2.1. Influences of Conventional, Behavioral and Environmental Risk Factors According to Gender
The putative non-genetic categorical risk factors associated to all lumbar spine diseases in the overall population and in males or females were shown in
Table 1. Cases and controls did not differ by gender (
p = 0.19). Males and females did not differ by age (
p = 0.70).
In the overall cohort of cases, age over 45 years or over 50 years, overweight or obesity, family history, past and present smoking habit, present smoking ≥10 cigarettes per day, and more than sedentary or intense job physical demand were all significantly associated with the development of lumbar spine pathologies, with significant ORs (odds ratio) ranging approximately from 2 to 3. Of note, present smoking ≥20 cigarettes per day had an elevated OR = 6.05; 95% CI (95% confidence interval) = 1.76–20.8; p = 0.001. A strong dose-response effect was observed concerning the increasing numbers of hours/day of exposure to vehicular vibration; the increased risk to develop spine pathologies ranged from a 1.6-fold at >1 h/day, to 2.9-fold at >2 h/day, to 3.7-fold at >3 h/day and to 8.5-fold increased risk at >4 h/day of vibration exposure. In our Italian cohort, controls subjects practiced leisure physical activity at least once per week 2-fold more frequently than the pathological subjects (OR = 1.98; 95% CI = 1.50–2.62; p < 0.001).
Almost all the associations found for the entire cohort were confirmed for male patients compared to male controls, the only exceptions were an age ≥50 years and present smoking (both these categories corresponded to tendencies in males). Notably, family history was a six-fold risk factor for males. Unexpectedly, for female patients compared to female controls the only conventional risk factors significantly associated with an approximately 2- to 3-fold increased risk for lumbar spine pathologies were age ≥45 to ≥50 years, overweight, and family history. Additionally, in females, a lower frequency of spine pathologies was associated with leisure physical activity once or more or twice or more per week. Thus, a remarkable gender difference was noted in regard to association of lumbar spine disease with physical job demand and exposure to vibrations. Particularly, intense physical job demand was associated to a six-fold increased risk for men, while it was indifferent for women. However, it is to note that, in our cohort, males and females differed in frequency of intense physical job demand (p = 0.003). Women had in general less risky behaviors, for example, percentages of smokers were not different between genders, but males more than females smoked ≥10 cigarettes/day (p = 0.023) or ≥20 cigarettes/day (p = 0.030), indeed, only very few females (n = 5) smoked ≥20 cigarettes/day vs. 16 males. Moreover, women were exposed to less severe environmental risk factors, exposure to vibration over 1 h/day was more frequent in males than in females (p < 0.001), notably only 1 woman (a case) in the entire sample was exposed to more than 4 h of vibrations/day vs. 35 males (31 cases and 4 controls), p < 0.001.
2.2. VDR-FokI Genotypes and Alleles According to Gender
Data concerning the FokI genotypes in the entire cohort of 521 subjects (267 cases and 254 controls) and gender-related were reported in
Table 2. Male and female cases and controls did not differ in genotype frequencies. The
VDR-FokI genotypes were in Hardy-Weinberg equilibrium (HWE) in male controls (χ
2 = 0.49,
p = 0.48), female controls (χ
2 = 0.15,
p = 0.69), male cases (χ
2 = 0.38,
p = 0.54), and female cases (χ
2 = 0.11,
p = 0.74).
Concerning the genotype frequencies of all pathological cases compared with controls, we did not observe significant differences, with the exception of a just significant lower frequency of the homozygous ff genotype in male cases (8.1%) than in male controls (15.7%); crude OR = 0.47; 95% CI = 0.22–1.00; p = 0.047). However, the observed significant difference for ff in males was lost after adjustment for conventional risk factors. Moreover, in the male cohort there was a tendency for an association of the F allele with lumbar spine pathologies (69.8% of cases vs. 62.2% of controls; crude OR = 1.40; 95% CI = 0.99–2.00; p = 0.060); thus, for the f allele there was a protective tendency.
Confirmatory with our previous investigation [
21], by cumulative analysis including both genders, significant
FF associations were found for some specific patients; Subgroup 2 (
i.e., discopathies and/or osteochondrosis with disc herniation), crude OR = 1.95; 95% CI = 1.19–3.20,
p = 0.007; adjusted OR = 2.09; 95% CI = 1.19–3.66,
p = 0.011, and Subgroup C (
i.e., all discopathies), crude OR = 2.08; 95% CI = 1.19–3.62,
p = 0.009; adjusted OR = 1.88; 95% CI = 1.03–3.43,
p = 0.039. The
ff genotype was protective in crude analysis only for Subgroup B (
i.e., all discopathies and/or osteochondrosis), crude OR = 0.46; 95% CI = 0.22–0.99,
p = 0.043, adjusted OR = 0.42; 95% CI = 0.18–1.00,
p = 0.051; and for Subgroup D (
i.e., all osteochondrosis) crude OR = 0.25; 95% CI = 0.06–1.08,
p = 0.047, adjusted OR = 0.23; 95% CI = 0.05–1.17,
p = 0.078. The complete data analysis of genotype association in different pathologic Subgroups not stratified for sex was reported in
Supplementary Table S1.
Gender-related analysis of genotypes in pathological Subgroups was shown in
Table 3 (males) and
Table 4 (females). Regarding the male population (
Table 3), in Subgroup 2 the
FF genotype had a frequency of 52.7%
vs. 40.2% of male controls (crude OR not significant; adjusted OR = 2.32; 95% CI = 1.02–5.30,
p = 0.045). Moreover, in Subgroup A and C the
FF genotype had a tendency for risk. In males, the
ff genotype was protective in crude analysis for Subgroup A (crude OR = 0.39; 95% CI = 0.16–0.96,
p = 0.036) and Subgroup 1 + 2 + 3 (all patients excluding stenosis and/or spondilolysthesis) (crude OR = 0.42; 95% CI = 0.18–0.96,
p = 0.035). Finally, the
ff genotype was protective for Subgroup B in adjusted analysis (adjusted OR = 0.23; 95% CI = 0.06–0.88,
p = 0.032).
Table 1.
Categorical risk factors for all subjects (n = 521), and for males (n = 276) or females (n = 245) controls and cases.
Table 1.
Categorical risk factors for all subjects (n = 521), and for males (n = 276) or females (n = 245) controls and cases.
Categorical Variable | All Controls | All Cases | OR (95% CI) | Male Controls | Male Cases | OR (95% CI) | Female Controls | Female Cases | OR (95% CI) |
---|
n
= 254 | n
= 267 | p
Value | n
= 127 (50.0%) | n
= 149 (55.8%) | p
Value | n
= 127 (50.0%) | n
= 118 (44.2%) | p
Value |
---|
Age ≥ 45 years | 79 (31.1) | 136 (50.9) | 2.30 (1.61–3.29) p < 0.001 | 41 (32.3) | 72 (48.3) | 1.96 (1.20–3.21) p = 0.007 | 38 (29.9) | 64 (54.2) | 2.78 (1.64–4.69) p < 0.001 |
Age ≥ 50 years | 45 (17.7) | 83 (31.1) | 2.10 (1.39–3.17) p < 0.001 | 23 (18.1) | 40 (26.8) | 1.66 (0.93–2.96) p = 0.085 | 22 (17.3) | 43 (36.4) | 2.74 (1.51–4.95) p = 0.001 |
BMI ≥ 25.0 kg/m2 | 87 (34.3) | 132 (49.4) | 1.88 (1.32–2.67) p < 0.001 | 61 (48.0) | 92 (61.7) | 1.75 (1.08–2.82) p = 0.022 | 26 (20.5) | 40 (33.9) | 1.99 (1.12–3.54) p = 0.018 |
BMI ≥ 30.0 kg/m2 | 17 (6.7) | 37 (13.9) | 2.24 (1.23–4.10) p = 0.007 | 11 (8.7) | 27 (18.1) | 2.33 (1.11–4.92) p = 0.023 | 6 (4.7) | 10 (8.5) | 1.87 (0.66–5.31) |
Family history | 37 (14.6) | 97 (36.3) | 3.35 (2.18–5.14) p < 0.001 | 13 (10.2) | 61 (40.9) | 6.08 (3.14–11.8) p < 0.001 | 24 (18.9) | 36 (30.5) | 1.88 (1.04–3.41) p = 0.035 |
Past and present smoking | 104 (40.9) | 144 (53.9) | 1.69 (1.19–2.39) p = 0.003 | 61 (48.0) | 93 (62.4) | 1.80 (1.11–2.91) p = 0.016 | 43 (33.9) | 51 (43.2) | 1.49 (0.89–2.50) |
Present smoking | 57 (22.4) | 86 (32.2) | 1.64 (1.11–2.43) p = 0.013 | 31 (24.4) | 52 (34.9) | 1.66 (0.98–2.81) p = 0.058 | 26 (20.5) | 34 (28.8) | 1.57 (0.87–2.83) |
Smoking ≥ 10 cigarettes/day | 23 (9.1) | 54 (20.2) | 2.55 (1.51–4.29) p < 0.001 | 12 (9.4) | 38 (25.5) | 3.28 (1.63–6.60) p = 0.001 | 11 (8.7) | 16 (13.6) | 1.65 (0.73–3.73) |
Smoking ≥ 20 cigarettes/day | 3 (1.2) | 18 (6.7) | 6.05 (1.76–20.8) p = 0.001 | 1 (0.8) | 15 (10.1) | 14.1 (1.84–108) p = 0.001 | 2 (1.6) | 3 (2.5) | 1.63 (0.27–9.93) |
Physical job demand more than sedentary | 155 (61.0) | 192 a (73.3) | 1.75 (1.21–2.54) p = 0.003 | 71 (55.9) | 110 (74.8) b | 2.35 (1.41–3.91) p = 0.001 | 84 (66.1) | 82 (71.3) d | 1.27 (0.74–2.20) |
Medium or intense | 91 (35.8) | 117 a (44.7) | 1.45 (1.02–2.06) p = 0.041 | 40 (31.5) | 80 (54.4) b | 2.60 (1.58–4.26) p < 0.001 | 51 (40.2) | 37 (32.2) d | 0.71 (0.42–1.20) |
Intense | 21 (8.3) | 53 a (20.2) | 2.81 (1.64–4.82) p < 0.001 | 8 (6.3) | 43 (29.3) b | 6.15 (2.77–13.7) p < 0.001 | 13 (10.2) | 10 (8.7) d | 0.84 (0.35–1.99) |
Exposure to vibration > 0 h/day | 219 (86.2) | 218 (81.6) | 0.71 (0.44–1.14) | 111 (87.4) | 127 (85.2) | 0.83 (0.42–1.66) | 108 (85.0) | 91 (77.1) | 0.59 (0.31–1.14) |
Exposure to vibration > 1 h/day | 89 (35.0) | 124 (46.4) | 1.61 (1.13–2.29) p = 0.008 | 47 (37.0) | 86 (57.7) | 2.32 (1.43–3.77) p = 0.001 | 42 (33.1) | 38 (32.2) | 0.96 (0.56–1.64) |
Exposure to vibration > 2 h/day | 26 (10.2) | 66 (20.7) | 2.88 (1.76–4.71) p < 0.001 | 14 (11.0) | 52 (34.9) | 4.33 (2.26–8.28) p < 0.001 | 12 (9.4) | 14 (11.9) | 1.29 (0.57–2.92) |
Exposure to vibration > 3 h/day | 13 (5.1) | 44 (16.5) | 3.66 (1.92–6.97) p < 0.001 | 7 (5.5) | 39 (26.2) | 6.08 (2.61–14.2) p < 0.001 | 6 (4.7) | 5 (4.2) | 0.89 (0.27–3.01) |
Exposure to vibration > 4 h/day | 4 (1.6) | 32 (12.0) | 8.51 (2.97–24.4) p < 0.001 | 4 (3.1) | 31 (20.8) | 8.08 (2.77–23.6) p < 0.001 | 0 (0) | 1 (0.8) | - |
Leisure physical activity once or more per week | 148 (58.3) | 85 (31.8) | 0.34 (0.24–0.48) p < 0.001 | 81 (63.8) | 59 (39.9) c | 0.38 (0.23–0.61) p < 0.001 | 67 (52.8) | 26 (22.0) | 0.25 (0.15–0.44) p < 0.001 |
Leisure physical activity 2-fold or more per week | 104 (40.9) | 55 (20.6) | 0.38 (0.26–0.55) p < 0.001 | 60 (47.2) | 40 (27.0) c | 0.41 (0.25–0.68) p = 0.001 | 44 (34.6) | 15 (12.7) | 0.28 (0.14–0.53) p < 0.001 |
Table 2.
Association of VDR-FokI genotypes and alleles in healthy controls and cases, and in males and females.
Table 2.
Association of VDR-FokI genotypes and alleles in healthy controls and cases, and in males and females.
Variables | Controls n = 254 (%) | Cases n = 267 (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value |
---|
All Subjects n = 254 | Males n = 127 (50.0) | Females n = 127 (50.0) | All Subjects n = 267 | Males n = 149 (55.8) | Females n = 118 (44.2) | All Subjects n = 521 | Males n = 276 | Females n = 245 | All Subjects | Males | Females |
---|
VDR-FokI genotypes | FF | 101 (39.8) | 51 (40.2) | 50 (39.4) | 117 (43.8) | 71 (47.7) | 46 (39.0) | 1.18 (0.83–1.68) | 1.36 (0.84–2.19) | 0.98 (0.59–1.64) | 1.13 (0.77–1.66) | 1.40 (0.79–2.48) | 1.08 (0.62–1.88) |
Ff | 117 (46.1) | 56 (44.1) | 61 (48.0) | 120 (44.9) | 66 (44.3) | 54 (45.8) | 0.96 (0.68–1.35) | 1.01 (0.63–1.62) | 0.91 (0.55–1.51) | 0.94 (0.64–1.38) | 0.97 (0.55–1.72) | 0.81 (0.47–1.39) |
ff | 36 (14.2) | 20 (15.7) | 16 (12.6) | 30 (11.2) | 12 (8.1) | 18 (15.3) | 0.77 (0.46–1.29) | 0.47 (0.22–1.00) p = 0.047 | 1.25 (0.60–2.58) | 0.89 (0.50–1.58) | 0.48 (0.19–1.20) | 1.34 (0.61–2.92) |
VDR-FokI alleles | F | 319/508 (62.8) | 158/254 (62.2) | 161/254 (63.4) | 354/534 (66.3) | 208/298 (69.8) | 146/236 (61.9) | 1.17 (0.90–1.50) | 1.40 (0.99–2.00) p = 0.060 | 0.94 (0.65–1.35) | 1.10 (0.83–1.45) | 1.42 (0.93–2.17) | 0.97 (0.65–1.43) |
f | 189/508 (37.2) | 96/254 (37.8) | 93/254 (36.6) | 180/534 (33.7) | 90/298 (30.2) | 90/236 (38.1) | 0.86 (0.67–1.11) | 0.71 (0.50–1.01) p = 0.060 | 1.07 (0.74–1.54) | 0.91 (0.69–1.21) | 0.71 (0.46–1.08) | 1.04 (0.70–1.53) |
Table 3.
Association of VDR FokI genotypes with lumbar spine pathologies in males. Total 276 male subjects (127 controls and 149 cases) evaluated. Male patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3 (i.e., all discopathies and/or osteochondrosis); Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Table 3.
Association of VDR FokI genotypes with lumbar spine pathologies in males. Total 276 male subjects (127 controls and 149 cases) evaluated. Male patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3 (i.e., all discopathies and/or osteochondrosis); Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Variables | FF n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value | Ff n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value | ff n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value |
---|
Controls n =127 | 51 (40.2) | - | - | 56 (44.1) | - | - | 20 (15.7) | - | - |
Subgroup 1 n = 48 | 25 (52.1) | 1.62 (0.83–3.16) | 1.46 (0.65–3.27) | 19 (39.6) | 0.83 (0.42–1.63) | 0.82 (0.37–1.84) | 4 (8.3) | 0.49 (0.16–1.51) | 0.62 (0.18–2.22) |
Subgroup 2 n = 55 | 29 (52.7) | 1.66 (0.88–3.14) | 2.32 (1.02–5.30) p = 0.045 | 23 (41.8) | 0.91 (0.48–1.73) | 0.72 (0.32–1.62) | 3 (5.5) | 0.31 (0.09–1.09) p = 0.055 | 0.24 (0.05–1.14) p = 0.073 |
Subgroup 3 n = 21 | 7 (33.3) | 0.75 (0.28–1.97) | 0.70 (0.22–2.23) | 12 (57.1) | 1.69 (0.67–4.30) | 2.34 (0.75–7.31) | 2 (9.5) | 0.56 (0.12–2.61) | 0.30 (0.04–2.04) |
Subgroup 4 n = 25 | 10 (40.0) | 0.99 (0.41–2.38) | 0.93 (0.33–2.58) | 12 (48.0) | 1.17 (0.50–2.76) | 1.24 (0.47–3.31) | 3 (12.0) | 0.73 (0.20–2.67) | 0.80 (0.19–3.37) |
Subgroup 1 + 2 + 3 n = 124 | 61 (49.2) | 1.44 (0.88–2.38) | 1.48 (0.81–2.69) | 54 (43.5) | 0.98 (0.59–1.61) | 0.95 (0.52–1.74) | 9 (7.3) | 0.42 (0.18–0.96) p = 0.035 | 0.43 (0.16–1.17) p = 0.097 |
Subgroup A n = 103 | 54 (52.4) | 1.64 (0.97–2.78) p = 0.063 | 1.80 (0.94–3.43) p = 0.074 | 42 (40.8) | 0.87 (0.52–1.48) | 0.75 (0.39–1.44) | 7 (6.8) | 0.39 (0.16–0.96) p = 0.036 | 0.47 (0.16–1.36) |
Subgroup B n = 76 | 36 (47.4) | 1.34 (0.76–2.38) | 1.59 (0.78–3.22) | 35 (46.1) | 1.08 (061–1.92) | 1.06 (0.53–2.14) | 5 (6.6) | 0.38 (0.14–1.05) p = 0.054 | 0.23 (0.06–0.88) p = 0.032 |
Subgroup C n = 27 | 16 (59.3) | 2.17 (0.93–5.05) p = 0.069 | 2.59 (0.89–7.50) p = 0.079 | 10 (37.0) | 0.75 (0.32–1.76) | 0.67 (0.23–1.90) | 1 (3.7) | 0.21 (0.03–1.60) p = 0.098 | 0.18 (0.02–1.84) |
Subgroup D n = 40 | 19 (47.5) | 1.35 (0.66–2.76) | 1.94 (0.79–4.79) | 19 (47.5) | 1.15 (0.56–2.34) | 0.90 (0.37–2.16) | 2 (5.0) | 0.28 (0.06–1.26) p = 0.080 | 0.22 (0.04–1.31) p = 0.096 |
Table 4.
Association of VDR FokI genotypes and lumbar spine pathologies in females. Total 245 female subjects (127 controls and 118 cases) evaluated. Female patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Table 4.
Association of VDR FokI genotypes and lumbar spine pathologies in females. Total 245 female subjects (127 controls and 118 cases) evaluated. Female patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Variables | FF n (%) | Crude OR | Adjusted OR 1 | Ff n (%) | Crude OR | Adjusted OR 1 | ff n (%) | Crude OR | Adjusted OR 1 |
---|
(95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) |
---|
p
Value | p Value | p Value | p Value | p Value | p Value |
---|
Controls n = 127 | 50 (39.4) | - | - | 61 (48.0) | - | - | 16 (12.6) | - | - |
Subgroup 1 n = 41 | 12 (29.3) | 0.64 (0.30–1.36) | 0.75 (0.34–1.66) | 21 (51.2) | 1.14 (0.56–2.30) | 0.96 (0.45–2.04) | 8 (19.5) | 1.68 (0.66–4.28) | 1.81 (0.65–4.99) |
Subgroup 2 n = 32 | 20 (62.5) | 2.57 (1.15–5.71) p = 0.018 | 2.48 (1.07–5.74) p = 0.034 | 9 (28.1) | 0.42 (0.18–0.99) p = 0.043 | 0.38 (0.16–0.93) p = 0.033 | 3 (9.4) | 0.72 (0.20–2.63) | 1.02 (0.25–4.06) |
Subgroup 3 n = 19 | 7 (36.8) | 0.90 (0.33–2.44) | 0.90 (0.32–2.54) | 11 (57.9) | 1.49 (0.56–3.94) | 1.41 (0.50–3.96) | 1 (5.3) | 0.39 (0.05–3.09) | 0.43 (0.05–3.72) |
Subgroup 4 n = 26 | 7 (26.9) | 0.57 (0.22–1.45) | 0.55 (0.19–1.57) | 13 (50.0) | 1.08 (0.47–2.52) | 0.89 (0.34–2.30) | 6 (23.1) | 2.08 (0.73–5.96) | 3.20 (0.94–11.0) p = 0.064 |
Subgroup 1 + 2 + 3 n = 92 | 39 (42.4) | 1.13 (0.66–1.96) | 1.25 (0.70–2.24) | 41 (44.6) | 0.87 (0.51–1.49) | 0.77 (0.43–1.37) | 12 (13.0) | 1.04 (0.47–2.32) | 1.10 (0.46–2.59) |
Subgroup A n = 73 | 32 (43.8) | 1.20 (0.67–2.15) | 1.30 (0.69–2.42) | 30 (41.1) | 0.76 (0.42–1.35) | 0.67 (0.36–1.25) | 11 (15.1) | 1.23 (0.54–2.82) | 1.39 (0.56–3.44) |
Subgroup B n = 51 | 27 (52.9) | 1.73 (0.90–3.34) p = 0.098 | 1.74 (0.88–3.46) | 20 (39.2) | 0.70 (0.36–1.35) | 0.64 (0.32–1.28) | 4 (7.8) | 0.59 (0.19–1.86) | 0.71 (0.21–2.36) |
Subgroup C n = 37 | 21 (56.8) | 2.02 (0.96–4.24) p = 0.060 | 1.88 (0.87–4.08) | 12 (32.4) | 0.52 (0.24–1.12) p = 0.093 | 0.49 (0.22–1.10) p = 0.083 | 4 (10.8) | 0.84 (0.26–2.69) | 1.07 (0.31–3.65) |
Subgroup D n = 10 | 5 (50.0) | 1.54 (0.42–5.59) | 1.62 (0.43–6.06) | 5 (50.0) | 1.08 (0.30–3.92) | 1.01 (0.26–3.85) | 0 (-) | - | - |
Regarding the female population (
Table 4) in Subgroup 2 the
FF genotype had a frequency of 62.5%
vs. 39.4% of female controls (crude OR = 2.57; 95% CI = 1.15–5.71,
p = 0.018; adjusted OR = 2.48, 95% CI = 1.07–5.74,
p = 0.034), while the heterozygous
Ff genotype was protective (crude OR = 0.42; 95% CI = 0.18–0.99,
p = 0.043; adjusted OR = 0.38, 95% CI = 0.16–0.93,
p = 0.033). No other significant finding was observed for FokI genotypes in female Subgroups. An intriguing observation was that the
ff genotype showed a tendency for risk in the female Subgroup 4 (adjusted OR = 3.20, 95% CI = 0.94–11.0,
p = 0.064).
FokI alleles associations with detailed lumbar pathologic conditions in the entire sample including both sexes are reported in the Supplementary file (
Supplementary Table S2). The
F allele was a risk factor for several Subgroups of patients (and consequently the
f allele was protective) as follow: Subgroup 2 (crude OR = 1.75; 95% CI = 1.19–2.58,
p = 0.004; adjusted OR = 1.76; 95% CI = 1.14–2.73,
p = 0.011); Subgroup A (crude OR = 1.34; 95% CI = 1.00–1.79,
p = 0.048; adjusted OR not significant); Subgroup B (crude OR = 1.47; 95% CI = 1.06–2.04,
p = 0.020; adjusted OR = 1.49; 95% CI = 1.04–2.13,
p = 0.032), and Subgroup C (crude OR = 1.78; 95% CI = 1.15–2.76,
p = 0.010; adjusted OR = 1.64; 95% CI = 1.02–2.62,
p = 0.040).
Gender related FokI alleles associations with detailed lumbar pathologic conditions were reported in
Table 5 (males) and
Table 6 (females).
In males (
Table 5) frequency of the
F allele was almost 2-fold higher in several Subgroups of patients. Specifically, Subgroup 2 (crude OR = 1.70; 95% CI = 1.04–2.78,
p = 0.035; adjusted OR = 2.16; 95% CI = 1.15–4.05,
p = 0.017), Subgroup 1 + 2 + 3 (crude OR = 1.49; 95% CI = 1.02–2.16,
p = 0.038; adjusted OR = 1.50; 95% CI = 0.95–2.35,
p = 0.080), Subgroup A (crude OR = 1.63; 95% CI = 1.09–2.42,
p = 0.016; adjusted OR = 1.66; 95% CI = 1.02–2.70,
p = 0.042), Subgroup B (crude OR = 1.45; 95% CI = 0.94–2.22,
p = 0.093; adjusted OR = 1.72; 95% CI = 1.01–2.95,
p = 0.048), and Subgroup C (crude OR = 2.13; 95% CI = 1.07–4.24,
p = 0.029; adjusted OR = 2.36; 95% CI = 1.02–5.44,
p = 0.044) in respect to male controls. Consequently the
f allele was protective for male patients of Subgroups 2, 1 + 2 + 3, A, B, and C.
As shown in
Table 6, no significant finding was observed for FokI alleles in specific subgroups of female patients, with the exception of Subgroup 2 for which the
F allele (frequency 76.6% in female cases
vs. 63.4% in female controls) in a crude analysis had almost 2-fold increased risk (crude OR = 1.89; 95% CI = 1.00–3.55,
p = 0.047; adjusted OR not significant). Consequently the
f allele in females was protective for Subgroup 2, although significance was lost in adjusted analysis. Of note, an inverse trend was observed for the
f allele in female Subgroup 4 (
f frequency 48.1%
vs. 36.6% of female controls), crude OR not significant; adjusted OR = 1.82; 95% CI = 0.92–3.59;
p = 0.085. Overall in our study, the Subgroup 4 (
i.e., stenosis and/or spondilolysthesis) seems to differ in respect to all other Subgroups.
Table 5.
Association of VDR FokI alleles with lumbar spine pathologies in males. Total 276 male subjects (127 controls and 149 cases) evaluated. Male patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Table 5.
Association of VDR FokI alleles with lumbar spine pathologies in males. Total 276 male subjects (127 controls and 149 cases) evaluated. Male patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Male Subjects |
---|
Variables | F n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value | f n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value |
---|
Controls n = 254 | 158 (62.2) | - | - | 96 (37.8) | - | - |
Subgroup 1 n = 96 | 69 (71.9) | 1.55 (0.93–2.59) p = 0.091 | 1.37 (0.75–2.50) | 27 (28.1) | 0.64 (0.39–1.08) p = 0.091 | 0.73 (0.40–1.34) |
Subgroup 2 n = 110 | 81 (73.6) | 1.70 (1.04–2.78) p = 0.035 | 2.16 (1.15–4.05) p = 0.017 | 29 (26.4) | 0.59 (0.36–0.97) p = 0.035 | 0.46 (0.25–0.87) p = 0.017 |
Subgroup 3 n = 42 | 26 (61.9) | 0.99 (0.50–1.93) | 1.09 (0.50–2.37) | 16 (38.1) | 1.01 (0.52–1.98) | 0.92 (0.42–2.01) |
Subgroup 4 n = 50 | 32 (64.0) | 1.08 (0.58–2.03) | 1.01 (0.49–2.09) | 18 (36.0) | 0.93 (0.49–1.74) | 0.99 (0.48–2.03) |
Subgroup 1 + 2 + 3 n = 248 | 176 (71.0) | 1.49 (1.02–2.16) p = 0.038 | 1.50 (0.95–2.35) p = 0.080 | 72 (29.0) | 0.67 (0.46–0.98) p = 0.038 | 0.67 (0.43–1.05) p = 0.080 |
Subgroup A n = 206 | 150 (72.8) | 1.63 (1.09–2.42) p = 0.016 | 1.66 (1.02–2.70) p = 0.042 | 56 (27.2) | 0.61 (0.41–0.92) p = 0.016 | 0.60 (0.37–0.98) p = 0.042 |
Subgroup B n = 152 | 107 (70.4) | 1.45 (0.94–2.22) p = 0.093 | 1.72 (1.01–2.95) p = 0.048 | 45 (29.6) | 0.69 (0.45–1.07) p = 0.093 | 0.58 (0.34–0.99) p = 0.048 |
Subgroup C n = 54 | 42 (77.8) | 2.13 (1.07–4.24) p = 0.029 | 2.36 (1.02–5.44) p = 0.044 | 12 (22.2) | 0.47 (0.24–0.94) p = 0.029 | 0.42 (0.18–0.98) p = 0.044 |
Subgroup D n = 80 | 57 (71.3) | 1.51 (0.87–2.60) | 1.92 (0.97–3.80) p = 0.060 | 23 (28.8) | 0.66 (0.38–1.15) | 0.52 (0.26–1.03) p = 0.060 |
Table 6.
Association of VDR FokI alleles with lumbar spine pathologies in females. Total 245 female subjects (127 controls and 118 cases) evaluated. Female patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Table 6.
Association of VDR FokI alleles with lumbar spine pathologies in females. Total 245 female subjects (127 controls and 118 cases) evaluated. Female patients were subdivided in Subgroups 1 to 4 and A to D according to specific pathologic conditions. Subgroup 1 = patients with disc herniation alone; Subgroup 2 = patients with discopathies and/or osteochondrosis associated with disc herniation; Subgroup 3 = patients with discopathies and/or osteochondrosis without herniation; and Subgroup 4 = patients with stenosis and/or spondilolysthesis. Subgroup A, Subgroup 1 grouped with Subgroup 2 (i.e., all hernia cases with or without concomitant additional conditions); Subgroup B, Subgroup 2 grouped with Subgroup 3; Subgroup C, all discopathies cases with or without concomitant disc herniation; Subgroup D, all osteochondrosis cases with or without concomitant disc herniation.
Female Subjects |
---|
Variables | F n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value | f n (%) | Crude OR (95% CI) p Value | Adjusted OR 1 (95% CI) p Value |
---|
Controls n = 254 | 161 (63.4) | - | - | 93 (36.6) | - | - |
Subgroup 1 n = 82 | 45 (54.9) | 0.70 (0.42–1.16) | 0.75 (0.44–1.28) | 37 (45.1) | 1.42 (0.86–2.36) | 1.33 (0.78–2.27) |
Subgroup 2 n = 64 | 49 (76.6) | 1.89 (1.00–3.55) p = 0.047 | 1.71 (0.89–3.28) | 15 (23.4) | 0.53 (0.28–1.00) p = 0.047 | 0.59 (0.31–1.13) |
Subgroup 3 n = 38 | 25 (65.8) | 1.11 (0.54–2.28) | 1.08 (0.52–2.26) | 13 (34.2) | 0.90 (0.44–1.84) | 0.93 (0.44–1.94) |
Subgroup 4 n = 52 | 27 (51.9) | 0.62 (0.34–1.14) | 0.55 (0.28–1.09) p = 0.085 | 25 (48.1) | 1.60 (0.88–2.92) | 1.82 (0.92–3.59) p = 0.085 |
Subgroup 1 + 2+ 3 n = 184 | 119 (64.7) | 1.06 (0.71–1.57) | 1.10 (0.73–1.67) | 65 (35.3) | 0.95 (0.64–1.41) | 0.91 (0.60–1.38) |
Subgroup A n = 146 | 94 (64.4) | 1.04 (0.68–1.60) | 1.06 (0.68–1.67) | 52 (35.6) | 0.96 (0.63–1.46) | 0.94 (0.60–1.48) |
Subgroup B n = 102 | 74 (72.5) | 1.53 (0.92–2.53) p = 0.099 | 1.45 (0.86–2.44) | 28 (27.5) | 0.66 (0.40–1.09) p = 0.099 | 0.69 (0.41–1.16) |
Subgroup C n = 74 | 54 (73.0) | 1.56 (0.88–2.77) | 1.40 (0.77–2.53) | 20 (27.0) | 0.64 (0.36–1.14) | 0.72 (0.40–1.29) |
Subgroup D n = 20 | 15 (75.0) | 1.73 (0.61–4.92) | 1.74 (0.60–5.00) | 5 (25.0) | 0.58 (0.20–1.64) | 0.58 (0.20–1.66) |