Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: Variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV‐2c/KM19 B haplotype

Abstract

We have reinvestigated a classification of clinical heterogeneity among cystic fibrosis (CF) patients that we previously reported and investigated the possible relationship of the identified CF subgroups to haplotypes around the CF gene and to HLA-DR haplotypes. Age-corrected values for sweat electrolytes, rate of progression of lung disease as assessed by Brasfield chest x-ray scores, and severity of pancreatic insufficiency as assessed by daily supplemented enzyme dosage were obtained for 55, 59, and 59 patients, respectively. XV-2c and KM19 RFLPs were determined by hybridization to TaqI and PstI digests of human genomic DNA, respectively, and analysis of mutations by PCR amplification followed by allele-specific oligo-deoxynucleotide hybridization was performed for 29 patients. HLA-DR restriction fragment length polymorphisms (RFLPs) were determined by hybridization of cDNA beta 1 and genomic DQ alpha probes to TaqI digests of human genomic DNA. The results show that the previous subdivision on the basis of age-corrected levels of sweat electrolytes, as well as measures of severity of lung disease and pancreatic disease, is valid. In addition, the C and D haplotypes are associated with lower age-corrected sweat sodium level. No significant relationship between CF haplotypes and the other two disease variables or between HLA-DR haplotypes and any of the clinical variables was found.

HLA frequencies and associations in cystic fibrosis

“…We undertook these investigations recognizing that the CFTR gene and the HLA complex are on different chromosomes. While the limited number of previous investigations found no evidence to suggest a relation of the CF gene to the HLA class complex , a study in France found that several HLA variants, such as HLA‐DR7, HLA‐DR4 and HLA‐DQA*02:01 , are more frequent in CF patients when compared with population controls . The data in this study, with a substantial sample size, confirm the general conclusion as no significant differences were found in HLA allele frequencies and SNP epitope counts between CF patients and the control population.…”

“…There have been several attempts to check if the CFTR mutation segregates with specific HLA antigen types (4)(5)(6)(7)(8)(9)(10). In a large cohort of CF patients, Duthie et al showed that the frequencies of HLA class I antigens were similar in CF patients when compared with healthy controls (11).…”

Blood Pressure and the Cystic Fibrosis Gene

“…A lower incidence of stroke and heart disease might be the explanation. The B haplotype has been more closely associated with actual levels of sweat sodium and chloride than specific CFTR mutations, including ⌬F508 in CF patients, 28 and it is possible that there are genes just outside the CFTR gene but in strong linkage equilibrium with it, which are as important in regulating sweat electrolytes as is CFTR.…”

A potential animal model for studying CF heterozygote advantage: Genetic variation in theophylline-inducible colonic chloride currents among inbred strains of mice

“…It has been hypothesized that such a defect might be advantageous in the presence of diarrhea-producing bacterial toxins (24) thus explaining the high frequency of the CF gene. The genetic variation in theophylline-inducible CF transport which we have found among inbred strains may be of the order to be expected between AF508 heterozygotes (AF508 is the most common mutant and is correlated with variability in sweat electrolyte levels (25)) and normal homozygotes. As such, it may be useful for studies on heterozygote selection.…”