The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.

We have used a stepwise approach consisting of initial interrogation, confirmation and fine mapping to analyze STAT3, IL1B and IFNGR1 as modifiers of cystic fibrosis disease building upon the data and sample collection of the European Cystic Fibrosis Twin and Sibling Study. We have observed direct correlation between the length of the intronic microsatellite STAT3Sat to STAT3 expression levels among F508del-CFTR homozygous patients (P=0.0075), and an association of longer STAT3Sat-alleles with the presence of CFTR-mediated residual chloride secretion (P=0.0031), measured as the manifestation of the CF basic defect in intestinal tissue. Both, family-based analysis by TDT and case-reference comparison identified consistently the same intragenic IL1B haplotype as a risk variant (P(raw)=0.055 for TDT, P(raw)<0.3 for case-reference comparison). Using haplotype-guided hierarchical fine mapping, we have identified two single nucleotide exchanges for which concordant and discordant sibling pairs differ at a 7 kb-spanning core haplotype in IFNGR1 (P(raw)=0.0113). Taken together, our findings imply that immunorelevant pathways and ion secretion, dominated by CFTR in intestinal and respiratory epithelium, merge at the level of the epithelial cell to integrate the signaling of cytokines due to innate and acquired immune defense.

The explanation for why some patients develop psychotic change in Alzheimer's disease (AD) is unclear. Psychosis-modifier genes may act in the setting of neurodegeneration to produce AD plus psychosis in a similar way to how genetic modulation during neurodevelopment leads to schizophrenia. Because there is increasing interest in the common disruption of cytokine pathways seen in both AD and schizophrenia, we tested the association between the functional interleukin-1beta -511 promoter polymorphism with delusions and hallucinations in AD. Significant associations between psychotic symptoms and the CC genotype (p = 0.001 - p = 0.043) and C allele (p = 0.014 vs p = 0.048) were found, thus confirming the previously noted increased risk in schizophrenia.

Sickle cell anemia (SCA), a disorder characterized by both acute and chronic inflammation, exhibits substantial phenotypic variability. Interleukin-1 beta (IL-1β) and IL-6 are important in acute and chronic diseases, and their single nucleotide polymorphisms (SNPs) have been considered as predictors of prognosis in several inflammatory conditions. This study aims at exploring possible association of IL-1β and IL-6 SNPs as potential genetic modifiers and or predictors of SCA clinical and laboratory phenotypes. This cross-sectional study involved 107 SCA patients and 110 age, sex and ethnicity-matched healthy individuals. The SNPs were identified by PCR-RFLP for IL-1β (-511C>T and +3954C>T) and IL-6 (-597G>A and -174G>C) genes. Associations between these SNPs and the clinical and laboratory profiles of patients with SCA were then determined. Allelic and genotypic frequencies of IL-1β and IL-6 SNPs between patients with SCA and controls were similar and followed HWE. IL-1β +3954C>T SNP was associated with increased risk of osteonecrosis, elevated pulmonary arterial pressure and lower absolute reticulocyte count, while IL-6 -597G>A was associated with higher likelihood of retinopathy and leg ulcer. These data indicate that IL-1β and IL-6 gene SNPs are associated with SCA complications among Brazilian patients and may act as genetic predictors of SCA clinical heterogeneity.