No Gene Is an Island: The Flip-Flop Phenomenon

Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2007; 80(3):531-8. DOI: 10.1086/512133
Source: PubMed


An increasing number of publications are replicating a previously reported disease-marker association but with the risk allele reversed from the previous report. Do such "flip-flop" associations confirm or refute the previous association findings? We hypothesized that these associations may indeed be confirmations but that multilocus effects and variation in interlocus correlations contribute to this flip-flop phenomenon. We used theoretical modeling to demonstrate that flip-flop associations can occur when the investigated variant is correlated, through interactive effects or linkage disequilibrium, with a causal variant at another locus, and we show how these findings could explain previous reports of flip-flop associations.

    • "homozygous A-carriers vs. GA and GG genotype ). Finally, the so-called flip flop, the phenomena by which both alleles in a biallelic SNP show association as a result of linkage to a nearby, causal polymorphism, might also explain apparently inconsistent findings(Lin et al., 2007). One strength of our study is that we have investigated several SNPs across the LEP and LEPR genes, most of which have not been analyzed for AIWG yet. "

    No preview · Conference Paper · May 2015
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    • "However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, but it only attained borderline statistical significance in females. It is possible that this result could be explained by the presence of a flip-flop mutation [31] or allelic heterogeneity [8]. The rs915942 polymorphism (and others in LD) was found to be associated with asymptomatic malaria in Dogon females. "
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    ABSTRACT: Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.
    Full-text · Article · Jul 2014 · Malaria Journal
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    • "This finding, already described in the literature as “flip-flop phenomenon” where significant associations for the same disease occur at opposite alleles of the same polymorphism, has been observed quite frequently [23]. Some authors hypothesized that this phenomenon can occur due to variation in linkage disequilibrium architecture [23], which is also present within the same ethnic origin [24]; while others explain it through differences in haplotypic frequencies [25]. Whatever the case, it has been proven that the probability of randomly observing a significant allele flip in samples ascertained similarly from a common population is negligible [26]. "
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    ABSTRACT: Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11-1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14-1.53)]. Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.
    Full-text · Article · Mar 2014 · PLoS ONE
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