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A Trans-acting Factor May Modify Age at Onset in Familial Amyloid Polyneuropathy ATTRV30M in Portugal
Miguel Alves-Ferreira1,2, Teresa Coelho3, Diana Santos1,2
1UnIGENe, IBMC-Institute for Molecular and Cell Biology; Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135, Porto, Portugal.
Abstract:
Although all familial amyloid polyneuropathy (FAP) ATTRV30M patients carry the same causative mutation, early (<40) and late-onset forms (≥50 years) of FAP may coexist in the same family. However, this variability in age at onset is still unexplained. To identify modifiers closely linked to the TTR locus that may in part be associated with age at onset of FAP ATTRV30M, in particular in a group of very early-onset patients (≤30 years) when compared with late-onset individuals. A clinical genetic study at a referral center comprising a sample of 910 Portuguese individuals includes 589 Val30Met carriers, 102 spouses, and 189 controls from the general population. Haplotype analysis was performed, using eight intragenic single nucleotide polymorphisms (SNPs) at the TTR locus. We compared haplotypes frequency in FAP samples and controls and in parent-offspring pairs using appropriated statistical analysis. Haplotype A was the most common in the general population. Noteworthy, haplotype C was more frequent in early-onset (<40) than in late-onset patients (≥50 years) (p = 0.012). When comparing allelic frequencies of each SNP within haplotype C between "very early" (≤30 years) and late-onset (≥50 years) cases, the A allele of rs72922947 was associated with an earlier onset (p = 0.009); this remained significant after a permutation-based correction. Also, the heterozygous genotype (GA) for this SNP was associated with a decrease in mean age at onset of 8.6 years (p = 0.014). We found a more common haplotype (A) linked to the Val30Met variant and a possible modulatory trans effect on age at onset. These findings may lead to potential therapeutical targets.
Insights
Genetic variations near the TTR gene influence the age of onset for familial amyloid polyneuropathy (FAP) ATTRV30M. Specific TTR haplotypes and SNPs may explain why some FAP patients develop symptoms much earlier than others.
Area of Science:
- Genetics
- Neurology
- Medical Research
Background:
- Familial amyloid polyneuropathy (FAP) ATTRV30M is caused by a specific mutation, yet age of onset varies significantly, even within families.
- This variability in age at onset for FAP ATTRV30M remains unexplained, highlighting a need to identify genetic modifiers.
- Understanding these modifiers is crucial for predicting disease progression and developing targeted therapies.
Purpose of the Study:
- To identify genetic modifiers closely linked to the TTR locus that influence the age of onset in FAP ATTRV30M patients.
- To specifically compare genetic factors associated with very early-onset (≤30 years) versus late-onset (≥50 years) FAP ATTRV30M.
Main Methods:
- A clinical genetic study involving 910 Portuguese individuals, including 589 Val30Met carriers, spouses, and general population controls.
- Haplotype analysis was conducted using eight intragenic single nucleotide polymorphisms (SNPs) at the TTR locus.
- Statistical analysis compared haplotype frequencies between FAP patients and controls, and between parent-offspring pairs, focusing on age at onset differences.
Main Results:
- Haplotype C was found to be significantly more frequent in early-onset (<40 years) FAP patients compared to late-onset (≥50 years) patients (p=0.012).
- Within haplotype C, the 'A' allele of SNP rs72922947 was associated with an earlier age of onset (p=0.009), a finding robust to permutation-based correction.
- Carrying the heterozygous genotype (GA) for rs72922947 was linked to an average decrease of 8.6 years in the age of onset (p=0.014).
Conclusions:
- A common haplotype (A) linked to the Val30Met variant may modulate the age of onset in FAP ATTRV30M.
- The SNP rs72922947 within haplotype C appears to be a significant genetic factor influencing early disease manifestation.
- These findings suggest potential therapeutic targets for modifying FAP ATTRV30M onset and progression.
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