Genome-wide Association Analysis of Proinflammatory Cytokines and Gene–lifestyle Interaction for Invasive Breast Cancer Risk: The WHI dbGaP Study

Su Yon Jung; Peter A. Scott; Jeanette C. Papp; Eric M. Sobel; Matteo Pellegrini; Herbert Yu; Sihao Han; Zuo-Feng Zhang

doi:10.1158/1940-6207.CAPR-20-0256

DOI: 10.1158/1940-6207.CAPR-20-0256 Published January 2021

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Figure 1.
Regional plots for the SNP association [Note: LD (r²) shown by color intensity gradient]. A, Twenty SNPs nearby CRP and CRPP1 (r² > 0.7) with CRP. B, Fifty-four SNPs nearby HNF1A-AS1 and HNF1A (r² > 0.7) with CRP. C, Six SNPs nearby C12orf43 (r² > 0.9) with CRP. D, Two SNPs nearby MAPK1 (r² > 0.8) with IL6.

Table 1.

Distributions of proinflammatory phenotypes in six GWASs (N = 10,798).

		Phenotype
Study^a	N	IL6	CRP
Circulating plasma level		pg/mL, mean (SD)	mg/L, mean (SD)
AS264	1,603	4.478 (2.22)	3.883 (1.74)
GARNET	2,382	4.380 (3.16)	4.189 (7.50)
GECCO-CYTO	1,177	4.315 (3.04)	3.911 (3.81)
GECCO-INIT	216	3.221 (4.35)	4.323 (5.33)
HIPFX	1,909	4.548 (7.68)	3.752 (3.62)
WHIMS	3,511	4.472 (3.26)	3.360 (5.42)

		^b	≤3.0 mg/L/>3.0 mg/L^b
Binary analysis		n (%)/n (%)	n (%)/n (%)
AS264	1,603	1,195 (74.5)/408 (25.5)	517 (32.3)/1,086 (67.7)
GARNET	2,382	1,748 (73.4)/634 (26.6)	1,446 (60.7)/936 (39.3)
GECCO-CYTO	1,177	901 (76.6)/276 (23.4)	497 (42.2)/680 (57.8)
GECCO-INIT	216	187 (86.6)/29 (13.4)	124 (57.4)/92 (42.6)
HIPFX	1,909	1,436 (75.2)/473 (24.8)	813 (42.6)/1,096 (57.4)
WHIMS	3,511	2,649 (75.4)/862 (24.6)	2,325 (66.2)/1,186 (33.8)

↵^aGenotyping was run on several platforms: AS264 via Affymetrix Gene Titan, Axiom Genome-Wide Human CEU I Array Plate; GARNET via Illumina HumanOmni1-Quad v1–0 B; GECCO via Illumina 610 and Cytochip 370K; HIPFX via Illumina 550K and 610K; and WHIMS via HumanOmniExpress Exome-8v1_B.
↵^bEach phenotype was categorized via the corresponding cut-off value (4.4 pg/mL for IL6 and 3.0 mg/L for CRP); higher blood level than the threshold to be considered either the fourth quartile of the participants (≥ 75%, 4.4 pg/mL for IL6) or high immune response and chronic low-grade inflammation (> 3.0 mg/L for CRP; refs. 39, 40).

Table 2.

Participants' characteristics stratified by breast cancer.

	Participants without breast cancer	Participants with breast cancer
	(n = 9,642)	(n = 537)
Characteristics	n (%)	n (%)	P
Age in years, median (range)	67 (50–81)	67 (50–79)	0.085
Education			0.011
≤High school	3,476 (36.1)	164 (30.5)^a
>High school	6,166 (63.9)	373 (69.5)
Family income			0.002
<$35,000	4,344 (46.1)	207 (39.2)^a
≥$35,000	5,088 (53.9)	321 (60.8)
Family history of breast cancer			0.032
No	7,838 (81.3)	416 (77.5)^a
Yes	1,804 (18.7)	121 (22.5)
BMI in kg/m², median (range)	26.84 (16.83–58.49)	28.23 (17.55–49.31)^a	<0.001
BMI^b			<0.001
<30.0 kg/m²	6,859 (71.1)	320 (59.6)^a
≥30.0 kg/m²	2,783 (28.9)	217 (40.4)
WHR, median (range)	0.807 (0.444–1.393)	0.813 (0.640–1.263)^a	0.013
WHR^b			0.011
≤0.85	6,895 (71.5)	356 (66.3)^a
>0.85	2,747 (28.5)	181 (33.7)
Waist in cm, median (range)	85.00 (62.00–125.00)	88.50 (63.50–125.00)^a	<0.001
Waist^b			<0.001
≤88 cm	5,756 (59.7)	268 (49.9)^a
>88 cm	3,886 (40.3)	269 (50.1)
METs·hour/week^c	7.25 (0.00–134.17)	6.75 (0.00–81.67)	0.487
METs·hour/week^c			0.844
≥10.0	4,001 (41.5)	220 (41.0)
<10.0	5,641 (58.5)	317 (59.0)
How many cigarettes per day			<0.001
<15 cigarettes	5,432 (56.3)	250 (46.6)^a
≥15 cigarettes	4,210 (43.7)	287 (53.4)
Depressive symptoms^d, median (range)	0.002 (0.0004–0.937)	0.002 (0.0005–0.880)	0.836
Dietary alcohol per day in g, median (range)	1.04 (0.00–183.76)	1.86 (0.00–127.15)^a	0.001
% calories from SFA, median (range)	11.33 (2.22–32.39)	11.46 (3.73–21.50)	0.967
% calories from SFA^e			0.297
<9.0%	2,174 (22.5)	132 (24.6)
≥9.0%	7,468 (77.5)	405 (75.4)
Age at menarche in years, median (range)	13 (≤ 9–≥ 17)	12 (≤9–≥17)^a	0.002
Hysterectomy ever			0.004
No	6,143 (63.7)	376 (70.0)^a
Yes	3,499 (36.3)	161 (30.0)
Age at menopause in years, median (range)	50 (20–60)	50 (21–63)	0.050
Oral contraceptive duration in years, median (range)	5.66 (0.08–47.00)	5.18 (0.08–21.00)^a	<0.001
Exogenous estrogen use (E only use)			0.001
Never use	6,697 (69.5)	411 (76.5)^a
<5 years	1,361 (14.1)	51 (9.5)
5 to <10 years	516 (5.4)	17 (3.2)
10 + years	1,068 (11.1)	58 (10.8)
Exogenous estrogen use (E + P use)			0.001
Never use	7,940 (82.3)	412 (76.7)^a
<5 years	927 (9.6)	64 (11.9)
5 to <10 years	406 (4.2)	30 (5.6)
10 + Years	369 (3.8)	31 (5.8)

Abbreviations: E, estrogen; E+P, estrogen plus progestin.
↵^aP < 0.05, χ² or Wilcoxon rank-sum test.
↵^bBMI, WHR, and WST were categorized using 30 kg/m², 0.85, and 88 cm, respectively, where cut-off levels or higher fall within the overall or visceral obese range (https://www.cdc.gov/obesity/adult/defining.html).
↵^cPhysical activity was estimated from recreational physical activity combining walking and mild, moderate, and strenuous physical activity. Each activity was assigned a MET value corresponding to intensity; the total MET·hours/week was calculated by multiplying the MET level for the activity by the hours exercised per week and summing the values for all activities. The total MET was stratified into two groups, with 10 METs as the cutoff according to current American College of Sports Medicine and American Heart Association recommendations (63).
↵^dDepression scales were estimated via a short form of the Center for Epidemiologic Studies Depression Scale.
↵^ePercent calories from SFA was classified by 9%, addressing low sample power (i.e., containing a quarter in one side) and adherent to the American Heart Association and American College of Cardiology dietary guidelines, which are aligned with the 2015–2020 Dietary Guidelines for Americans to help cardiovascular and metabolic diseases reductions (64).

Table 3.

Genome-wide associated SNPs with CRP and their associations with breast cancer risk in overall analysis.

			Allele^a
SNP	Chr	Position^b	(Ref/Alt)	OR^c	P	Q	HR^d (95% CI)	P
HNF1A rs2259852	12	121434833	A/G	0.84	4.95E-09	0.347	1.13 (1.00–1.27)	0.058
HNF1A rs2464195	12	121435475	A/G	0.84	4.96E-09	0.358	1.13 (1.00–1.27)	0.057
HNF1A rs2259816	12	121435587	T/G	0.84	5.16E-09	0.360	1.13 (1.00–1.28)	0.054
HNF1A rs1169306	12	121438311	T/C	0.84	5.13E-09	0.371	1.13 (1.00–1.27)	0.058
HNF1A rs735396	12	121438844	C/T	0.84	5.25E-09	0.375	1.13 (1.00–1.27)	0.058
HNF1A rs1169309	12	121439192	T/G	0.84	6.61E-09	0.356	1.13 (1.00–1.27)	0.057
HNF1A rs1169310	12	121439433	A/G	0.84	5.28E-09	0.376	1.13 (1.00–1.27)	0.058
C12orf43 rs1169311	12	121440731	T/C	0.84	5.64E-09	0.375	1.13 (1.00–1.27)	0.057

Note: Only SNPs significant on genome-wide level included (N = 10,179).
Abbreviations: Alt, alternative; Chr, chromosome; CI, confidence interval; Q, Cochran Q; Ref, reference.
↵^aAdditive genetic model regressed.
↵^bGRCh 37 coordinated.
↵^cGWA analysis for CRP adjusted for age and 10 PCs.
↵^dHR adjusted by age, education, annual family income, family history of breast cancer, BMI, waist-to-hip ratio, physical activity, depressive symptoms, How many cigarettes per day, dietary alcohol in g/day, % calories from SFA/day, hysterectomy, ages at menarche and menopause, oral contraceptive use, and exogenous estrogen only-use and plus progestin use.

Table 4.

Genome-wide associated SNPs with CRP and their relationships with breast cancer risk in obesity-stratified (BMI and WST) analysis.

			Allele^b	Non-obese group					Obese group
SNP	Chr	Position^a	(Ref/Alt)	OR^c	P^d	Q	HR^e (95% CI)	P	OR^c	P^d	Q	HR^e (95% CI)	P
				Non overall-obese group, BMI < 30 (n = 7,179)					<Overall obese group, BMI ≥ 30 (n = 3,000)
HNF1A-AS1 rs11065365	12	121392040	G/A	0.79	1.42E-08	0.209	0.92 (0.76–1.10)	0.360	0.76	2.75E-05	0.724	1.27 (1.02–1.58)	0.031
HNF1A-AS1 rs7953249	12	121403724	G/A	0.81	6.45E-09	0.154	0.94 (0.80–1.10)	0.432	0.78	7.58E-05	0.746	1.26 (1.04–1.53)	0.017
HNF1A-AS1 rs7135337	12	121404155	A/C	0.80	3.19E-09	0.150	0.95 (0.81–1.11)	0.505	0.77	4.75E-05	0.790	1.28 (1.06–1.56)	0.012
HNF1A-AS1 rs1920792	12	121404584	C/T	1.22	1.56E-08	0.062	1.06 (0.91–1.24)	0.451	1.28	0.0001	0.456	0.75 (0.62–0.91)	0.004
HNF1A-AS1 rs10774579	12	121405210	C/T	1.22	1.72E-08	0.062	1.06 (0.91–1.24)	0.457	1.28	0.0001	0.456	0.75 (0.62–0.91)	0.004
HNF1A-AS1 rs2393792	12	121406293	A/G	1.22	2.96E-08	0.081	1.04 (0.89–1.22)	0.605	1.27	0.0002	0.349	0.73 (0.60–0.89)	0.002
HNF1A-AS1 rs142632970	12	121413345	G/A	0.80	8.81E-09	0.805	0.96 (0.81–1.14)	0.633	0.80	0.001	0.219	1.24 (1.01–1.51)	0.041
HNF1A-AS1 rs7139079	12	121415293	G/A	0.80	1.37E-09	0.140	0.95 (0.81–1.12)	0.566	0.75	5.26E-06	0.762	1.26 (1.04–1.53)	0.018
HNF1A-AS1 rs2464190	12	121415390	C/T	0.80	3.22E-09	0.163	0.94 (0.80–1.10)	0.441	0.75	1.02E-05	0.615	1.26 (1.03–1.53)	0.023
HNF1A rs1169289	12	121416622	G/C	0.81	1.68E-08	0.156	0.96 (0.81–1.12)	0.580	0.77	3.62E-05	0.703	1.25 (1.03–1.52)	0.027
HNF1A rs7979473	12	121420260	A/G	0.80	7.62E-10	0.123	1.01 (0.86–1.18)	0.944	0.74	3.95E-06	0.896	1.24 (1.02–1.51)	0.032
HNF1A rs7979478	12	121420263	A/G	0.79	1.17E-10	0.167	0.99 (0.84–1.16)	0.864	0.75	1.15E-05	0.937	1.24 (1.01–1.51)	0.036
HNF1A rs7970695	12	121423376	G/A	0.79	5.40E-10	0.139	1.01 (0.86–1.18)	0.928	0.75	4.96E-06	0.911	1.24 (1.02–1.50)	0.031
HNF1A rs9738226	12	121423659	A/G	0.79	5.94E-10	0.130	1.01 (0.86–1.19)	0.902	0.75	4.96E-06	0.912	1.24 (1.02–1.51)	0.031
HNF1A rs2393791	12	121423956	C/T	0.79	5.16E-10	0.139	1.01 (0.86–1.18)	0.916	0.75	4.80E-06	0.911	1.24 (1.02–1.50)	0.031
HNF1A rs2393776	12	121424406	G/A	0.79	3.23E-10	0.218	1.01 (0.86–1.18)	0.918	0.74	2.31E-06	0.731	1.23 (1.01–1.49)	0.037
HNF1A rs2393775	12	121424574	G/A	0.79	3.25E-10	0.225	1.01 (0.86–1.18)	0.915	0.74	2.30E-06	0.732	1.23 (1.01–1.49)	0.037
HNF1A rs7310409	12	121424861	A/G	0.79	3.30E-10	0.225	1.01 (0.86–1.18)	0.915	0.74	2.31E-06	0.731	1.23 (1.01–1.49)	0.037
HNF1A rs2264782	12	121432603	T/C	0.82	4.64E-08	0.241	1.06 (0.90–1.24)	0.512	0.76	1.50E-05	0.616	1.24 (1.02–1.51)	0.030
HNF1A rs2259852	12	121434833	A/G	0.81	2.91E-08	0.273	1.05 (0.90–1.24)	0.519	0.76	2.45E-05	0.643	1.25 (1.03–1.51)	0.027
HNF1A rs2464195	12	121435475	A/G	0.81	2.82E-08	0.283	1.05 (0.90–1.24)	0.517	0.76	2.51E-05	0.641	1.25 (1.03–1.51)	0.027
HNF1A rs2259816	12	121435587	T/G	0.81	3.05E-08	0.281	1.06 (0.90–1.24)	0.498	0.76	2.54E-05	0.642	1.25 (1.03–1.51)	0.027
HNF1A rs1169306	12	121438311	T/C	0.81	2.81E-08	0.305	1.05 (0.90–1.24)	0.522	0.76	2.54E-05	0.637	1.25 (1.03–1.51)	0.027
HNF1A rs735396	12	121438844	C/T	0.81	2.83E-08	0.309	1.05 (0.90–1.24)	0.520	0.76	2.54E-05	0.637	1.24 (1.02–1.51)	0.027
HNF1A rs1169309	12	121439192	T/G	0.81	3.11E-08	0.294	1.05 (0.90–1.24)	0.513	0.77	2.97E-05	0.626	1.25 (1.03–1.51)	0.027
HNF1A rs1169310	12	121439433	A/G	0.81	2.85E-08	0.311	1.05 (0.90–1.24)	0.520	0.76	2.54E-05	0.637	1.24 (1.02–1.51)	0.027
C12orf43 rs1169311	12	121440731	T/C	0.81	2.98E-08	0.312	1.05 (0.90–1.24)	0.514	0.76	2.60E-05	0.637	1.24 (1.02–1.51)	0.027
				Non visceral-obese group, WST ≤ 88 (n = 6,024)					Visceral obese group, WST > 88 (n = 4,155)
HNF1A rs2393776	12	121424406	G/A	0.82	1.25E-06	0.168	0.97 (0.81–1.15)	0.708	0.75	3.47E-08	0.530	1.23 (1.04–1.46)	0.017
HNF1A rs2393775	12	121424574	G/A	0.82	1.27E-06	0.173	0.97 (0.81–1.15)	0.711	0.75	3.42E-08	0.528	1.23 (1.04–1.46)	0.017
HNF1A rs7310409	12	121424861	A/G	0.82	1.28E-06	0.172	0.97 (0.81–1.15)	0.711	0.75	3.47E-08	0.530	1.23 (1.04–1.47)	0.017

Note: Only SNPs significant on genome-wide level included. Numbers in bold face are statistically significant.
Abbreviations: Alt, alternative; Chr, chromosome; CI, confidence interval; Q, Cochran Q; Ref, reference.
↵^aGRCh 37 coordinated.
↵^bAdditive genetic model regressed.
↵^cGWA analysis for CRP adjusted for age and 10 PCs.
↵^dP values were adjusted to correct for multiple testing via the Benjamini–Hochberg approach.
↵^eHR adjusted by age, education, annual family income, family history of breast cancer, body mass index (not in BMI-stratified), WHR (not in WST-stratified), physical activity, depressive symptoms, how many cigarettes per day, dietary alcohol in g/day, % calories from SFA/day, hysterectomy, ages at menarche and menopause, oral contraceptive use, and exogenous estrogen only-use and plus progestin use.

Table 5.

GWA analysis for the association with CRP, stratified by obesity-related lifestyle factors (physical activity and fat diet).

			Allele^b	Interaction test			Active/less-fat diet group			Inactive/high-fat diet group
SNP	Chr	Position^a	(Ref/Alt)	OR^c	P	Q	OR^c	P^d	Q	OR^c	P^d	Q
				Interaction test for PA			MET ≥ 10 (n = 4,221)			MET < 10 (n = 5,958)
CRPP1 rs2808628	1	159676011	G/A	0.97	0.354	0.401	1.16	0.002	0.203	1.26	9.13E-09	2.00E-04
CRPP1 rs2808629	1	159676796	G/A	0.97	0.368	0.352	1.16	0.002	0.210	1.26	1.28E-08	2.00E-04
CRPP1/CRP rs2794520	1	159678816	C/T	0.97	0.361	0.350	1.16	0.002	0.244	1.26	9.62E-09	2.00E-04
CRP rs1205	1	159682233	C/T	0.97	0.335	0.306	1.16	0.002	0.246	1.26	1.03E-08	2.00E-04
CRP rs3091244	1	159684665	G/A	1.03	0.354	0.037	0.85	0.001	0.078	0.80	1.01E-08	<8E-03
CRP rs1341665	1	159691559	G/A	0.97	0.377	0.528	1.15	0.003	0.258	1.25	4.85E-08	9.00E-04
CRP rs2211320	1	159693605	G/A	0.98	0.450	0.361	1.17	0.001	0.273	1.26	2.24E-08	3.00E-04
CRP rs7551731	1	159694779	T/C	0.97	0.322	0.381	1.15	0.003	0.292	1.26	1.57E-08	6.00E-04
CRP rs7553007	1	159698549	G/A	0.97	0.350	0.414	1.16	0.003	0.296	1.26	1.86E-08	9.00E-04
CRP rs4546916	1	159699249	G/T	0.97	0.354	0.412	1.16	0.003	0.303	1.26	1.87E-08	8.00E-04
CRP rs4287174	1	159703442	T/A	0.97	0.344	0.431	1.16	0.003	0.315	1.26	2.06E-08	9.00E-04
CRP rs12037186	1	159706230	A/G	0.97	0.332	0.342	1.15	0.004	0.264	1.26	2.01E-08	5.00E-04
				Interaction test for SFA			% cal. from SFA < 9.0 (n = 2,306)			% cal. from SFA ≥ 9.0 (n = 7,873)
CRPP1 rs2592887	1	159652939	C/T	0.99	0.725	0.053	1.15	0.033	0.008	1.21	1.27E-08	0.007
CRPP1 rs1470515	1	159653599	C/T	0.99	0.787	0.023	1.18	0.015	0.002	1.22	4.70E-09	0.010
CRPP1 rs2592902	1	159655726	G/T	0.99	0.773	0.022	1.18	0.015	0.002	1.22	4.59E-09	0.008
CRPP1 rs2808624	1	159665921	C/G	0.99	0.741	0.028	1.17	0.017	0.002	1.22	3.53E-09	0.010
CRPP1 rs11265257	1	159668984	C/T	0.99	0.730	0.029	1.17	0.018	0.002	1.22	3.17E-09	0.010
CRPP1 rs876537	1	159674933	C/T	0.99	0.730	0.032	1.17	0.017	0.002	1.22	2.73E-09	0.011
CRPP1 rs2808628	1	159676011	G/A	1.01	0.854	0.037	1.24	0.002	0.010	1.23	4.53E-09	7.00E-04
CRPP1 rs2808629	1	159676796	G/A	1.01	0.766	0.041	1.24	0.002	0.010	1.22	7.62E-09	0.001
CRPP1/CRP rs2794520	1	159678816	C/T	1.01	0.732	0.033	1.24	0.002	0.009	1.22	6.36E-09	0.001
CRP rs1205	1	159682233	C/T	1.01	0.736	0.049	1.24	0.002	0.013	1.22	9.46E-09	0.002
CRP rs3091244^e	1	159684665	G/A	0.99	0.826	0.266	0.81	0.002	0.152	0.83	3.12E-08	9.00E-04
CRP rs2027471^e	1	159689388	T/A	1.01	0.758	0.018	1.23	0.003	0.010	1.21	2.74E-08	0.001
CRP rs1341665^e	1	159691559	G/A	1.01	0.797	0.018	1.22	0.004	0.010	1.21	2.49E-08	0.002
CRP rs2211320	1	159693605	G/A	1.01	0.677	0.027	1.26	0.001	0.009	1.23	9.94E-09	0.002
CRP rs7551731^e	1	159694779	T/C	1.01	0.659	0.031	1.25	0.002	0.009	1.22	1.82E-08	0.003
CRP rs7553007^e	1	159698549	G/A	1.02	0.636	0.029	1.25	0.001	0.009	1.22	2.04E-08	0.005
CRP rs4546916^e	1	159699249	G/T	1.02	0.639	0.028	1.25	0.001	0.009	1.22	1.99E-08	0.005
CRP rs4287174^e	1	159703442	T/A	1.01	0.662	0.026	1.25	0.002	0.009	1.22	2.30E-08	0.004
CRP rs4428887^e	1	159703462	A/G	1.01	0.753	0.014	1.23	0.003	0.010	1.21	4.50E-08	0.003
CRP rs12037186^e	1	159706230	A/G	1.02	0.581	0.017	1.25	0.002	0.007	1.22	3.00E-08	0.002
HNF1A-AS1 rs11065365	12	121392040	G/A	1.13	0.0003	0.701	0.64	5.91E-10	0.461	0.87	0.0002	0.460
HNF1A-AS1 rs7953249	12	121403724	G/A	1.10	0.002	0.766	0.68	7.19E-09	0.444	0.88	0.0001	0.304
HNF1A-AS1 rs7135337	12	121404155	A/C	1.10	0.002	0.763	0.67	5.16E-09	0.431	0.87	6.09E-05	0.319
HNF1A-AS1 rs1920792	12	121404584	C/T^f	0.91	0.002	0.544	1.45	7.64E-09	0.208	1.12	0.0004	0.440
HNF1A-AS1 rs10774579	12	121405210	C/T	0.91	0.002	0.546	1.43	2.92E-08	0.075	1.12	0.0004	0.435
HNF1A-AS1 rs2393792^e	12	121406293	A/G	0.91	0.002	0.568	1.43	4.67E-08	0.061	1.12	0.001	0.572
HNF1A-AS1 rs2255531	12	121414915	A/G	1.11	0.002	0.977	0.67	1.05E-08	0.913	0.86	2.73E-05	0.133
HNF1A-AS1 rs7139079	12	121415293	G/A	1.10	0.001	0.745	0.66	8.91E-10	0.631	0.87	2.04E-05	0.145
HNF1A-AS1 rs2464190	12	121415390	C/T	1.11	0.001	0.459	0.66	8.24E-10	0.526	0.87	5.72E-05	0.082
HNF1A rs1169289	12	121416622	G/C	1.09	0.006	0.239	0.68	1.69E-08	0.338	0.87	6.50E-05	0.085
HNF1A rs1169288	12	121416650	C/A	1.10	0.005	0.907	0.66	2.90E-08	0.793	0.84	1.94E-06	0.160
HNF1A rs2244608	12	121416988	G/A	1.09	0.006	0.944	0.67	2.07E-08	0.796	0.84	9.16E-07	0.291
HNF1A rs1169284	12	121419926	C/T	1.10	0.003	0.941	0.66	6.49E-09	0.849	0.84	1.05E-06	0.242
HNF1A rs7979473	12	121420260	A/G^f	1.11	0.001	0.696	0.65	2.29E-10	0.683	0.86	1.50E-05	0.158
HNF1A rs7979478	12	121420263	A/G^f	1.11	0.001	0.656	0.65	1.88E-10	0.639	0.86	9.31E-06	0.299
HNF1A rs1183910	12	121420807	A/G	1.10	0.003	0.904	0.65	3.58E-09	0.900	0.84	1.33E-06	0.236
HNF1A rs11065384	12	121423285	T/C	1.10	0.003	0.908	0.65	4.11E-09	0.904	0.84	1.24E-06	0.226
HNF1A rs7970695	12	121423376	G/A^f	1.10	0.001	0.570	0.65	3.60E-10	0.626	0.86	1.09E-05	0.149
HNF1A rs11065385	12	121423386	A/G	1.10	0.003	0.902	0.65	4.01E-09	0.906	0.84	1.13E-06	0.228
HNF1A rs9738226	12	121423659	A/G^f	1.10	0.002	0.616	0.65	4.49E-10	0.649	0.86	1.11E-05	0.146
HNF1A rs2393791	12	121423956	C/T^f	1.10	0.001	0.543	0.65	3.13E-10	0.626	0.86	1.16E-05	0.141
HNF1A rs2393776	12	121424406	G/A^f	1.11	0.001	0.669	0.65	1.80E-10	0.765	0.86	8.07E-06	0.218
HNF1A rs2243458	12	121424490	T/A^f	1.11	0.002	0.824	0.65	1.58E-09	0.937	0.84	1.09E-06	0.300
HNF1A rs2393775	12	121424574	G/A^f	1.11	0.001	0.666	0.65	1.84E-10	0.767	0.86	8.16E-06	0.223
HNF1A rs7310409	12	121424861	A/G^f	1.11	0.001	0.665	0.65	1.84E-10	0.768	0.86	8.23E-06	0.222
HNF1A rs1169292	12	121426478	T/C	1.10	0.004	0.732	0.66	1.08E-08	0.928	0.84	1.74E-06	0.295
HNF1A rs1169294	12	121426594	A/G	1.10	0.004	0.734	0.66	1.16E-08	0.921	0.84	1.20E-06	0.284

Note: Only genome-wide significant SNPs included. Numbers in bold face are statistically significant.
Abbreviations: Alt, alternative; Chr, chromosome; PA, physical activity; Q, Cochran Q; Ref, reference.
↵^aGRCh 37 coordinated.
↵^bAdditive genetic model regressed.
↵^cGWA analysis for CRP adjusted for age and 10 PCs.
↵^dP values were adjusted to correct for multiple testing via the Benjamini–Hochberg approach.
↵^eSNPs did not reach the genome-wide significant level after multiple testing was corrected.
↵^fThe results from the additive model are presented; the dominant model had similar effect sizes and P values.

Table 6.

GWA analysis for the association with IL6.

				Overall analysis/Interaction test			Nonobese/less-fat diet/Active group			Obese/high-fat diet/Inactive group
SNP	Chr	Position^a	Allele^b (Ref/Alt)	OR^c	P	Q	OR^c	P^d	Q	OR^c	P^d	Q
				Overall analysis
DEC1 rs149109490	9	118330052	T/C	2.81	3.77E-08	0.36
				Interaction test for WHR			Non-visceral-obese group			Visceral obese group
							(WHR ≤ 0.85, n = 7,251)			(WHR > 0.85, n = 2,928)
DEC1 rs149109490	9	118330052	T/C	0.70	0.056	0.169	3.61	3.42E-08	0.078	1.74	0.105	0.770
				Interaction test for SFA			Less-fat diet group			High-fat diet group
							(% cal. from SFA < 9.0, n = 2,306)			(% cal. from SFA ≥ 9.0, n = 7,873)
DEC1 rs149109490	9	118330052	T/C	1.14	0.607	0.891	2.01	0.199	0.907	3.19	4.21E-08	0.144
				Interaction test for PA			Active group			Inactive group
							(MET ≥ 10, n = 4,221)			(MET < 10, n = 5,958)
MAPK1 rs56398890	22	22190785	A/T	1.16	5.29E-06	0.533	0.74	4.54E-08	0.978	1.00	0.909	0.335
MAPK1 rs9607320	22	22202164	T/C	1.17	3.73E-06	0.718	0.73	1.18E-08	0.938	0.99	0.897	0.292

Note: Only genome-wide significant SNPs included in overall and interaction tests (G × E or stratified analysis). Numbers in bold face are statistically significant.
Abbreviations: Alt, alternative; Chr, chromosome; PA, physical activity; Q, Cochran Q; Ref, reference.
↵^aGRCh 37 coordinated.
↵^bAdditive genetic model regressed.
↵^cGWA analysis for IL6 adjusted for age and 10 PCs.
↵^dP values were adjusted to correct for multiple testing via the Benjamini–Hochberg approach.