Background/Purpose:
Structural foot disorders, such as hallux valgus, deformities of the lesser toes (toes 2-5) and plantar soft-tissue atrophy, commonly affect ~ 60% of older adults at the population level and are often linked with foot pain, chronic mobility limitations, and disability. Although, body weight and other environmental factors are considered possible causes of these foot conditions, the importance of genetics is commonly suspected in clinical observations of family aggregation. Previously, we reported strong heritability (h2) for lesser-toe deformity (61% in men; 85% in women) and moderate h2 for hallux valgus (~35%) and plantar soft-tissue atrophy (~20%) in older men and women, suggesting potential genetic predisposition to structural foot disorders. To identify their genetic determinants, we have undertaken a GWAS using 2.5M imputed SNPs (HapMapII CEU reference panel) to localize susceptible genes in the population-based Framingham Foot Study.
Methods:
Structural foot disorders were indicated as present or absent and were assessed based on an atlas of pictorial depictions. Plantar soft tissue atrophy was determined by palpating the plantar fat pad at the forefoot and heel during a validated foot examination. Among 2,446 Framingham participants (mean age 66 yrs; 57% women; Caucasian), we identified 753 (31%), 764 (31%) and 665 (27%) participants with deformities of the lesser-toes, hallux valgus and plantar soft-tissue atrophy, respectively. A mixed-effect regression model was performed and adjusted for age, sex, weight and principal components of ancestral genetic background. A kinship covariance matrix was used to take into account within-family correlations among siblings. We filtered out SNPs with low imputation quality (O/E variance ratio of allele frequency < 0.3) and SNPs with MAF < 1%. In addition, p-values were also adjusted for λGC.
Results:
We found several associations achieved genome-wide significance (p < 5x10-8), i.e. SNPs on TBC1D22A and OR5D13 gene for lesser-toe deformity. For hallux valgus, the most significant SNP (p=4.9×10-7) is located in GATAD2B gene. For plantar soft-tissue atrophy, the most significant SNP (p=4.76×10-7) is located near ADAMTS16 gene. Pathway and gene-set analyses for the genome-wide significant and suggestive genes suggested significant clustering of genes involved in connective tissue disorders (such as oligoarticular arthritis, osteoarthritis and osteosclerosis). Of note, a few SNPs were reported to associate with longevity. These results are undergoing replication in independent samples.
Conclusion:
In conclusion, our results identify novel candidate genes to further elucidate the etiology of structural foot disorders.
Disclosure:
M. T. Hannan,
None;
Y. H. Hsu,
None;
C. H. Cheng,
None;
Y. Liu,
None;
J. M. Jordan,
Algynomics, Inc. ,
1,
Johnson and Johnson,
5,
Johnson & Johnson,
2,
Interleukin Genetics, Inc. ,
5,
Eli Lilly and Company,
5,
Mutual Pharmaceutical Company,
5.
ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-candidate-genes-for-structural-foot-disorders-a-genome-wide-association-study-in-an-older-caucasian-population/