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ZFAT gene variant association with multiple sclerosis in the Arabian Gulf population: A genetic basis for gender-associated susceptibility.

ABSTRACT: Single nucleotide polymorphisms (SNPs) are useful genetic markers to investigate the onset of multiple sclerosis (MS). A genome wide association study identified 7 SNPs associated with interferon?? therapy response, however, not with MS risk in a Spanish population. To investigate these findings in a different cohort, the 7 SNPs were investigated in an Arabian Gulf population. The SNPs were analyzed in 268 subjects (156 patients and 112 healthy volunteers) from the Arabian Gulf region using restriction fragment length polymorphism-polymerase chain reaction (PCR) and KBioscience Competitive Allele Specific PCR genotyping methods. Associations between the SNPs and MS were investigated using logistic regression. The present study observed, for the first time, that in an Arabian Gulf population, the ZFAT rs733254 polymorphism (T>G) is a gender?specific risk marker for MS. ZFAT was associated with MS in women but not in men. The G variant was highly associated with the risk of MS [odds ratio (OR)=2.38 and 95% confidence interval (CI), 1.45?3.91); P=0.0014]. Whereas variant T was a significantly protective factor [OR=0.420 (95% CI, 0.25?0.69); P=0.0014, recessive model]. The findings of the present study provide a genetic basis for the gender?associated susceptibility to MS. In addition, this MS-associated rs733254 SNP may predict MS onset in females from the Arabian Gulf population.

SUBMITTER: Bourguiba-Hachemi S

PROVIDER: S-EPMC5042798 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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ZFAT gene variant association with multiple sclerosis in the Arabian Gulf population: A genetic basis for gender-associated susceptibility.

Bourguiba-Hachemi Sonia S Ashkanani Tebah K TK Kadhem Fatema J FJ Almawi Wassim Y WY Alroughani Raed R Fathallah M Dahmani MD

Molecular medicine reports 20160830 4

Single nucleotide polymorphisms (SNPs) are useful genetic markers to investigate the onset of multiple sclerosis (MS). A genome wide association study identified 7 SNPs associated with interferon‑β therapy response, however, not with MS risk in a Spanish population. To investigate these findings in a different cohort, the 7 SNPs were investigated in an Arabian Gulf population. The SNPs were analyzed in 268 subjects (156 patients and 112 healthy volunteers) from the Arabian Gulf region using rest ...[more]

PMID: 27572828

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Project description:BACKGROUND: MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors. METHODS: A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America. RESULTS: For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ? 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely. CONCLUSIONS: The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (? 5.2%) are even susceptible to getting MS.

Dataset Information

ZFAT gene variant association with multiple sclerosis in the Arabian Gulf population: A genetic basis for gender-associated susceptibility.

Publications

ZFAT gene variant association with multiple sclerosis in the Arabian Gulf population: A genetic basis for gender-associated susceptibility.

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