POSSIBLE ASSOCIATION OF THE ALLELE STATUS OF THE CS.7 HHAI POLYMORPHISM-5' OF THE CFTR GENE WITH POSTNATAL FEMALE SURVIVAL/

Cystic fibrosis (CF) patients show a high degree of linkage disequilib rium between the CF transmembrane conductance regulator (CFTR) gene an d polymorphisms 5' of that gene. To determine whether the region 5' of CFTR contains biologically important sequences, the allele frequencie s of six CFTR-linked polymorphisms (metH/MspI, XV-2c/TaqI, CS.7/HhaI, KM19/PstI, MP6-d9/MspI, J44/XbaI) were determined in 417 randomly sele cted elderly individuals (over 75 years of age) from the Czech populat ion. The elderly individuals were considered ''escapees'' of strong se lective pressures that had operated during their lifetime, prior to th e introduction of modem health care since 1950. The pooled allele freq uencies of the analyzed marker polymorphisms in the elderly did not si gnificantly differ from published data. However, when analyzed by sex, the allele frequencies of markers CS.7/HhaI and KM19/PstI differed si gnificantly (P < 0.05) between elderly females and males. The allele f requencies of the six polymorphisms were then determined in 646 newbor ns and 345 young adults of reproductive age; these individuals were se lected in a similar manner and drawn from the same population. In thes e control groups, the studied marker polymorphisms exhibited no statis tically significant differences between sexes and/or between individua ls of the same sex, only between different age groups. A gradual relat ive increase in the frequency of allele ''2'' of marker CS.7/HhaI was observed from newborn females to elderly women, the overall difference in allele frequencies of this marker polymorphism between newborn fem ales and elderly women reaching statistical significance (P < 0.05). I nterestingly, allele ''2'' is the major constituent of the extended '' B-haplotype'', which is in strong linkage disequilibrium with common C F alleles. Taken together, our data suggest that the region spanning m arkers CS.7 and KM19 is associated with a genetic factor that influenc es postnatal female survival, providing a possible mechanism for incre asing the frequency of particular mutations in the adjacent CFTR gene.