Abstract
Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed.
Highlights
Familial aggregation and twin studies have established a genetic etiology for polycystic ovary syndrome (PCOS) [1]
Legro [13], 16 PCOS subjects and 2 healthy controls recruited at Cedars-Sinai Medical Center using the same criteria as those used in the discovery cohort; and 233 white control women derived from the Cholesterol and Atherosclerosis Pharmacogenetics (CAP) study, a component of the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) Study [14]
In an attempt to circumnavigate arbitrary bias introduced in the selection of candidate genes for PCOS, we evaluated mRNA and protein expression data reported from several PCOS tissues in order to identify novel susceptibility genes, dickkopf homolog 1 (DKK1) and DNAJB1
Summary
Familial aggregation and twin studies have established a genetic etiology for polycystic ovary syndrome (PCOS) [1]. DNAJB1 was selected as a positional and functional candidate It acts in concert with molecular chaperones to regulate protein folding, protein complex assembly and disassembly, and transport of proteins across cellular membranes, in the androgen signaling pathway, and is under transcriptional regulation by insulin [9]. It is located within the chromosome 19p13.2 linkage region that has been identified in PCOS susceptibility [10], implicating DNAJB1 as a potential positional candidate. A SNP in DNABJ1 was associated with a measure of insulin resistance in women with PCOS in both cohorts
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