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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

Objective

To estimate the heritability of 3 common disorders affecting the forefoot, i.e., hallux valgus, lesser toe deformities, and plantar forefoot soft tissue atrophy, in white adult men and women.

Methods

Between 2002 and 2008, a trained examiner used a validated foot examination to document the presence of hallux valgus, lesser toe deformities, and plantar soft tissue atrophy in 2,446 adults from the Framingham Foot Study. Among these, 1,370 participants with an available pedigree structure were included. Heritability was estimated using pedigree structures by the Sequential Oligogenic Linkage Analysis Routines package. Results were adjusted for age, sex, and body mass index.

Results

The mean age of the participants was 66 years (range 39–99 years) and 57% were women. The prevalence of hallux valgus, lesser toe deformities, and plantar soft tissue atrophy was 31%, 29.6%, and 28.4%, respectively. Significant heritability was found for hallux valgus (range 0.29–0.89, depending on age and sex) and lesser toe deformity (range 0.49–0.90, depending on age and sex). The heritability for lesser toe deformity in men and women ages >70 years was 0.65 (P = 9 × 10−7). Significant heritability was found for plantar soft tissue atrophy in men and women ages >70 years (H2 = 0.37, P = 3.8 × 10−3).

Conclusion

To our knowledge, these are the first findings of heritability of foot disorders in humans, and they confirm the widely-held view that hallux valgus and lesser toe deformities are highly heritable in white men and women of European descent, underscoring the importance of future work to identify genetic determinants of the underlying genetic susceptibility to these common foot disorders.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

Structural foot disorders affect up to 60% of community-dwelling older adults ([1, 2]) and are associated with mobility limitations ([3, 4]) and decreased health-related quality of life ([5]). Previous studies have identified female sex, older age, and higher body mass index (BMI) as risk factors for foot disorders ([5, 6]). However, there is little knowledge of the role played by genetic variations. The importance of genetics is commonly suspected in clinical observations that individuals with foot disorders tend to have other affected family members ([7-13]). These studies estimated that a family history of hallux valgus was present in 63–90% of patients. To our knowledge, no study has yet estimated the heritability of foot disorders. In addition, no linkage, candidate gene association, or genome-wide association studies on foot disorders have been performed.

Hallux valgus is one of the most common foot disorders, affecting approximately 23% of people ages 18–65 years and 36% of those ages >65 years ([14]). The condition is characterized by the progressive subluxation of the first metatarsophalangeal joint due to lateral deviation of the hallux and medial deviation of the first metatarsal head. The etiology of hallux valgus is not well understood. Several factors have been implicated, including ill-fitting footwear, sex, structural factors, biomechanical factors ([15]), and family history ([7-10]). Piqué-Vidal et al ([10]) constructed pedigree charts from 350 patients across 3 generations and found that family history was positive in 90% of cases, with vertical transmission affecting some families across all 3 generations.

Deformities of the lesser toes (i.e., potentially all but hallux) affect between 24% and 60% of older people ([1, 16-18]). There are several different types of lesser toe deformities, which are classified according to the relative alignment of the metatarsophalangeal and interphalangeal joints. A hammer toe is a deformity in which the proximal interphalangeal joint is plantarflexed and the metatarsophalangeal joint may be hyperextended. A mallet toe is a fixed deformity in which the distal interphalangeal joint is plantarflexed. A claw toe is a deformity in which the metatarsophalangeal joint is hyperextended and both the proximal and distal interphalangeal joints are plantarflexed ([19, 20]). The Feet First Study of 784 Americans ages >65 years found that 35% of the sample had hammer toes, 33% had mallet toes, and 9% had claw toes ([1]). Factors considered to be associated with the development of lesser toe deformities include ill-fitting footwear ([19, 21, 22]), abnormal foot posture (both pes planus [23] and pes cavus [24]), and excessively long toes ([25]). Lesser toe deformities are also considered to have a hereditary basis in mutant mouse models ([26]), which narrowed down to a genomic region near the D5Mit387 marker on mouse chromosome 5.

Many individuals with hallux valgus and/or lesser toe deformity also develop atrophy of the plantar soft tissues under the metatarsal heads ([27]). However, whether this is also a heritable component of each of these conditions is unclear, since degeneration of plantar soft tissues is also associated with aging and conditions such as rheumatoid arthritis, peripheral vascular disease, and diabetic neuropathy ([28-30]). Determining which aspects of these common forefoot disorders are heritable would improve our understanding of their underlying pathophysiology and assist in identifying high-risk individuals for early intervention. Therefore, the aim of this study was to examine the overall heritability (adjusting for age, sex, and BMI) as well as the age- and sex-adjusted heritability of hallux valgus, lesser toe deformities, and plantar forefoot soft tissue atrophy in white adult men and women from the Framingham Foot Study families.

Box 1. Significance & Innovations

  • To our knowledge, no study has yet estimated the heritability of foot disorders. Therefore, these are the first findings of heritability of foot disorders in humans.
  • Hallux valgus and lesser toe deformities, two types of common structural foot disorders in older adults, were highly heritable in a white adult population (n = 1,370), suggesting genetic predisposition.
  • This study reveals new findings in an area that has received little attention, yet is critically important to general populations. Identifying those genetic determinants linked to the risk of developing hallux valgus and lesser toe deformities can further our understanding of the etiology and biologic mechanisms underlying these foot disorders, with an eye toward early prevention.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

Study population

The Framingham Foot Study (n = 2,446 participants examined in 2002–2008) was designed to examine common foot disorders and functional limitations. A trained examiner used a validated foot examination to assess specific foot disorders in 1,076 male and 1,370 female participants ([31]). The structural foot disorders (hallux valgus, lesser toe deformities, and plantar forefoot soft tissue atrophy) were assessed in the Framingham participants. Disorders were indicated as present or absent based on an atlas of pictorial depictions of each foot disorder. Presence of hallux valgus (yes/no) was evaluated based upon visual inspection and considered to be present if there was a medial bony enlargement of the first metatarsal head and if the weight-bearing angle of the hallux toward the lesser toes was observed to be >15°. For this study, lesser toe deformities included hammer toes, claw toes, and overlapping toes. Hammer toes (yes/no) were considered present if the second, third, fourth, or fifth toes appeared contracted at one or both joints while weight bearing. Claw toes (yes/no) were similarly assessed and present when both joints were contracted or clenched while weight bearing. Overlapping toes were considered present when any toe was observed to be at least 50% on top of an adjacent toe. Plantar forefoot soft tissue atrophy was determined by standardized palpatory clinical examination (with the examiner calibrated to 3 pounds of palpatory pressure against a dolorimeter) of the bony prominence of the metatarsal heads and the surrounding soft tissues. Possible confounders that we used as covariates in our analyses consisted of age, sex, and BMI. Age at examination was recorded. Weight in pounds was measured using a standardized balance beam scale and recorded to the nearest one-half pound. Height (without shoes) was measured in inches using a calibrated stadiometer and recorded to the nearest one-quarter inch. BMI was calculated as weight in kilograms divided by height in square meters. The study participants have given informed consent for the data collection and this study has undergone institutional review by both the Hebrew SeniorLife Institutional Review Board and the Boston University Medical Center Institutional Review Board.

Statistical analysis

Among examined individuals, 1,370 participants (from 429 families with family sizes that ranged from 2 examined individuals to 22 examined individuals) with an available pedigree structure were included in the statistical analysis for heritability estimation. Briefly, pedigree structure is a family tree that shows the relationship among each family member within a family. The parent–offspring and offspring–offspring (siblings) relationships were used in our study to estimate heritability. When the parents' information about foot disorders was unknown, only offspring–offspring relationships were used. All of the relationship pairs in our study had their foot phenotype measured.

Heritability is the proportion of total variation between individuals in pedigrees in a given population attributable to genetic variation ([32]). This narrow-sense heritability is defined as a ratio of variances, i.e., the proportion of total variance in a population for a particular measurement (phenotype) that is attributable to variation in additive genetic or total genetic effects. Heritability can range from 0 (no genetic contribution; the phenotype is not heritable) to 1 (all differences on a trait reflect genetic variation; the phenotype is highly heritable). As benchmarks for heritability in the adult human population, one may consider adult height, which ranges from 0.68–0.93, depending on sex, age, geographic locations, and populations ([33]). The heritability of BMI in a white population is estimated at 0.44 ([34]), whereas the heritability was estimated at 0.26 for type 2 diabetes mellitus in white populations ([35]). Our estimates of heritability were obtained from a standard quantitative genetic variance components model implemented in the Sequential Oligogenic Linkage Analysis Routines package. A liability threshold model was applied for dichotomous traits in the current study ([36]). Briefly, in order to estimate the variance of a dichotomous trait (all-or-none disease status) that is due to additive genetic effects, one assumes an underlying normally-distributed liability phenotype, which is the sum of the independent normally-distributed genetic and environmental components. The assumption indicates that the liability to disease is multifactorial and the contributions from each genetic risk factor are small. When the score on the scale of the liability distribution exceeds a specific threshold, then the individual has a disease value of 1, and otherwise it is 0. The proportion that exceeds the threshold of the underlying liability distribution is equal to the disease incidence.

Due to the small sample size in each of the age- and sex-specific strata, for statistical analyses, we pooled individuals ages ≤60 years together and we also grouped individuals ages >70 years, so that we had similar sample sizes across the 3 age groups. We estimated overall sex- and age-specific (≤60, 61–70, and >70 years) heritability values for hallux valgus, lesser toe deformities, and plantar forefoot soft tissue atrophy. Overall, heritability estimates were adjusted for age, sex, and BMI.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

The mean age of the participants was 66 years (range 39–99 years). Among the participants, 57% were women. The prevalence of hallux valgus, lesser toe deformities, and plantar soft tissue atrophy was 31%, 29.6%, and 28.4%, respectively. Table 1 reports the age- and sex-specific prevalence of hallux valgus, lesser toe deformity, and plantar soft tissue atrophy. The prevalence of hallux valgus and plantar soft tissue atrophy was higher in women compared to the prevalence in men across the age groups. However, compared to men, the prevalence of lesser toe deformities was higher only in women ages >70 years. Increased prevalence of these 3 foot disorders was found in older age groups for both men and women. Almost half of the women ages >70 years had hallux valgus, lesser toe deformity, and/or plantar soft tissue atrophy.

Table 1. Prevalence of hallux valgus, lesser toe deformity, and plantar soft tissue atrophy by age and sex in Framingham Foot Study participants*
 Age 39–50 yearsAge 51–60 yearsAge 61–70 yearsAge 71–80 yearsAge 81–90 yearsAge 91–100 years
  1. Values are the number (percentage) unless otherwise indicated.

Men, no.4324841423412413
Hallux valgus7 (16)45 (18)75 (18)51 (22)29 (23)5 (38)
Lesser toe deformity6 (14)39 (16)121 (29)71 (30)66 (53)6 (46)
Plantar soft tissue atrophy0 (0)11 (4)70 (17)95 (41)65 (52)9 (69)
Women, no.4635444429120530
Hallux valgus14 (30)113 (32)162 (36)127 (44)120 (59)16 (53)
Lesser toe deformity7 (15)55 (16)116 (26)128 (44)118 (58)20 (67)
Plantar soft tissue atrophy0 (0)21 (6)101 (23)145 (50)132 (64)16 (53)

Due to the small sample size in each of the age- and sex-specific strata seen in Table 1, we pooled individuals ages ≤60 years together and we also pooled individuals ages >70 years, so that we had similar sample sizes across the 3 age groups. The numbers of parent–offspring pairs, same-sex sibling pairs, and same-sex half-sibling pairs among our study participants within each sex- and age-specific stratum used in analyses are shown in Table 2. There were 248 parent–offspring pairs, 296 same-sex sibling pairs, and 5 same-sex half-sibling pairs. All 3 types of informative family relationships (parent–offspring, siblings, and half-siblings) were used to estimate the heritability. The total numbers of informative family relationship pairs were 134, 72, and 35 pairs for men in the age ≤60, 61–70, and ≥71 years groups, respectively, and 154, 84, and 70 pairs for women in the age ≤60, 61–70, and ≥71 years groups, respectively. The number of these informative family relationship pairs, especially the parent–offspring pairs, decreased in the older age groups, which affected the statistical power of the heritability estimation.

Table 2. Number of informative family relationship pairs in Framingham Foot Study participants
 MenWomen
Age 39–60 yearsAge 61–70 yearsAge 71–100 yearsAge 39–60 yearsAge 61–70 yearsAge 71–100 yearsTotal
Parent–offspring7736388422248
Same-sex siblings543632664167296
Same-sex half-siblings3000115
All13472351548470549

Table 3 reports the heritability, SE of the heritability, and P values of hallux valgus, lesser toe deformity, and plantar soft tissue atrophy using the 1,370 study participants in the heritability analyses. The overall age-, sex-, and BMI-adjusted heritability of hallux valgus was 0.29 (P = 3.9 × 10−3, H2 = 0.39 for women and 0.36 for men). The highest heritability was observed in women ages ≤60 years (H2 = 0.89, P = 3.2 × 10−3). Due to the smaller sample size, we could not estimate the heritability of hallux valgus for men in the age 71–100 years group due to lack of informative family relationships. In addition, the heritability value for hallux valgus in men did not reach statistical significance.

Table 3. Heritability of hallux valgus, lesser toe deformity, and plantar soft tissue atrophy overall and stratified by age and sex in Framingham Foot Study participants*
 Men and womenMenWomen
AllAge 39–60 yearsAge 61–70 yearsAge 71–100 yearsAllAge 39–60 yearsAge 61–70 yearsAge 71–100 yearsAllAge 39–60 yearsAge 61–70 yearsAge 71–100 years
  1. Overall heritability estimates were adjusted by age, sex, and body mass index. N/A = insufficient informative families available to estimate heritability.

Hallux valgus       
H20.290.450.150.380.360.840.28N/A0.390.890.310.39
SE0.2480.1950.2790.3450.2520.7500.417N/A0.1220.2020.2530.231
P3.9 × 10−33.7 × 10−32.1 × 10−18.0 × 10−31.2 × 10−12.0 × 10−12.9 × 10−1N/A9.0 × 10−33.2 × 10−41.6 × 10−14.0 × 10−2
Lesser toe deformity       
H20.560.560.490.650.610.660.640.900.850.600.690.80
SE0.1070.0270.2920.1161.1670.4810.3610.3280.2071.1801.1070.199
P4.0 × 10−75.2 × 10−34.5 × 10−39.0 × 10−76.8 × 10−36.0 × 10−24.0 × 10−24.5 × 10−32.3 × 10−58.0 × 10−21.0 × 10−31.4 × 10−4
Plantar soft tissue atrophy       
H20.090.730.190.370.240.550.620.640.210.900.110.43
SE0.1480.3290.1610.3020.3211.8500.3950.2050.2290.4780.580.381
P2.5 × 10−16.0 × 10−22.0 × 10−13.8 × 10−32.2 × 10−14.2 × 10−11.0 × 10−11.8 × 10−21.7 × 10−14.6 × 10−24.2 × 10−12.8 × 10−2

The age-, sex-, and BMI-adjusted heritability of lesser toe deformities was 0.56 (P = 4 × 10−7, H2 = 0.85 for women and 0.61 for men). The highest heritability of lesser toe deformities was observed in the >70 years age group (H2 = 0.90, P = 4.5 × 10−3 for men and H2 = 0.80, P = 1.4 × 10−4 for women when examined by sex). The age-, sex-, and BMI-adjusted heritability of plantar soft tissue atrophy was 0.09 (nonsignificant P = 2.5 × 10−1). Significant heritability was found for plantar soft tissue atrophy only in men and women ages >70 years (H2 = 0.37, P = 3.8 × 10−3).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

In the Framingham Foot Study, we found samples of European ancestry indicating that hallux valgus and lesser toe deformities are heritable. To our knowledge, these are the first findings of heritability of these foot disorders in humans. We observed significant moderate to high heritability for hallux valgus (H2 = 0.29–0.89, depending on age and sex) and lesser toe deformity (H2 = 0.49–0.90, depending on age and sex), suggesting that there are genetic variants, common and/or rare, affecting hallux valgus and lesser toe deformity, two of the most common structural foot disorders affecting up to half of older adults in the US and Europe. In contrast, plantar soft tissue atrophy did not demonstrate significant heritability in the same study population. This study reveals new findings in an area that has received little attention, yet is critically important to general populations.

Despite having data from (thus far) the largest study of these foot disorders with family data, we were unable to estimate the distribution of heritability within the specified age groups and we had to pool several age strata for heritability estimation. In addition, we observed several higher heritability estimations, particularly in the younger age group, that were not statistically significant. This may be due to lack of statistical power in some age- and sex-specific strata. The original study sampling was not designed for age- and sex-specific heritability estimation. Even though we attempted to pool samples across age strata, the number of informative family relationship pairs in the older age group is far less than the number of informative family relationship pairs in the age groups of middle-aged participants (Table 2), especially for the parent–offspring pairs, since far fewer parents of the elderly participants were available (i.e., alive) for us to ascertain their foot phenotypes. When we compared our sample size to a previous simulation for statistical power of heritability, we did not have adequate power (70%) when the number of informative family relationship pairs was fewer than 50 pairs ([37]). In addition to the small numbers of informative family relationship pairs, statistical power was also affected by the number of affected participants with foot disorders within each sex and age stratum, affecting our ability to obtain a robust estimation of heritability. This is especially true for those age and sex strata with very high heritability that did not achieve statistical significance. Therefore, additional samples are needed to obtain the robust age-specific heritability of several subsets of the foot disorders considered in our study.

Given that congenital hallux valgus is extremely rare ([38]), our finding that hallux valgus is heritable in adults raises questions as to which anatomic or functional characteristics are inherited that may predispose to the development of the condition in later life. Anatomic factors such as a large first and second intermetatarsal angle, an excessively long first metatarsal head, and a round first metatarsal head have recently been shown to be associated with increased hallux valgus severity in older people, and it has been speculated that these foot structures may be more susceptible to lateral deviation of the hallux and subsequent hallux valgus deformity as a result of footwear compression ([39]). It is also possible that anomalous muscle insertions may predispose to hallux valgus. An analysis of cadaver feet by Gunal et al ([40]) revealed that an abnormal tendinous expansion of the tibialis posterior tendon onto the oblique head of adductor hallucis was present in all feet with hallux valgus and none without. Theoretically, this anatomic variation would provide a mechanical advantage of adductor hallucis over abductor hallucis, thereby pulling the hallux laterally. Similarly, Al-Saggaf ([41]) reported that cadaver feet with hallux valgus were more likely to have accessory tendinous insertions of extensor hallucis longus into the dorsal and medial aspects of the proximal phalanx, which would also promote lateral displacement of the hallux when the first metatarsophalangeal joint dorsiflexes.

The underlying anatomic or functional mechanism responsible for the high heritability of lesser toe deformities is similarly speculative, although it has been suggested that individuals with excessively long toes may be predisposed to subsequent toe deformity due to footwear compression ([25]). Alternatively, it is possible that abnormal foot posture (either pes planus [23] or pes cavus [24]) is also heritable, and that the muscular adaptations that occur over time in these foot types may lead to the development of toe deformity.

Plantar soft tissue atrophy was not significantly heritable in our sample, with the exception of those ages 71–100 years (H2 = 0.37). This result was expected, since although degeneration of plantar soft tissues is frequently observed in people with toe deformities, it is most commonly associated with other systemic conditions such as rheumatoid arthritis, peripheral vascular disease, and diabetic neuropathy ([28-30]). The significant (but modest and age-specific) heritability we observed could simply represent heritability of these comorbidities rather than the association with toe deformities. In addition, plantar soft tissue atrophy was documented from a simple clinical assessment rather than diagnostic ultrasound or magnetic resonance imaging. Therefore, it is likely that some degree of misclassification occurred, particularly in those with retracted toes, where the plantar soft tissues are commonly displaced anteriorly.

To our knowledge, the current study is thus far the largest study to estimate the heritability of 3 common foot disorders in an adult population. Nevertheless, there are limitations that must be acknowledged. As noted above, with our sample size, after stratifying by sex and age, particularly for the younger age groups, we had limited statistical power to estimate heritability either due to small sample size or the lack of available informative families. In addition, the heritability was estimated in a white population of European descent, and the heritability estimation may not be generalizable to other ethnic groups. It would be interesting to know the heritability of these foot disorders in African populations, since the prevalence of hallux valgus and lesser toe deformity is thought to be high in African Americans and their ancestral genetic background is different from the ancestral genetic background of white populations. Also, we evaluated hallux valgus visually as present or absent. Other methods allow quantification of hallux valgus and its severity, such as foot radiographs or the noninvasive Manchester scale for hallux valgus ([42-44]). Another limitation is that we used the age at examination (prevalence), since we did not have information on age at onset of the foot condition (incidence). Although using prevalence data is done in many studies, we may have underestimated heritability in younger age groups, since many study participants certainly already had these foot disorders years before our foot examination. In addition, our narrow-sense heritability estimation only captures the portion of the variance due to additive (allelic) genetic effects, but did not consider potential epistatic (multigenic interactions) effects, which may also underestimate heritability. The heterogeneity of anatomic and mechanical factors of these foot disorders may also affect heritability estimations. Heritability estimates reflect the amount of variation in genotypic effects compared to variation in environmental effects. A better assessment of other environmental risk factors relevant to these foot disorders would also improve the accuracy of heritability estimation.

In conclusion, we observed that hallux valgus and lesser toe deformities, two types of common structural foot disorders in older adults, were highly heritable in a white adult population, suggesting genetic predisposition to the risk of developing hallux valgus and lesser toe deformities. Identifying these genetic determinants can further our understanding of the etiology of and biologic mechanisms underlying hallux valgus and lesser toe deformities, with an eye toward early prevention.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Hannan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Hannan, Hsu.

Acquisition of data. Hannan, Hsu.

Analysis and interpretation of data. Hannan, Menz, Jordan, Cupples, Cheng, Hsu.

Acknowledgments

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

The authors thank the Framingham Foot Study research team and study participants for the contribution of their time, effort, and dedication. We also thank Dr. Virginia Casey and Ms. Gouri Vadali, MS (Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts).

REFERENCES

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  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES
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