected  between another  9  SNPs in the TNF  alpha gene  and     the risk for  PCOS. Another   meta analysis      including  a total   of 14 studies investigated the  association    of SNPs in the interleukins  lL-6 and lL- 1 beta  and did not   find a significant   relationship  with the  susceptibility   for PCOS.

Genome   Wide   Association  Studies On PCO –What does such studies tell us on candidate   genes related to insulin signaling,  gonadotropic   hormone function   and type  2 diabetes. Other   candidate   genes were related   to calcium signaling   and endocytosis.

 

The  first   GWAS  in PCOS   was performed by a  group based  at Shandong   University    in china.  The discovery  set included 744 PCOS   cases and 895   controls and   subsequent   replications  involved   tow independent   large cohorts  of Han Chinese    women with PCOS  and controls. Three   genome wide significant   loci were   identified   showing strong   associations with PCOS  located    at chromosome  2  and chromosome 9   . In a second   GWAS  published one year   later  they identified  9 new loci that  significantly   associated  with PCOS. The  PCOS  associated   signals   showed evidence   of enrichment for candidate   genes related to insulin signaling gonadotropic   hormone function   and type  2 diabetes. Other   candidate   genes were related   to calcium  signaling   and endocytosis.

A  few  years later   a study  in American   women from  European   descent was published identifying two   new loci   reach   mapping to chromosome    8 and  chromosome   11 and a  known  locus  on chromosome  9  previously found in Chinese  GWAS. The  SNP  on chromosome 11 in the region of the   follicle   stimulating hormone  B   polypeptide     gene   was strongly  associated   with  the former PCOS   NIH   diagnosis   as well as  with  luteinizing   hormone  levels. In the  same   year a large  European   collaboration   produced  another  GWAS   on PCOS.

Six signals   for PCOS  in or near known   genes were identified   . Mendelian randomization analyses   indicate   causal roles  in PCOS etiology  for higher  BMI, higher  insulin  resistance   and lower serum sex hormone   binding globulin  concentrations .

Furthermore, genetic   susceptibility   to later menopause  is significantly associated with   higher   PCOS risk   and PCOS. Susceptibility alleles  are significantly associated   with higher serum anti Mullerian hormone   concentration  in girls.

Another   GWAS   in Korean women consisted  of 976   PCOS   cases and   946  controls   with a replication   cohort   including    249 PCOS   cases and  778   controls . One   novel   locus   with genome   wide significance   and seven    moderately   associated   loci for PCOS   were identified.   The strongest association    was on   chromosome 8  .

The latter   signal  was located  upstream  of the KHDRBS3  gene, which    is associated    with telomerase   activity  and could drive  PCOS   and related   phenotypes.

Another   GWAS  compared   patients  with PCOS  with   women   from infertile couples  due to tubal   occlusion or male factor    infertility genes   identified  were the  known THADA, DENND 1A   and a new   locus in the TOX3  gene.

A recent   meta analysis   cross ethnic effects  of the  through    GWAS    identified  genetic   variants   showed  that  overall  for 12 of 17  genetic variants   mapping to the  Chinese   PCOS   loci similar effect sizes  and identical   directions in PCOS    patients   from Northern European   ancestry indicating   a common genetic   risk profile   for PCOS across   populations. Therefore   it is    expected   that large   GWAS  in PCOS   patients   from Northern European   ancestry will partly identify similar   loci as the GWAS   in Chinese   PCOS   patients.

Indeed   in the most   recent   study  in over 10,000 cases   of PCOS and over  100,000   controls of  European  ancestry   identified   only 3 novel    loci  and replicated   11   previously     reported loci    . Strikingly  this study    showed that the genetic   architecture   was similar     between PCOS   diagnosed by  self report   and PCOS  diagnosed by NIH  or non  NIH   . Rotterdam  criteria   across common   variants   at 13 loci. Identified  variants  were associated   with hyperandrogenism ,  gonadotropin   regulation and testosterone   levels in affected women. Moreover linkage   disequilibrium  score regression analysis   revealed   genetic  correlations with   obesity , fasting insulin type 2  diabetes , lipid  levels   and coronary  artery disease, indicating   shared genetic architecture between  metabolic    traits   and PCOS. Finally   , Mendelian randomization analysis    indicate    causal   roles in PCOS   etiology  for higher DMI, higher    insulin   resistance   and lower   serum sex hormone   binding  globulin concentrations. Furthermore     genetic susceptibility   to later   menopause  is significantly associated with higher  PCOS risk and  PCOS  susceptibility alleles are significantly associated    with higher  serum   anti Mullerian  hormone   concentration  in girls.

Another GWAS  in Korean   women consisted of 976   PCOS cases in 946   controls   with a replication cohort   including   249 PCOS   cases  and 778   controls . One  novel locus   with genome   identified    were the  known   THADA, DENND1A  and a new   locus  in the TOX3 gene .

A recent   meta analysis  cross ethnic   effects  of the through GWAS   identified genetic    variants  showed   that overall  for 12 of 17   gene   variants    mapping   to the Chinese PCOS  loci similar  effect sizes and   identical directions   in PCOS  patients from  Northern European   ancestry indicating   a common genetic  risk profile   for PCOS   across populations . Polycystic ovary  syndrome   is the  most common   endocrine   disorder  in women   characterized  by ovulatory   dysfunction , hyperandrogenism, and  polycystic   ovarian   morphology   . The   diagnosis   is made according   to the so called  2003   Rotterdam   consensus criteria   . The prevalence varies   between  5 and 20 5  depending  on  which    population is assessed. The incidence    is generally lower in unselected population   based samples   compared  to hospital  referred  patients.