Table 1.
Frequency of non-synonymous missense PRLR variants in prolactinoma patients
| Prolactinoma patients | ExAc a | OBB b | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PRLR Variant | L + T (n = 46 patients) c | L (n = 35 samples) d | T (n = 15 samples) e | n = 60 706 | n = 7045 | ||||||
| Number (MAF) f | Fisher’s exact test | Number (MAF) | Fisher’s exact test | Number (MAF) | Fisher’s exact test | Number (MAF) | Number (MAF) | ||||
| ExAc | OBB | ExAc | OBB | ExAc | OBB | ||||||
| Gly57Ser | 1 (0.01) |
NS | NS | 1 (0.02) |
NS | NS | 1 (0.04) |
0.022 | 0.025 | 14 (0.0001) |
1 (0.00005) |
| Ile76Val | 7 (0.08) |
NS | NS | 7 (0.10) |
NS | 0.02 | 0 (0) |
NS | NS | 5274 (0.04) |
411 (0.03) |
| Ile146Leu | 7 (0.08) |
NS | 0.01 | 7 (0.10) |
0.0018 | NS | 0 (0) |
NS | NS | 2305 (0.02) |
412 (0.03) |
| Glu376Gln | 9 (0.10) |
<0.0001 | <0.0001 | 6 (0.09) |
<0.0001 | <0.0001 | 6 (0.2) |
<0.0001 | <0.0001 | 108 (0.0009) |
28 (0.002) |
| Arg453Trp | 4 (0.04) |
<0.0001 | N/A | 2 (0.03) |
<0.0001 | N/A | 2 (0.07) |
<0.0001 | N/A | 0 (0) |
- (-) |
| Asn492Ile | 9 (0.10) |
<0.0001 | <0.0001 | 6 (0.09) |
<0.0001 | <0.0001 | 6 (0.2) |
<0.0001 | <0.0001 | 106 (0.0009) |
28 (0.002) |
aExAc contains DNA sequence data from 60 706 individuals, without known pituitary tumors, and thus provides a useful reference set of control allele frequencies for this study. bOBB cohort (31) consists of an age-stratified random sample of 7045 healthy men and non-pregnant women (aged 30–50 years of European origin), thereby representing a population of similar ethnicity to prolactinoma patients within this study. Statistical analyses were performed by Fisher’s exact test. cIn the prolactinoma cohort of 46 patients, the occurrences of the PRLR ICD rare variants Glu376Gln and Asn492Ile were significantly greater than in the ExAc and OBB cohorts (Fig 1); and the PRLR ICD rare variant Arg453Trp, which was not available (N/A) on the OBB exome chip, was also significantly greater than in the ExAc cohort; while the PRLR ECD low-frequency variant Ile146Leu had a greater occurrence only when compared to the OBB cohort. The samples from the 46 patients consisted of leucocyte (L) DNA samples from 35 patients and 11 tumor (T) (prolactinoma) samples from unrelated patients. The associations between prolactinomas and the PRLR ICD variants remained significant in subanalyses of d35 leucocyte DNA samples from 31 patients from whom only leucocyte DNA was available, and 4 patients from whom both leucocyte and tumor DNA were available; and e15 tumor (prolactinoma) DNA samples from unrelated patients (representing 11 patients for whom only tumor DNA was available, and 4 patients for whom both leucocyte and tumor DNA were available). fMAF for rare, low-frequency and common variants is defined as <1%, 1–5% and >5%, respectively (30). NS, not significant.