A novel FoxD3 Variant Is Associated With Vitiligo and Elevated Thyroid Auto-Antibodies.
BACKGROUND
Vitiligo frequently coincides with autoimmune endocrinopathies, particularly Hashimoto's thyroiditis (HT). Genetic susceptibility may underlie this coincident occurrence. One candidate region is the autoimmunity susceptibility locus on chromosome 1, which encompasses forkhead transcription factor D3 (FoxD3), a gene involved in embryonal melanogenesis. We identified a promotor variant (rs78645479) in an index case of vitiligo + HT + candidiasis and evaluated its clinical and functional relevance.


METHODS
We genotyped 281 patients with variable autoimmune endocrinopathies: HT, Graves' disease (GD), type 1 diabetes (T1D), Addison's disease (AD), autoimmune polyglandular syndrome (APS), and/or vitiligo and 1858 controls. Furthermore, we experimentally assessed the effect of the variant on promotor activity and assessed the expression of FoxD3 in human thyroid tissue samples.


RESULTS
Patients with vitiligo had a higher frequency of the risk allele (30%) compared with healthy controls (18.2%). In addition, the variant was associated with the incidence of elevated anti-TPO antibodies and anti-Tg antibodies, but not with TSH, FT3, or FT4 levels and also not with GD, T1D, AD, or APS. Functionally, the variant increased transcriptional activity in Jurkat and in Hek293 cells. We confirmed gene expression of FoxD3 in human thyroid tissue, which seemed elevated in thyroid tissue samples of some patients with GD and nonautoimmune goiter but not in patients with HT.


CONCLUSIONS
In addition to a possible association of rs78645479 in FoxD3 with vitiligo, our data on the association of this FoxD3 variant with thyroid autoantibodies suggest a potential involvement of FoxD3 in thyroid immunoregulation.
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Jo Ana
JA
Schunter
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Dennis
D
Löffler
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Tobias
T
Wiesner
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Peter
P
Kovacs
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Klaus
K
Badenhoop
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Gabriela
G
Aust
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Anke
A
Tönjes
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Peter
P
Müller
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Ronny
R
Baber
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Jan C
JC
Simon
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Dagmar
D
Führer
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Roland W
RW
Pfäffle
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Joachim
J
Thiery
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Michael
M
Stumvoll
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Wieland
W
Kiess
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Jürgen
J
Kratzsch
Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany.
Antje
A
Körner
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001323:Autoantibodies / Q000097:blood*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013954:Thyroglobulin / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000097:blood / Q000235:genetics / Q000276:immunology; D014820:Vitiligo / Q000097:blood / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
D001323:Autoantibodies; C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; D013954:Thyroglobulin; D007453:Iodide Peroxidase