Complex disease, gender and epigenetics

Figures & data

Figure 1 Complex non‐Mendelian diseases displaying differential susceptibility to complex diseases (based on epidemiological data obtained from Harrison's ‘Principles of Internal Medicine’ 15th edition, 2001) 111.

Table I. Some loci and markers exhibiting gender‐specific evidence for association (A) and linkage (B) in complex diseases and traits. Not all significant findings from each reference are reported. A. Association studies:

Disease or trait Gene	Polymorphism (allele, genotype, haplotype)	Sex	Statistic	Reference
Age‐related maculopathy
DRD2	141C Ins/Del	Female	P<0.05	112
DRD3	MscI Gly/Gly	Female	P<0.05	112
Alzheimer's disease
TFAM	rs1937 G/G	Female	P<0.05	113
COMT	RS4680, RS4680, RS737865	Female	P<0.05	114
Asthma
Cox‐2	765 C/C	Female	P = 0.01	115
Atopy
Angiotensinogen gene	235 Met/Thr	Female	P = 0.04	116
Angiotensinogen gene	‐6 A/G	Female	P = 0.016	116
Autism
SLC6A4	rs140700	Male	P<0.05	117
Behcet's disease (uveitis)
CCL2	−2518 GA/AA	Female	P = 0.02	118
CCR5	‐403 AA	Male	P = 0.005	118
CCL2	−2076 AA/AA or AA/AT	Male	P = 0.02	118
Bipolar disorder
GPR78	rs1282	Female	P = 0.038	119
MTHFR	677 CT and TT	Female	P = 0.023	120
Hepatic Lipase (HL)	250 G/A	Male	P = 0.025	121
CHD metabolic syndrome
LRPAP	LRPAP1_1b	Female	P = 0.0003	122
PRCP	PRCP_1	Male	P = 0.039	122
LDLR	LDLR_3b	Male	P = 0.046	122
Multiple sclerosis
IFNG	325 A	Male	P = 0.044	123
IFNG	761C/A	Male	P = 0.050	123
Obsessive compulsive disorder
DRD2 with COMT	A2A2 with NlaIII	Male	P = 0.035	124
Osteoporosis
MTHFR	677 TT	Female	P<0.05	125
APOE	Haplotype CGTC	Male	P = 0.001	126
APOE	Haplotype GGTT	Male	P = 0.002	126
APOE	Haplotype GATC	Male	P = 0.006	126
Parkinson's disease
DJ1	rs161799	Female	P = 0.03	127
DJ1	rs226253	Female	P = 0.002	127
Schizophrenia
DISC1	Hep3 Haplotype	Female	P = 0.00024	21
GPR78	rs1282	Female	P = 0.015	119
PLP1	rs475827	Male	P = 0.0294	128
Type I diabetes
AR	CAG Repeat	Female	P = 0.03	129
Longevity
APOE	Allele E2, E3, E4	Female	P<0.03	130
APOC‐I	Hpa I RFLP	Female	P<0.05	130
ACE	Homozygous ALU insertion	Female	P<0.05	130
Myocardial infarction
FXIII‐A	Leu34	Male	P<0.001	131
ERα	397 C/C	Male	P = 0.003	132
CCR2	64I Val/Ile	Female	P<0.01	133
Whole blood serotonin levels
Chromosome 10	D10S1677	Female	P = 0.0005	134
Chromosome 17	ITGB3_33	Male	P = 0.0003	134

B. Linkage studies:

Disease or trait Genomic Location	Marker	Sex	Statistic	Reference
Autism
15q	D15S117‐D15S125	Female	MLS = 2.62	17
17q11	D17S1294‐D17S798	Male	P = 0.008	16
7q	D7S480‐D7S530	Male	MLS = 2.55	17
16p	D16S407‐D16S497	Male	MLS = 2.48	17
Major depression
3centr	D3S2323	Female	LOD = 2.9	135
18q	D18S1270	Female	LOD = 3.5	135
2q35	D2S2208	Female	LOD = 6.87	19
2q33	D2S2321	Female	LOD = 6.3	19
1p36	D1S450	Female	LOD = 3.03	136
4q	D4S2631	Male	LOD = 2.6 (P = 0.00027)	135
15q	D15S1515	Male	LOD = 2.88 (P = 0.0001)	135
Early onset major depressive disease
12q22‐q23.2	D12S1300	Male	P = 0.00003	18
Osteoporosis
18p11	D18S53‐D18S478	Female	LOD = 2.83	137
20q13	D20S196‐D20S173	Female	LOD = 3.2	137
2p	194 cM	Male	LOD = 3.97	138
4q	90 cM	Male	LOD = 4.16	138
10q21	D10S196‐D10S537	Male	LOD = 4.42	137
Bone mineral density
3p22	76 cM	Female	LOD = 2.72	139
13q14	D13S788	Male	LOD = 3.46	140
Cortisol
10q	97 cM	Female	P = 0.024	22
Eosinophilia
10q	77 cM	Female	P = 0.0041	22
Serotonin
17q	70 cM	Female	P = 0.0049	22
Forced expiratory volume at 1 s/forced vital capacity
5q	154 cM	Male	P = 0.022	22
7p	55 cM	Male	P = 0.0025	22
High‐density lipoprotein cholesterol
9q	117 cM	Male	P = 0.0084	22
Systolic blood pressure
8q	109cM	Male	P = 0.0007	22
Lymphocyte count
16q	129 cM	Male	P = 0.029	22
% Lymphocyte count per white blood cell count
19p	43 cM	Male	P = 0.027	22
Triglycerides
21q	30 cM	Male	P = 0.048	22
Whole blood serotonin levels
6q	183 cM	Female	P<0.002	134
16p	56 cM	Male	P<0.002	134

Figure 2 In the absence of ligand or in the presence of antagonist, steroid receptors(SR) recruit transcriptional corepressor complexes to the DNA, producing an epigenetically silenced state through histone deacetylation or methylation. In the presence of hormone, SR recruit coactivator complexes, histone‐modifying machines or ATP‐dependent chromatin remodeling machines, to acetylate histones and produce a euchromatic chromatin formation suitable for transcriptional activation.

Figure 3 Loci identified as significantly different in DNA methylation between male and female postmortem brain samples. DNA methylation profiles were measured by human CpG island microarrays in a common reference design. Each microarray interrogates 12,912 loci whose locations on the chromosomes are shown in white in the plot. Data were logarithmically transformed and then normalized, by the print‐tip loess method, to remove nonbiological effects. Vertically: human chromosomes 1 to 22. The t‐statistic of the male group versus female group was calculated for each locus and its P‐value was also obtained. Loci with P‐values below 0.05 are painted black in the plot.

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