locus that is implicated in the rare recessively inherited disease ataxia-telangiectasia (A-T) has attracted attention following the report of a threefold increased risk in heterozygotes from linkage analyses in families containing A-T sufferers [9
]. Several studies have since screened A-T cases for protein-truncating and other mutations in the gene (eg [10
]) without finding supporting evidence. However, only large, well-conducted population-based studies have the statistical power and credibility to resolve the issue, and those of even several hundred cases and control individuals have little chance of detecting such rare, modest risks [11
]. Interest is now shifting to mis-sense mutations [12
] - clearly the jury is still out.
Common polymorphisms in other 'candidate' genes, chosen for their presumed role in aetiological pathways, have been examined without much success to date [13
]. Based on epidemiological evidence, genes that are involved in the metabolism of oestrogen would seem a logical place to start. Initially there was evidence that a TtoC variant in the CYP17
gene (allele frequency about 0.4) played a role in serum oestrogen and progesterone levels [14
], and was associated with an increased risk of advanced disease [15
]. Subsequent case-control and cohort studies [13
] failed to support this as a genetic risk factor. Tantalizing new evidence that women with two copies of this allele may have a twofold to fourfold increased risk of early-onset disease [16
] demands further study.
A common polymorphism in BRCA2
with an allele frequency of about 0.25 may be associated with a 1.4- to 1.5-fold recessively inherited risk of the disease [18
] (Spurdle AB, et al
, unpublished data). The roles of such common polymorphisms are worthy of study because, in terms of attributable risk and explaining familial aggregation on a population basis, they could be more important than the rare high-penetrance mutations in genes such as BRCA1
, or even BRCAX
. For example, a twofold risk carried by 20% of the population explains 20 out of 120 (17%) cases, whereas a 20-fold risk carried by 0.5% explains just 9.5 out of 109.5 (9%) cases.