The LD structure at the chromosome 4 locus and the results of the conditional analysis motivated us to explore if the four LD blocks form a haplotype that better captures the observed signal. A tag SNP was chosen for each of the four LD blocks based on two factors. First, we prioritized SNPs on both the Affymetrix and Illumina platforms to facilitate replication. Second, we prioritized SNPs with the fewest missing values in the genotyped data set. Based on model likelihood with phased data (Supplementary Methods, available online), a haplotype was formed using a SNP from each LD block (tag SNPs, rs4323056:A(freq:0.59), rs13114936:G(freq:0.51), rs4402990:C(freq:0.41), rs9999820:G(freq:0.57)) with an adjusted odds ratio of 1.70 (95% confidence interval [CI] = 0.48 to 6.44) for one copy of the haplotype and 23.00 for two copies (95% CI = 6.55 to 98.06), with 16 of 30 cases being homozygous carriers (two copies). This is consistent with a recessive-risk pattern for the haplotype. Frequency of the haplotype is 0.36 in individuals with European ancestry and 0.39 in individuals with African ancestry, corresponding to expected homozygosities of 0.13 and 0.15, respectively (14). Stratification by ancestry yielded results consistent with the combined analysis (Supplementary Methods, available online). Sixty percent of survivors exposed to ovarian RT and homozygous for the haplotype had PM and had the highest PM prevalence (OR = 25.89, 95% CI = 6.18 to 138.31, exact P = 8.2×10-6) (Table 3; Supplementary Methods, available online).
Association of premature menopause prevalence with homozygosity for the risk haplotype, with the counts (No.) of cases and controls, counts (N+) of those who are homozygous for the risk haplotype, and odds ratios, by treatment group in both the discovery and replication cohorts after adjusting for treatment exposures
| Treatment . | SJLIFE (clinically diagnosed PM) . | CCSS (self-reported PM) . | ||||||
|---|---|---|---|---|---|---|---|---|
| No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P* . | No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P† . | |
| Ovarian RT = 0, CED < 8 g/m2 | 2 (1) | 486 (66) | 6.06 (0.28 to 57.62) | .06 | 20 (2) | 993 (165) | 0.52 (0.12 to 2.22) | .38 |
| Ovarian RT = 0, CED ≥ 8 g/m2 | 5 (3) | 194 (26) | 13.27 (2.11 to 85.50) | 9.0×10-3 | 26 (2) | 253 (29) | 0.68 (0.15 to 3.00) | .61 |
| Ovarian RT > 0 | 23 (12) | 89 (8) | 25.89 (6.18 to 138.31) | 8.2×10-6 | 35 (10) | 297 (34) | 3.97 (1.67 to 9.41) | .002 |
| Treatment . | SJLIFE (clinically diagnosed PM) . | CCSS (self-reported PM) . | ||||||
|---|---|---|---|---|---|---|---|---|
| No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P* . | No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P† . | |
| Ovarian RT = 0, CED < 8 g/m2 | 2 (1) | 486 (66) | 6.06 (0.28 to 57.62) | .06 | 20 (2) | 993 (165) | 0.52 (0.12 to 2.22) | .38 |
| Ovarian RT = 0, CED ≥ 8 g/m2 | 5 (3) | 194 (26) | 13.27 (2.11 to 85.50) | 9.0×10-3 | 26 (2) | 253 (29) | 0.68 (0.15 to 3.00) | .61 |
| Ovarian RT > 0 | 23 (12) | 89 (8) | 25.89 (6.18 to 138.31) | 8.2×10-6 | 35 (10) | 297 (34) | 3.97 (1.67 to 9.41) | .002 |
Two-sided P value obtained through the Fisher exact test (see the “Methods”). CCSS = Childhood Cancer Survivor Study; CED = cyclophosphamide equivalent dose; CI = confidence interval; OR = odds ratio; PM = premature menopause; RT = radiotherapy; SJLIFE = St. Jude Lifetime Cohort Study.
Two-sided P value obtained through the Wald test.
Association of premature menopause prevalence with homozygosity for the risk haplotype, with the counts (No.) of cases and controls, counts (N+) of those who are homozygous for the risk haplotype, and odds ratios, by treatment group in both the discovery and replication cohorts after adjusting for treatment exposures
| Treatment . | SJLIFE (clinically diagnosed PM) . | CCSS (self-reported PM) . | ||||||
|---|---|---|---|---|---|---|---|---|
| No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P* . | No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P† . | |
| Ovarian RT = 0, CED < 8 g/m2 | 2 (1) | 486 (66) | 6.06 (0.28 to 57.62) | .06 | 20 (2) | 993 (165) | 0.52 (0.12 to 2.22) | .38 |
| Ovarian RT = 0, CED ≥ 8 g/m2 | 5 (3) | 194 (26) | 13.27 (2.11 to 85.50) | 9.0×10-3 | 26 (2) | 253 (29) | 0.68 (0.15 to 3.00) | .61 |
| Ovarian RT > 0 | 23 (12) | 89 (8) | 25.89 (6.18 to 138.31) | 8.2×10-6 | 35 (10) | 297 (34) | 3.97 (1.67 to 9.41) | .002 |
| Treatment . | SJLIFE (clinically diagnosed PM) . | CCSS (self-reported PM) . | ||||||
|---|---|---|---|---|---|---|---|---|
| No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P* . | No. of cases (No.+) . | No. of controls (No.+) . | OR (95% CI) . | P† . | |
| Ovarian RT = 0, CED < 8 g/m2 | 2 (1) | 486 (66) | 6.06 (0.28 to 57.62) | .06 | 20 (2) | 993 (165) | 0.52 (0.12 to 2.22) | .38 |
| Ovarian RT = 0, CED ≥ 8 g/m2 | 5 (3) | 194 (26) | 13.27 (2.11 to 85.50) | 9.0×10-3 | 26 (2) | 253 (29) | 0.68 (0.15 to 3.00) | .61 |
| Ovarian RT > 0 | 23 (12) | 89 (8) | 25.89 (6.18 to 138.31) | 8.2×10-6 | 35 (10) | 297 (34) | 3.97 (1.67 to 9.41) | .002 |
Two-sided P value obtained through the Fisher exact test (see the “Methods”). CCSS = Childhood Cancer Survivor Study; CED = cyclophosphamide equivalent dose; CI = confidence interval; OR = odds ratio; PM = premature menopause; RT = radiotherapy; SJLIFE = St. Jude Lifetime Cohort Study.
Two-sided P value obtained through the Wald test.
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