Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone.

CYP11A, the gene encoding p450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies.

Prevalence of polycystic ovaries in women with androgenic alopecia.

OBJECTIVE: Although androgenic alopecia is recognised to be a symptom of polycystic ovary syndrome (PCOS), it is not known whether polycystic ovaries (PCO) and associated endocrine abnormalities are present in patients who present with alopecia as a primary complaint. We therefore set out to determine the strength of the association between androgenic alopecia and PCO. We examined the prevalence of ultrasound-based polycystic ovarian morphology and associated clinical and biochemical features in a large multiethnic group of women whose presenting complaint was of alopecia, and in a control group. SUBJECTS AND METHODS: We studied 89 women of mixed ethnic origin with androgenic alopecia and compared them to 73 control women. A detailed history was taken, anthropometry was performed and assessment of body-hair distribution was made. The presence of PCO was established by pelvic ultrasound scan. Serum gonadotrophins, testosterone, androstenedione, dihydrotestosterone and sex hormone binding globulin concentrations were measured. RESULTS: Women with alopecia had a higher prevalence of PCO and hirsutism than the control population (PCO: 67% vs 27%, P<0.00001; hirsutism: 21% vs 4%, P=0.003). Women with alopecia (with or without PCO) had higher testosterone, androstenedione and free androgen index than controls, even though few had frankly abnormal androgens. CONCLUSIONS: These findings confirm an association between androgenic alopecia and PCO, and other symptoms of hyperandrogenaemia. Thus most women who present with androgenic alopecia as their primary complaint also have PCO and have indices of abnormal androgen production. Since PCO is a well known risk factor for development of type 2 diabetes, this association has important implications for long-term management.

Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome.

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.