Dataset Information

Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

ABSTRACT: Hallux valgus (HV) affects ?36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV.HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5?M imputed SNPs. Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327).The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10(-7)); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10(-7)). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10(-9)). The association signals diminished when combining men and women.The findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.

SUBMITTER: Hsu YH

PROVIDER: S-EPMC4864963 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

Hsu Yi-Hsiang YH Liu Youfang Y Hannan Marian T MT Maixner William W Smith Shad B SB Diatchenko Luda L Golightly Yvonne M YM Menz Hylton B HB Kraus Virginia B VB Doherty Michael M Wilson A G AG Jordan Joanne M JM

Journal of medical genetics 20150902 11

<h4>Objective</h4>Hallux valgus (HV) affects ∼36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV.<h4>Methods</h4>HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed SNPs. Mixed-effect regression with the additive genetic m ...[more]

PMID: 26337638

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Project description:BackgroundAlthough the etiology of hallux valgus is contested, in some patients it may be failure of the stabilizing soft tissue structures around the first ray of the foot. Because there is lack of effective soft tissue techniques, osteotomies have become the mainstream surgical approach to compensate for the underlying soft tissue deficiency; osteodesis, a soft tissue nonosteotomy technique, may be a third alternative, but its efficacy is unknown.Questions/purposesWe asked: (1) Can an osteodesis, a distal soft tissue technique, correct hallux valgus satisfactorily in terms of deformity correction and improvement in American Orthopaedic Foot and Ankle Society (AOFAS) score? (2) Is the effectiveness of an osteodesis affected by the patient's age or deformity severity? (3) What complications are associated with this procedure?MethodsBetween February and October 2010, we performed 126 operations to correct hallux valgus, of which 126 (100%) were osteodeses. Sixty-one patients (110 procedures) (87% of the total number of hallux valgus procedures) were available for followup at a minimum of 12 months (mean, 23 months; range, 12-38 months). This group formed our study cohort. During the study period, the general indications for this approach included failed conservative measures for pain relief and metatarsophalangeal angle greater than 20° or intermetatarsal angle greater than 9°. Intermetatarsal cerclage sutures were used to realign the first metatarsal and postoperative fibrosis was induced surgically between the first and second metatarsals to maintain its alignment. The radiologic first intermetatarsal angle, metatarsophalangeal angle, and medial sesamoid position were measured by Hardy and Clapham's methods for deformity and correction evaluation. Clinical results were assessed by the AOFAS score.ResultsThe intermetatarsal angle was improved from a preoperative mean of 14° to 7° (p<0.001; Cohen's d=1.8) at followup, the metatarsophalangeal angle from 31° to 18° (p<0.001; Cohen's d=3.1), the medial sesamoid position from position 6 to 3 (p<0.001; Cohen's d=2.4), and AOFAS hallux score from 68 to 96 points (p<0.001). Neither patient age nor deformity severity affected the effectiveness of the osteodesis in correcting all three radiologic parameters; however, the deformities treated in this series generally were mild to moderate (mean intermetatarsal angle, 14°; range, 9°-22°). There were six stress fractures of the second metatarsal (5%), five temporary metatarsophalangeal joint medial subluxations all resolved in one month by the taping-reduction method without surgery, and six metatarsophalangeal joints with reduced dorsiflexion less than 60°.ConclusionsThe osteodesis is a soft tissue nonosteotomy technique, and provided adequate deformity correction and improvement in AOFAS scores for patients with mild to moderate hallux valgus deformities, although a small number of the patients had postoperative stress fractures of the second ray develop. Future prospective studies should compare this technique with osteotomy techniques in terms of effectiveness of the correction, restoration of hallux function, complications, and long-term recurrence.Level of evidenceLevel IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Project description:BackgroundAfrican Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease.MethodsWe selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch.ResultsWe observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001).ConclusionsOverall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

Dataset Information

Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

Publications

Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

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