Monday, 24 August 2020

Candidate genes in PCO(Part II)

 

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.

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