Introduction
Methods
Results
Candidate gene studies
Gene | Number of inquiries | Number of positive associations [References] | Number of negative associations [References] |
---|---|---|---|
Connective tissue structure | |||
FBN1 | 1 | 0 | 1 [14] |
ELN | 1 | 0 | 1 [14] |
COL1A1 | 1 | 0 | 1 [14] |
COL1A2 | 2 | 0 | |
COL2A1 | 1 | 0 | 1 [14] |
ACAN | 2 | 0 | |
MATN1 | 3 | 1 [23] | |
LOX1, LOX2, LOX3, LOX4, LOX5 | 1 | 0 | 1 [24] |
TIMP2 | 1 | 1 [30] | 0 |
MMP3 | 3 | 1 [31] | |
DPP9 | 1 | 0 | 1 [37] |
Bone formation/metabolism | |||
BMP4 | 1 | 0 | 1 [33] |
LEP | 1 | 0 | 1 [33] |
CALM1 | 1 | 1 [45] | 0 |
IL6 | 4 | 1 [33]* | |
VDR | 2 | 1 [53] | 1 [54] |
TNFRSF11B (OPG) | 1 | 1 [55] | 0 |
RANKL | 1 | 0 | 1 [55] |
RANK | 1 | 0 | 1 [55] |
Melatonin signaling pathway | |||
MTNR1A | 3 | 0 | |
MTNR1B | 6 | 1 [62] | |
TPH1 | 3 | 1 [64] | |
ASMT (HIOMT) | 1 | 0 | 1 [60] |
AANAT (SNAT) | 2 | 0 | |
GPR50 | 1 | 0 | 1 [63] |
Puberty and growth | |||
CYP17 | 1 | 0 | 1 [54] |
ESR1 (alpha) | 6 | ||
ESR2 (beta) | 2 | 1 [73] | 1 [71] |
GPER (GPR30) | 1 | 1 [74] | 0 |
GHR | 2 | 0 | |
IGF1 | 3 | 1 [77] |
Gene | Number of cases/controls | Phenotype Cobb angle | Population [Reference] | Results |
---|---|---|---|---|
MATN1 1p35 | 50/100 | >5º | Italian [19] | Microsatellite (short tandem repeat) polymorphism 3′ untranslated region: predisposition (p = 0.0242) |
419/750 | Not mentioned | Chinese [22] | Promoter polymorphism rs1149048: predisposition and progression (
p = 0.0034*: OR = 1.34) | |
TIMP2 17q25 | 570/210 | >20º | Chinese [30] | Rs8179090: progression—thoracic curve only (p = 0.019; OR = 1.707) |
MMP3 11q22.3 | 53/206 | 25º–125º | Italian Caucasian [31] | rs3025058: predisposition—MMP3 5A/5A (p = 0.010, OR = 3.34) |
CALM1 14q24-q31 | 67 (40 with thoracic curve)/100 | >30º (double curve pattern only) | Chinese [45] | rs12885713: predisposition in double curve pattern (p = 0.034); rs5871: thoracic curves only (p = 0.0102) |
IL6 7p21 | 53/206 | 25º–125º | Italian Caucasian [31] | rs1800895: predisposition—IL6 G/C (p = 0.014, OR = 4.84); IL6 G/G (p < 0.001, OR = 10.54) |
198/120 | >10º | Korean [52] | IL6-572 G → C: comorbidity –lumbar low BMD density in AIS (p = 0.0159) | |
VDR 12q13.11 | 198/120 | >10º | Korean [53] | Bsml: predisposition (p = 0.0054); lumbar low BMD in IS (p = 0.0046) |
TNFRSF11B (OPG) 8q24 | 198/0 | >10º | Korean [55] | OPG1181 G → C: comorbidity—lumbar low BMD in IS girls (p = 0.0010) |
MTNR1B 11q21-22 | Stage I: 472/304 Stage II: 342/347 (umbilical cord blood controls) | >20º | Chinese [62] | rs4753426: predisposition (p = 0.045); meta-analysis on 2 stages of cohorts—(allele p = 0.0064, genotype p = 0.015) |
TPH1 11p15.3-p14 | 103/107 | >30º | Chinese [64] | rs10488682: predisposition (allele p = 0.002, OR = 2.909, genotype p = 0.001) |
ESR1 (alpha) 6q25.1 | 202/174 | 25º–125º | Chinese [68] | rs9340799 (XbaI): predisposition in females with AIS (p = 0.010) |
304/0 | >10º + rotational prominence | Japanese [67] | rs9340799 (XbaI): progression (p = 0.002) | |
67 (40 with thoracic curve)/100 | >30º (double curve pattern only) | Chinese [45] | rs2234693 (PvuII): predisposition in double curve pattern (p = 0.014); curves > 40º (p = 0.0128); thoracic curves only (p = 0.0184) | |
ESR2 (beta) 14q23.2 | 218/140 | 12º–135º | Chinese [73] | rs1256120: predisposition (p = 0.037, OR = 1.88) and progression (p = 0.005) |
GPER (GPR30) | 389/338 | >15º | Chinese [74] | Predisposition: rs3808351 (p = 0.004); rs10269151 (p = 0.048); rs426655s3 (p = 0.028) |
IGF1 12q23.2 | 506/227 | >20º | Chinese [77] | rs5742612: progression—IGF1 promoter associated with curve severity (p = 0.042) |
Gene (years) | SNP tested | Number of cases/controls | Phenotype cobb angle | Population |
---|---|---|---|---|
MATN1 (2011) | rs1149048 | 798/1,239 | >15º | Japanese [23] |
LOX1-5 (2011) | A total of 14 SNPs tested in replication cohort | Discovery cohort: 138/411 Replication cohort: 400/506 | >10º | Caucasian–American [24] |
MMP3 (2011) | rs3025058 | 126/197 | 64.7º ± 19.2º | Hungarian [33] |
MMP3 (2010) | rs3025058 | 487/494* | not measured | Chinese [32] |
DPP9 (2008) | rs10406145, rs11670570, rs2286367, rs2277733, rs732631 | 571/236 | >20º | Chinese [37] |
BMP4 (2011) | rs4898820 | 126/197 | 64.7º ± 19.2º | Hungarian [33] |
LEP (2011) | rs7799039 | 126/197 | 64.7º ± 19.2º | Hungarian [33] |
IL6 (2011) | rs1800795 | 126/197 | 64.7º ± 19.2º | Hungarian [33] |
RANKL (2009) | rs12721445, rs2277438 | 198/0 | >10º | Korean [55] |
RANK (2009) | RANK-421 C → T, RANK-575 C → T | 198/0 | >10º | Korean [55] |
MTNR1A (2011) | rs6847693, rs2165667, rs2165666 | 589/1,533 | >40º | Caucasian American [60] |
MTNR1A (2008) | rs2119882 | 226/277 | >10º | Chinese [59] |
MTNR1B (2011) | 10 SNPs tested | 589/1,533 | >40º | Caucasian–American [60] |
MTNR1B (2011) | rs4753426 | 798/1,239 | >15º | Japanese [23] |
MTNR1B (2011) | rs4753426 | 126/197 | 64.7º ± 19.2º | Hungarian [33] |
MTNR1B (2010) | rs4753426 | 406/479 | >10º | American [63] |
MTNR1B (2006) | rs10830963, rs3781637, rs10830964 | 473/311* | >20º | Chinese [61] |
TPH1 (2011) | rs1800532, rs10488683, rs211105, rs172423 | 589/1533 | >40º | Caucasian–American [60] |
TPH1 (2011) | rs10488682 | 798/1239 | >15º | Japanese [23] |
ASMT (HIOMT) (2011) | rs6588807, rs4521942, rs6588810 | 589/1533 | >40º | Caucasian–American [60] |
AANAT (SNAT) (2010) | rs16968964, rs11077823, rs11077821 | 406/479 | >10º | American [63] |
AANAT (SNAT) (2008) | tested rs3760138, rs4238989, rs28936679 | 103/107 | >30º | Chinese [64] |
GPR50 (2010) | rs561077, rs13440581 | 406/479 | >10º | American [63] |
PKCD (2011) | rs1483185, rs3821689, rs17052826, rs13084863 | 589/1,533 | >40º | Caucasian–American [60] |
ESR1 (2010) | rs1256120 | 798/637 | >15º | Japanese [71] |
ESR1 (2006) | rs2234693, rs9340799 | 540/260 | >20º | Chinese [70] |
ESR2 (2010) | rs9340799 | 798/637 | >15º | Japanese [71] |
GHR (2009) | 7 SNPs tested | 106/106 | >20º | Chinese [78] |
GHR (2007) | rs6179, rs6176, rs6180, rs6184, exon-3 deletion | 510/363* | >20º | Chinese [76] |
IGF1 (2011) | rs5742612 | 798/1,239 | >15º | Japanese [23] |
IGF1 (2009) | rs35767, rs5742612, rs17884626, rs3730195 | 106/106 | >20º | Chinese [78] |
Connective tissue structure
Bone formation and bone metabolism
Melatonin signaling pathway
Puberty and growth
Important considerations for candidate gene studies in IS
Genome-wide studies
Parametric linkage analysis
Reference | Pedigree characteristics | Cobb angle | Genetic inheritance | Locus | Statistics |
---|---|---|---|---|---|
Single-family studies | |||||
Salehi et al. [94] | 4 generations, 11 affected out of 17 | 10º–20º | AD, pen = 1 | 17p11 |
Z
max = 3.20 |
Justice et al. [95] | 6 affected | >10º | XLD, pen F = 0.90, pen M = 0.79 | Xq22.3-q27.2 | LOD = 2.23 |
Ocaka et al. [29] | 5 generations, 8 affected out of 21 | 15º–65º | AD, pen = 0.80 | 9q31.2-q34.2 |
Z
max = 3.64 |
Gurnett et al. [96] | 5 generations, 9 affected out of 22 + 4 pectus excavatum | 15º–70º | AD, pen = 0.80 | 18q12.1-q12.2 | LODmax AIS+PE = 3.86 LODmax AIS = 2.77 |
Edery et al. [98] | 3 generations, 11 affected out of 18 | 15º–41º | AD, pen not noted | 3q12.1 5q13.3 |
Z
max = 3.00
Z
max = 3.01 |
Multi-family studies | |||||
Chan et al. [35] | 7 families, 25 affected | >10º | AD, pen = 0.80 | 19p13.3 | LOD = 4.48 |
Ocaka et al. [29] | 2 families, 16 affected out of 49 | 11º–55º | AD, pen = 0.80 | 17q25.3-qtel | LODcomb = 3.78 |
Raggio et al. [97] | 7 families, 18 affected out of 50 | >10º | AR, α = 1 AD, α = 1 | 12p | HLOD = 3.2 HLOD = 3.7 |
Non-parametric linkage analysis
Study | Pedigree characteristics | Cobb angle | Locus | Statistics |
---|---|---|---|---|
Chan et al. [35] | 7 families 25 affected | > 20º | 19p13.3 | NPL = 5.36, p = 3.10−5 (**) |
Gao et al. [103] | 53 families 130 affected | 15º–113º | 8q12 (CDH7) | Zlr = 2.72, p = 2.10−4 (*)
p
TDTae = 2.10−4
p
HHRR = 0.001 |