Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

Table 1

Candidate SNP markers of circadian complications and/or comorbidities of Mendelian diseases as predicted by a significant change in the affinity of TATA-binding protein for human gene promoters.

Gene	dbSNP [24] rel. 146					, nM				Known Mendelian diseases (see [references]) and (hypothetically) circadian complications and comorbidities whose candidate SNP markers were predicted by us in [this work] (see Figure 2)	[References]; or  [this work]; (see Figure 2)
	ID or [reference]	SNP; wt→mut	5′ flank	wt; mut	3′ flank	wt; mut
HBB	rs397509430	-29tDEL	gggctgggca	t; —	atacaacagt	5; 29	↓	34	10^−6	Malaria resistance and β-thalassemia  and (hypothetically)  circadian symptoms (worse at night) in restless legs syndrome caused by iron deficiency anemia cooccurring with thalassemia and for sensorineural hearing loss as a complication of deferoxamine-based therapy in thalassemia	[24, 42],  [this work]; [43–47]
	rs33980857	-29t→a, g, c	gggctgggca	t; a, g, c	atacaacagt	5; 21	↓	27	10^−6
	rs34598529	-28a→g	ggctgggcat	a; g	aaagtcaggg	5; 18	↓	24	10^−6
	rs33931746	-27a→g, c	gctgggcata	a; g, c	aagtcagggc	5; 11	↓	14	10^−6
	rs33981098	-30a→g, c	agggctgggc	a; g, c	taaaagtcag	5; 9	↓	10	10^−6
	rs34500389	-31c→a, t, g	cagggctggg	c; a, t, g	ataaaagtca	5; 6	↓	3	10^−2
HBB	rs63750953	-25aaDEL	ctgggcataa	aa; —	gtcagggcag	5; 8	↓	9		(Hypothetically)malaria resistance, β-thalassemia, and circadian symptoms (worse at night) in restless legs syndrome and sensorineural hearing loss (for details, see above)	[This work]; [42–47]
	rs281864525	-25a→c	tgggcataaa	a; c	gtcagggcag	5; 7	↓	7
HBD	rs35518301	-31a→g	caggaccagc	a; g	taaaaggcag	4; 8	↓	11	10^−6	Malaria resistance and δ-thalassemia  and (hypothetically) circadian symptoms (worse at night)  for restless legs syndrome and sensorineural hearing loss (for details, see above)	[24, 42],  [this work]; [43–47]
HBD	rs34166473	-30t→c	aggaccagca	t; c	aaaaggcagg	4; 8	↓	18		(Hypothetically) malaria resistance, δ-thalassemia, and circadian symptoms (worse at night) for restless legs syndrome and sensorineural hearing loss (for details, see above)	[This work]; [42–47]
MMP12	rs2276109	-27a→g	gatatcaact	a; g	tgagtcactc	11; 14	↓	3	10^−2	Low risk of systemic sclerosis, psoriasis, and asthma whose symptoms are circadian (worse at night)	[48–51]
MMP12	rs572527200	-30a→g	gatgatatca	a; g	ctatgagtca	11; 14	↓	3		(Hypothetically) low risk of systemic sclerosis, psoriasis, and asthma whose symptoms are circadian (worse at night)	[This work]; [48–51]
IL1B	rs1143627	-31c→t	ttttgaaagc	c; t	ataaaaacag	5; 2	↑	15	10^−6	Gastric cancer in Helicobacter pylori infection, hepatocellular carcinoma in hepatitis C virus infection, non-small cell lung cancer, chronic gastritis and gastric ulcer in H. pylori infection, Graves’ disease, greater body fat in older men, recurrent major depressive disorder whose diagnosis and therapy are characterized by circadian optima for use, and (hypothetically)  bipolar disorder whose diagnosis and therapy are characterized by circadian optimafor usedepending on the diet	[24, 52–59],   [this work]; [60, 61]
IL1B	rs549858786	-28a→t	tgaaagccat	a; t	aaaacagcga	5; 6	↓	8		(Hypothetically) rheumatoid arthritis that can disrupt the circadian rhythm of IL1B gene expression	[This work]; [62, 63]
F3	rs563763767	-21c→t	ccctttatag	c; t	gcgcggggca	3; 2	↑	6	10^−6	Venous thromboembolism and myocardial infarction that are characterized by their circadian preference for the early morning in the elderly	[64–66]
F7	See [67]	-33a→c	ccttggaggc	a; c	gagaactttg	53; 62	↓	3	10^−2	Moderate bleeding tendency whose symptoms are circadian: worse with chronic change of time zones and in winter	[67, 68]
F7	rs749691733	-21c→t	agaactttgc	c; t	cgtcagtccc	53; 66	↓	4	10^−3	(Hypothetically) moderate bleeding tendency whose symptoms are circadian: worse with chronic change of time zones and in winter	[This work]; [67, 68]
F7	rs367732974	-19g→a	aactttgccc	g; a	tcagtcccat	53; 47	↑	2	0.05	(Hypothetically) heart attacks that are characterized by circadian preference for the early morning in the elderly and circadian (postprandial) flare-ups of thrombogenesis	[This work]; [69, 70]
	rs549591993	-13c→a	gcccgtcagt	c; a	ccatggggaa	53; 25	↑	13	10^−6
	rs777947114	-23g→a	agagaacttt	g; a	cccgtcagtc	53; 19	↑	19	10^−6
	rs770113559	-38g→a	gtcacccttg	g; a	aggcagagaa	53; 41	↑	5	10^−6
	rs754814507	-54c→t	cctcccccat	c; t	cctctgtcac	53; 45	↑	3	10^−3
NOS2	See [71]	-51t→c	gtataaatac	t; c	tcttggctgc	2; 1	↑	3	10^−2	Resistance to malaria and high risk of epilepsy that damages the hypothalamus and the circadian clock as a whole  and (hypothetically) remission of panic disorder whose symptoms are circadian (worse late in the evening)	[71–73],   [this work]; [74]
DHFR	rs10168	-26g→a	ctgcacaaat	g; a	gggacgaggg	15; 9	↑	9	10^−6	In leukemia, resistance to methotrexate therapy that is characterized by a circadian optimum for use	[13, 75]
DHFR	rs750793297	-25g→t	tgcacaaatg	g; t	ggacgagggg	15; 13	↑	3	0.01	(Hypothetically) in leukemia, resistance to methotrexate therapy that is characterized by a circadian optimum for use	[This work]; [13, 75]
DHFR	rs766799008	-28a→g	ctgcacaaat	a; g	tggggacgag	15; 19	↓	3	10^−3	(Hypothetically) enhancement of an apparent bioactivity of methotrexate therapy that may be characterized by a circadian optimum for use	[This work]; [13, 40, 75]
	rs764508464	-a28DEL	ctgcacaaat	a; —	tggggacgag	15; 37	↓	17	10^−6
	rs754122321	-31c→g	ctcgcctgca	c; g	aaatggggac	15; 25	↓	9	10^−3
StAR	rs16887226	-33c→t	cagccttcag	c; t	gggggacatt	10; 10	=	0	>0.5	Hypertension in diabetes (EMSA: an unknown TF-binding site is disrupted rather than a TBP-binding site)  and (hypothetically) weak circadian resistance to exotoxins (deficiency of the mediator between the circadian and immune systems)	[76]; [this work]; [11]
StAR	rs544850971	-22a→g	tcagcggggg	a; g	catttaagac	10; 12	↓	5		(Hypothetically) hypertension in diabetes and weak circadian resistance to exotoxins	[This work]; [11, 76]
CETP	See [77]	-54 18 bp DEL	cgtgggggct	[18]; —	gggctccagg	4; 7	↓	7	10^−6	Hyperalphalipoproteinemia reduces the risk of atherosclerosis that is characterized by circadian (postprandial) flare-ups	[77–79]
CETP	rs17231520	-68g→a	ggggctgggc	g; a	gacatacata	4; 2	↑	10		(Hypothetically) risk of atherosclerosis that is characterized by circadian (postprandial) flare-ups and hypoalphalipoproteinemia causing chronopathologies of the liver	[This work]; [80]
	rs569033466	-53g→a	atacatatac	g; a	ggctccaggc	4; 3	↑	4
	rs757176551	-49c→g	catatacggg	c; g	tccaggctga	4; 2	↑	10
APOA1	See [81]	-35a→c	tgcagacata	a; c	ataggccctg	3; 4	↓	5	10^−3	Hypoalphalipoproteinemia causing chronopathologies in the liver, as well as hematuria, fatty liver, and obesity,  and (hypothetically) atherosclerosis that is characterized by circadian (postprandial) flare-ups	[80, 81]; [this work]; [77–80]
CYP2B6	rs34223104	-28t→c	gatgaaattt	t; c	ataacagggt	4; 10	↓	15	10^−6	Better metabolic activation of anticancer prodrug cyclophosphamide that is characterized by a circadian optimum for use	[14, 82]
CYP2B6	rs563558831	-26t→c	tgaaatttta	t; c	aacagggtgc	4; 10	↓	13		(Hypothetically) better metabolic activation of cyclophosphamide that is characterized by a circadian optimum for use	[This work]; [14, 82]
INS	rs5505	-9c→t	agatcactgt	c; t	cttctgccat	53; 44	↑	4	10^−6	Type 1 diabetes after neonatal diabetes mellitus and risk of hyperinsulinemia that disturbs circadian rhythms of the reproductive system, of blood pressure, and of tumor-host balance	[24, 83–85]
INS	rs563207167	-28c→t	tcagccctgc	c; t	tgtctcccag	53; 44	↑	4	10^−3	(Hypothetically) type 1 diabetes after neonatal diabetes mellitus and risk of hyperinsulinemia that disturbs circadian rhythms of the reproductive system, of blood pressure, and of tumor-host balance	[This work]; [24, 83–85]
INS	rs11557611	-8c→t	gatcactgtc	c; t	ttctgccatg	53; 60	↓	2	0.05	(Hypothetically) hypothalamic amenorrhea	[This work]; [86]
ESR2	rs35036378; (see Figure 1(a))	-43t→g	cctctcggtc	t; g	ttaaaaggaa	6; 8	↓	5	10^−3	Preventive therapy for an ESR2-deficient pT1 primary tumor against its progression to breast cancer by means of tamoxifen when this treatment is characterized by a circadian optimum for use  and (hypothetically) disturbances in circadian (daytime) behavioral activity	[87–89]; [this work]; [90]
ESR2	rs766797386	-32g→t	ttaaaaggaa	g; t	aaggggctta	6; 7	↓	3	10^−2	(Hypothetically)  preventive therapy for an ESR2-deficient primary pT1 tumor against its progression to breast cancer by means of tamoxifen when this treatment is characterized by a circadian optimum for use; disturbances in circadian (daytime) behavioral activity	[This work]; [87–90]

wt, ancestral allele; mut, minor allele; , an estimate [35] of the dissociation constant () of the TBP-DNA complex in vitro [91]; Δ, a gene expression change in comparison with the norm (=): overexpression (↑) and underexpression (↓); , -score; , significance (where is a probability rate of acceptance of hypothesis “  ≠  ”; see Figure 1); TF, transcription factor; EMSA, electrophoretic mobility shift assay.