rate of acute-tsh-stimulated release of allele was associated with a decreased

Transcription

1 Supplementary Table 1 General overview of studies and their primary clinical endpoints. Pituitary thyroid axis (35) D , D , and other D2 variants 228 The effect on clinical and biochemical response to T4 replacement therapy in hypothyroid patients on T4 replacement therapy (37) 315 The effect on development of Graves disease, treatment efficiency and rate of remission in a Russian population (34) 83 The impact on acute-tsh stimulated release of T3 from the thyroid in healthy volunteers (36) 252 The impact on risk for Graves disease in a Russian population (20) D1-C785T, D1-A1814G, D2-ORFa-Gly3Asp, and 995 The effect on various serum thyroid hormone parameters in elderly subjects (30) 216 The effect on serum thyroid hormone parameters or thyroid autoimmunity in female subjects (33) 145 The effect on serum thyroid hormone parameters and thyreotoxic cardiomyopathy and echocardiography parameters in patients with Graves disease (28) 295 The effect on thyroid hormone levels and T4 dosage in patients treated for DTC and a group of AIH patients (15) D1-C785T, D1-A1814G, D2-ORFa-Gly3Asp, and (21) D1-C785T, D1 rs , and other D1/2/3 polymorphisms 148 The effect on the set-point of the hypothalamus pituitary thyroid axis in patients treated for DTC 3777 a The association with serum TSH and ft4 levels in a combined meta-analysis of four studies including Caucasian subjects The D2-92Ala variant was suggested to be protective regarding risk for Graves disease development (lower frequency of the variant in Graves patients; P!0.0001), severity of disease, and rate of remissions The homozygous status for D2-92Ala allele was associated with a decreased rate of acute-tsh-stimulated release of T3 from the thyroid (PZ0.029) The D2-92Ala allele was associated with increased risk for development of Graves disease (PZ0.031) The D1-785T variant was significantly associated with higher ft4 (PZ0.04) and rt3 levels (PZ0.03) and lower T3 (PZ0.004) and T3/rT3 (P%0.001). The D1-A1814G variant was associated with higher T3 (PZ0.02) and T3/rT3 (PZ0.06) The D2-92Ala allele was associated with decreased T3/T4 ratio and higher levels of auto-antibodies (anti-tsh, anti-tpo, and anti-tg; P!0.001 and P!0.01 respectively) The homozygous status for the D2-ORF- 3Asp variant was associated with a weaker negative feedback of ft4 on TSH in DTC patients on TSH suppression therapy (PZ0.036) The minor allele of the D1-C785T and rs variant was strongly, positively, and negatively associated with ft4 levels (PZ5!10 K10 and PZ8!10 K12 respectively)

2 (10) D1-C785T, D1 rs ,, and other D1/D2 polymorphisms (17) D1-C785T, D1-A1814G, and (6) D2-ORFa-Gly3Asp and 552 The effect on serum thyroid hormone parameters in patients on thyroid hormone replacement therapy and patients not on thyroid hormone replacement therapy 155 The effect on various serum thyroid hormone parameters in healthy European blood donors 156 (EBD) and 349 (HEM) The effect on various serum thyroid hormone parameters in healthy European blood donors and healthy elderly men (38) D2-ORFa-Gly3Asp 45 The thyroid hormone secretion in response to 500 mg i.v. TRH injection was studied in healthy volunteers (26) D1 rs no The effect on serum thyroid hormone parameters (TSH and ft 4 ) in a meta-analysis including euthyroid individuals (19) D1-C785T; D1 rs ; and 677 The effect on serum thyroid hormone parameters in young healthy euthyroid men (25) D1 rs The effect on serum thyroid hormone parameters in euthyroid patients (29) 191 The effect on T 4 doses needed to maintain target TSH levels in patients treated for DTC (11) D1-C785T and D1-A1814G 1192 The effect on serum thyroid hormone parameters in a population of healthy Danish twins GH IGF1 axis and body composition (24) D1-C785T and D1-A1814G 156 (EBD) and 350 (HEM) The impact on GH IGF1 system in healthy blood donors and elderly men The D1-C785T and D1 rs variants were significantly associated with lower and higher ft3/ft4 ratio respectively (PZ0.004 and PZ3.6!10 K13 respectively) The D1-785T variant was associated with increased rt3 (PZ0.017) and rt3/t4 (PZ0.01) and decreased T 3 /rt 3 (PZ0.003). D1-1814G variant with decreased rt3/t4 (PZ0.024) and increased T 3 /rt 3 (PZ0.08) D2-ORFa-3Asp variant was associated with lower ft4 (PZ0.001), T4 (PZ0.01), and rt 3 (PZ0.01) and higher T 3 /rt 3 (PZ0.03) and T3/T4 (PZ0.002) in healthy blood donors, but not in healthy elderly men The D2-ORF-3Asp variant was associated with a blunted ft4 secretion after TRH-induced acute TSH stimulation (P!0.01) The variant was positively associated with serum ft 4 levels (effect size 0.138; PZ7.87!10 K32 ) The D1-785T variant was associated with higher ft 4 and rt 3 and lower ft 3 /ft 4, T3/rT3, and the D1 rs C variant with higher ft3/ft4, T3/rT3, ft3, and lower rt 3 The variant was associated with T3/T4 ratio (PZ5.93!10 K4 ) a higher T4 dosage needed to suppress TSH levels (P!0.05) The D1-785T variant was associated with higher ft4 (PZ0.004), rt3 (P!0.001), and rt3/t4 (P!0.001) A haplotype of both D1 variants was associated with increased IGF1 levels in both cohorts (PZ0.02 and PZ0.01). In elderly men, the haplotype was linked to increased lean body mass (PZ0.03) and improved muscle strength (PZ0.047)

3 (19) D1-C785T, D1 rs , and Cognitive function and affective disorders (27) D2-ORFa-Gly3Asp and 677 The effect on body composition in healthy euthyroid men 141 Effect on well-being, neurocognitive function, or preference for combined T 4 /T 3 therapy in patients with PAH (45) 93 The association with response rate to the antidepressant paroxetine in patients treated for major depression (44) D1-C785T, D1-A1814G, D2-ORF a -Gly3Asp, and (47) D2-ORFa-Gly3Asp and (20) D1-C785T, D1-A1814G, D2-ORFa-Gly3Asp, and (76), D , and rs (46) D2-ORFa-Gly3Asp and (43) A variety of D1/D2/D3 polymorphisms (22) D1-C785T and other D1 polymorphisms (77) and other D2 polymorphisms 64 The association with response rate to combined antidepressant sertraline/t 3 therapy in patients treated for major depression 290 (SCH) and 198 (C) D1-785T variant was associated with significantly higher body height (PZ0.009) and higher values of other anthropometric variables (armspan, calf height, sitting, and sternum height). A negative association was found between the C-allele of rs and body height (PZ0.02) The DI-785T variant was associated with higher response rate to combined antidepressant sertraline/t3 therapy in patients treated for major depression (PZ0.01) The effect on risk of schizophrenia The D2-92Ala variant was significantly associated with increased risk of schizophrenia (PZ0.045) 995 The association with early magnetic resonance markers of Alzheimer s disease in elderly Caucasians 543 The association of D2 polymorphisms with mental retardation in a population from iodine-deficient areas in China 279 (BPAD) and 284 (C) The association between D2 polymorphisms and BPAD in Chinese Han population 552 The association with psychological well-being in patients on thyroid hormone replacement therapy 1555 The impact on risk for major depression in three independent populations 1461 The association with mental retardation in Chinese Han population derived from iodine deficient areas Positive association of the D2-rs (PZ ) and D2-rs (PZ0.044) polymorphism with mental retardation The D2-ORF-3Glya variant and D2-92Ala variant were significantly associated with increased BPAD risk (PZ0.005 and PZ7.0!10 K0.005 ) worse baseline psychological wellbeing on T4 (PZ0.02) and improved response to combined T 4 /T 3 therapy (P!0.05). No impact of the D1 or D3 polymorphisms on study outcomes The DI-C785T polymorphism was associated with lifetime major depression in white female subjects from high-risk cohorts (P!0.004) The major allele of D2 rs polymorphism was associated with mental retardation (PZ0.020)

4 Bone metabolism (51) 154 The effect on bone mineral density and bone turnover markers were assessed in patients treated for DTC (52) D1-C785T, D1 rs , and 677 The effect on bone mass parameters in healthy male siblings Risk for osteoarthritis (86) 31 To investigate allelic balance of the D2 variant in human osteoarthritis joints (see article for more details) (39) D2-ORFa-Gly3Asp,, and other D2 variants (18) Various D3 polymorphisms 3252 (OA) and 2132 (C) (55) D2-ORF a -Gly3Asp and O4500 The association with generalized osteoarthritis in four large cohorts including Caucasian subjects The association with generalized osteoarthritis in four large European populations 341 The effect on nonoptimal joint geometry and risk for osteoarthritis in Caucasian subjects Lipoprotein metabolism b BMI and obesity b Insulin resistance and DM2 (5) 183 The effect on insulin resistance parameters in patients with DM2 and D2 enzyme velocity in thyroid and skeletal muscle samples of nondiabetic subjects (58) 1573 The association with risk of DM2 in a case control study including diabetic and nondiabetic subjects a decreased femoral neck (PZ0.022) and total hip bone mineral density (PZ0.028) and several markers of bone turnover An allelic imbalance (difference in expression of alleles) in patients might explain the positive association between variant and osteoarthritis The variant was related to higher risk for generalized osteoarthritis and further study in three large cohorts showed that a haplotype including the D2-92Ala variant and the major allele of the D2-ORF a -Gly3Asp variant was also associated with osteoarthritis (PZ2.02!10 K5 ) The minor allele variant of D3 rs was associated with decreased risk of osteoarthritis (PZ0.004) A higher risk for osteoarthritis and certain hip shapes in carriers of the D2-ORFa- Gly3Asp variant (PZ0.005) The homozygous state for the D2-92Ala variant was significantly associated with higher fasting plasma insulin (PZ0.004) and decreased D2 enzyme velocity in thyroid (PZ0.05) and skeletal muscle (PZ0.04) samples The homozygous state for D2-92Ala variant was significantly associated with DM2 (PZ0.03). The pooled effect of DM2 in a meta-analysis yielded a risk for DM2 (PZ0.02)

5 (59) 721 The effect on insulin resistance parameters in patients with DM2 (60) 590 The effect on insulin resistance parameters in nondiabetic whites (61) 5843 The association with risk of DM2 in a case control study including diabetic and nondiabetic Danish white subjects (63) 1633 The association with risk of DM2 in a case control study including White subjects of mixed European ancestry (4) 972 The effect on insulin resistance parameters in nondiabetic patients (32) 1268 The effect on insulin resistance parameters in the old order Amish population (64) and other D2 variants 300 The association with development of DM2 in a native American population of Pima Indians Blood pressure and hypertension (5) 183 The effect on blood pressure or risk for arterial hypertension in DM2 patients The homozygous state for D2-92Ala variant was significantly associated with more severe insulin resistance compared with patients heterozygous (PZ0.022) or WT (PZ0.001) for the D2 variant Gene gene interaction between and Pro12Ala polymorphism and risk for metabolic syndrome (PZ0.02) with risk for DM2 with diabetes intermediate trait levels or risk for DM2 insulin resistance parameters (PZ0.0088) No clear association between and DM2 or impaired glucose intolerance A minor association between variant with early-onset DM2 (PZ0.01) c (60) 590 The effect on blood pressure in nondiabetic whites Significantly higher diastolic (PZ0.02) and systolic blood pressure (PZ0.01) in patients with D2-92Ala variant combined with the Pro12Ala polymorphism in the PPARg2 gene (33) 145 The effect on serum thyroid hormone parameters An association between D2-92Ala variant and thyreotoxic cardiomyopathy and echocardiography parameters in patients with Graves disease (31) 372 The association with hypertension and hypertension-related intermediate phenotypes in euthyroid subjects (63) 1633 The effect on blood pressure or risk for arterial hypertension in a large community-based cohort of mixed European ancestry (69) D2-ORF a -Gly3Asp and 2441 The effect on blood pressure or risk for arterial hypertension in two large cohorts of elderly subjects and the parameters of thyreotoxic cardiomyopathy in patients with Graves disease (P!0.05) The D2-92Ala variant was significantly associated with hypertension (odds ratio 2.11, PZ0.01)

6 Gynecological parameters (23) D1-C785T 100 The effect on degree of severity of preeclampsia and pregnancy outcome in pregnant women Sepsis and sepsis-related study endpoints (75) 405 (EA) and 302 (AA) Iodine and selenium deficiency (81) D1-A1814G, D2-ORFa- Gly3Asp,, and other D1/D2 variants (76), D , and rs Risk for sepsis and sepsis-related acute lung injury in European and African-Americans 798 The association with serum selenium levels in a Caucasian population 543 The association with mental retardation in Chinese Han population derived from iodine-deficient areas (82) 473 The effect on risk of Kashin Beck disease in the Chinese Han population living in selenium-deficient areas (77) and other D2 polymorphisms 1461 The association with mental retardation in Chinese Han population derived from iodine-deficient areas The D1-785T variant was associated with significantly lower birth weight (PZ0.023) of neonates at a significantly lower gestational age (PZ0.035) a reduced susceptibility for severe sepsis (PZ0.009) and sepsis-related acute lung injury (PZ0.004) in critically ill patients of European descent after correction for multiple testing Positive association of the D2 rs (PZ ) and D2 rs (PZ0.044) polymorphism with mental retardation in a patient population from an iodine-deficient area. No significant relationship with the Thr92Ala polymorphism The major allele of D2 rs polymorphism was associated with mental retardation (PZ0.020) AA, African-Americans; AIH, autoimmune hypothyroidism; C, controls; DM2, diabetes mellitus type 2; DTC, differentiated thyroid carcinoma; EA, European Americans; EBD, European blood donors; HEM, healthy elderly men; OA, osteoarthritis; PAH, primary autoimmune hypothyroidism; SCH, schizophrenia. a Consisted of four independent cohorts (Rotterdam Study; Scan Study; Healthy Twin; and Nijmegen Biochemical study). b These (secondary) clinical endpoints were studied in several studies investigating the effect of deiodinase variants on other (primary) endpoints. Further details on the clinical outcomes are to be found in the text. c Not significant after correction for multiple testing.

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