IGF-I and IGFBP-3 Polymorphisms in Relation to Circulating Levels among African American and Caucasian Women

Aimee A. D'Aloisio; Jane C. Schroeder; Kari E. North; Charles Poole; Suzanne L. West; Gregory S. Travlos; Donna D. Baird

doi:10.1158/1055-9965.EPI-08-0856

DOI: 10.1158/1055-9965.EPI-08-0856 Published March 2009

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Figure 1.
Estimated differences from mean plasma IGFBP-3 levels associated with IGFBP-3 diplotypes for premenopausal Caucasian and African American women based on race-specific linear regression models of each IGFBP-3 diplotype group on plasma IGFBP-3 levels. Posterior medians (95% posterior limits) were estimated using empirical-Bayes method of information-weighted averaging by assuming a prior mean of 0 and a prior variance (Caucasians 174,161 and African Americans 186,819) corresponding to 1 SD of mean plasma IGFBP-3 (2 * SD / 3.92)². For Caucasian models, group 1 includes n = 370 and group 2 includes n = 391. For African American models, group 1 includes n = 539, group 2 includes n = 563, and group 3 includes n = 547. Shaded area, ±200 ng/mL, which is ∼5% of the mean plasma IGFBP-3 levels (Caucasians group 1: 4,661 ng/mL and group 2: 4,587 ng/mL; African Americans group 1: 4,327 ng/mL, group 2: 4,060 ng/mL, and group 3: 4,106 ng/mL) for each reference diplotype.
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Figure 2.
Estimated differences from mean plasma IGF-I levels associated with IGF-I diplotypes for premenopausal Caucasian and African American women based on race-specific linear regression models of each IGF-I diplotype group on plasma IGF-I levels. Posterior medians (95% posterior limits) were estimated using empirical-Bayes method of information-weighted averaging by assuming a prior mean of 0 and a prior variance (Caucasians 901 and African Americans 1,419) corresponding to 1 SD of mean plasma IGF-I (2 * SD / 3.92)². For Caucasian models, group 1 includes n = 394, group 2 includes n = 393, group 3 includes n = 389, and group 4 includes n = 393. For African American models, group 1 includes n = 565, group 2 includes n = 558, group 3 includes n = 545, and group 4 includes n = 565. Shaded area, ±10% of the mean plasma IGF-I levels (Caucasians group 1: 171 ng/mL, group 2: 173 ng/mL, group 3: 165 ng/mL, and group 4: 172 ng/mL; African Americans group 1: 166 ng/mL, group 2: 162 ng/mL, group 3: 166 ng/mL, and group 4: 162 ng/mL) for each reference diplotype.

Table 1.

Characteristics of premenopausal Caucasian and African American women with genotype information from NIEHS UFS

Characteristics	Caucasians (n = 402), n (%)	African Americans (n = 582), n (%)
Age (y)
35-39	137 (34.1)	219 (37.6)
40-44	135 (33.6)	205 (35.2)
≥45	130 (32.3)	158 (27.1)
Education
High school	12 (3.0)	121 (20.8)*
Some postsecondary	33 (8.2)	265 (45.5)
College degree	133 (33.1)	123 (21.1)
Graduate degree	217 (54.0)	68 (11.7)
Missing	7 (1.7)	5 (0.9)
Current oral contraceptives^†	37 (9.2)	28 (4.8)
Parity
0	236 (58.7)	120 (20.6)
1	54 (13.4)	134 (23.0)
2	91 (22.6)	194 (33.3)
≥3	21 (5.2)	134 (23.0)
Body mass index
Underweight-normal weight (<25)	236 (58.7)	147 (25.3)
Overweight (25 to <30)	95 (23.6)	178 (30.6)
Obese (≥30)	71 (17.7)	257 (44.2)
Smoking status
Current smoker	31 (7.7)	172 (29.6)
Former smoker	139 (34.6)	133 (22.9)
Never smoked	232 (57.7)	277 (47.6)
Alcohol intake (past year)
<0.5 drinks/wk	60 (14.9)	300 (51.5)
≥0.5 drinks/wk	314 (78.1)	245 (42.1)
Missing	28 (7.0)	37 (6.4)

	Mean (SD)	Mean (SD)
Plasma IGF-I (ng/mL)^†	172 (58.7)	165 (74.0)
Plasma IGFBP-3 (ng/mL)^†	4,524 (822.3)	4,085 (859.7)

↵* Includes 11 women with less than high school education.
↵† n missing: oral contraceptives: 3 Caucasians and 4 African Americans; Plasma IGF-I and IGFBP-3: 1 Caucasian and 8 African Americans.

Table 2.

Estimated mean differences in plasma IGFBP-3 levels associated with IGFBP-3 SNP variants relative to estimated mean IGFBP-3 levels for reference genotypes (italicized) based on linear regression models for premenopausal Caucasian and African American women

IGFBP-3 SNP*	IGFBP-3 location	Caucasians											African Americans
IGFBP-3 SNP*	IGFBP-3 location			LD block^†	Diplotype group (position)^†	MAF (%)^‡	Genotype	n^§	Mean differences or means, ng/mL (95% CI)^∥	LD block^†	Diplotype group (position)^†	MAF (%)^‡	Genotype	n^§	Mean differences or means, ng/mL (95% CI)^∥
rs903889	Upstream	1	1 (1)	22.0	GG	22	−398 (−754 to −42)	Outside	1 (1)	9.4	GT, GG	97	−131 (−318 to 55)
													GT	131	−67 (−240 to 106)
													TT	246	4,572 (4,470-4,674)	TT	471	4,108 (4,031-4,185)
rs924140	Upstream	1	—	46.8	TT	82	581 (352-810)	1	—	38.9	CC	95	−560 (−761 to −360)
													CT	210	375 (190-560)	CT	251	−276 (−427 to −125)
													CC	107	4,210 (4,059-4,361)	TT	222	4,304 (4,194-4,414)
rs2854744	Upstream	1	1 (2)	46.3	AA	79	592 (364-819)	1	1 (2)	42.2	CC	107	−534 (−728 to −339)
													AC	204	353 (170-536)	AC	258	−258 (−412 to −105)
													CC	107	4,221 (4,073-4,370)	AA	195	4,305 (4,190-4,421)
rs2854746	Exon 1	1	1 (3)	41.7	CC	65	631 (398-864)	1	1 (3)	32.1	CC	52	897 (656-1,138)
													CG	203	379 (206-551)	CG	259	458 (318-598)
													GG	130	4,226 (4,091-4,360)	GG	256	3,798 (3,699-3,897)
rs2471551	Intron 1	1	1 (4)	19.4	CC	17	−345 (−745 to 55)	1	1 (4)	20.3	CC	27	−465 (−796 to −133)
													CG	119	−119 (−296 to 57)	CG	173	−258 (−412 to −105)
													GG	260	4,583 (4,484-4,682)	GG	364	4,193 (4,106-4,280)
rs9282734	Exon 2	—	—	0.4	AC	3	698 (−233 to 1,629)	—	1 (5)	3.3	AC, CC	36	24 (−263 to 311)
rs9282734	Exon 2	—	—	0.4				—	1 (5)	3.3			AA	393	4,520 (4,439-4,601)	AA	532	4,079 (4,007-4,151)
rs2453837	Intron 3	—	—	0	GG	397	4,524 (4,444-4,605)	—	—	0	GG	568	4,083 (4,012-4,154)
rs6953668	Intron 3	—	—	0.6	AG	5	394 (−330 to 1,119)	1	1 (6)	5.0	AG, AA	55	−124 (−362 to 115)
rs6953668	Intron 3	—	—	0.6				1	1 (6)	5.0			GG	394	4,522 (4,441-4,603)	GG	513	4,094 (4,020-4,169)
rs3110697	Intron 3	1	1 (5)	41.4	AA	62	−425 (−670 to −181)	Outside	1 (7)	36.1	AA	78	−551 (−764 to −338)
													AG	203	−188 (−366 to −10)	AG	251	−365 (−513 to −217)
													GG	131	4,693 (4,554-4,832)	GG	238	4,325 (4,219-4,431)
rs2453840	Intron 4	2	1 (6)	18.3	AA	12	−535 (−1,008 to −62)	2	2 (1)	9.2	AC, AA	98	209 (24-394)
													AC	121	−45 (−221 to 131)
													CC	263	4,560 (4,461-4,658)	CC	470	4,045 (3,969-4,122)
rs2453839	Intron 4	2	—	20.1	CC	14	−325 (−760 to 111)	2	2 (2)	40.9	CC	93	−167 (−380 to 45)
													CT	131	−114 (−285 to 57)	CT	279	−28 (−186 to 129)
													TT	250	4,574 (4,474-4,675)	TT	194	4,130 (4,009-4,251)
rs6670	Exon 5; 3′ untranslated	Outside	2 (1)	21.2	AA	12	74 (−402 to 551)	3	3 (1)	12.6	AT, AA	133	−44 (−210 to 121)
													AT	145	79 (−90 to 249)
													TT	240	4,494 (4,390-4,598)	TT	434	4,100 (4,020-4,180)
rs13223993	Downstream	Outside	2 (2)	21.4	AA	19	39 (−343 to 421)	3	3 (2)	43.6	AA	116	−17 (−216 to 182)
													AG	131	42 (−131 to 216)	AG	264	−147 (−308 to 14)
													GG	244	4,522 (4,419-4,624)	GG	184	4,163 (4,039-4,286)
rs2270628	Downstream	3	2 (3)	21.0	TT	15	−316 (−743 to 112)	4	3 (3)	36.2	TT	83	84 (−131 to 300)
													CT	137	−15 (−186 to 156)	CT	247	−64 (−218 to 90)
													CC	247	4,544 (4,441-4,646)	CC	236	4,101 (3,991-4,211)
rs12671457	Downstream	3	2 (4)	16.5	AC, CC	118	−119 (−296 to 59)	4	3 (4)	5.1	AC, CC	55	−218 (−456 to 21)
rs12671457	Downstream	3	2 (4)	16.5				4	3 (4)	5.1			AA	267	4,558 (4,460-4,657)	AA	510	4,106 (4,032-4,181)

↵* Represent tag SNPs except for 3 SNPs that were selected a priori: rs2854744 (-202 A/C), rs2854746 (Ala³²Gly), and rs9282734 (His¹⁵⁸Pro).
↵† LD blocks consist of SNPs with MAF ≥ 5% in strong LD (95% of pairwise SNP comparisons with one-sided 95% CIs for D′ within 0.70-0.98). Group refers to SNP combination for diplotype estimation; position refers to SNP order in each group. SNPs were excluded from diplotype estimation based on the Tagger algorithm (r² ≥ 0.8) or MAF < 5% for tag SNPs or MAF < 3% for SNPs selected a priori.
↵‡ Based on total n = 402 (Caucasians) and total n = 582 (African Americans).
↵§ Caucasians: n = 401, excluded 1 missing plasma IGFBP-3. African Americans: n = 574, excluded 8 missing plasma IGFBP-3.
↵∥ Mean plasma IGFBP-3 levels for reference genotypes estimated from linear regression intercepts are italicized in the last row for each SNP. Mean differences in plasma IGFBP-3 levels for heterozygous and homozygous variants relative to reference genotypes were estimated from β values in linear regression models.

Table 3.

Estimated mean differences in plasma IGF-I levels associated with IGF-I SNP variants relative to estimated mean IGF-I levels for reference genotypes (italicized) based on linear regression models for premenopausal Caucasian and African American women

IGF-I SNP*	IGF-I location	Caucasians											African Americans
IGF-I SNP*	IGF-I location			LD block^†	Diplotype group (position)^†	MAF (%)^‡	Genotype	n^§	Mean differences or means, ng/mL (95% CI)^∥	LD block^†	Diplotype group (position)^†	MAF (%)^‡	Genotype	n^§	Mean differences or means, ng/mL (95% CI)^∥
rs35767	Upstream	Outside	1 (1)	16.0	AG, AA	116	5 (−7 to 18)	1	1 (1)	40.8	AA	99	−1 (−19 to 17)
																AG	264	−2 (−16 to 11)
													GG	280	171 (164-177)	GG	205	166 (156-176)
rs5742612	Upstream	—	—	3.9	AG, GG	30	21 (−1 to 42)	—	—	3.3	AG, GG	35	5 (−20 to 31)
rs5742612	Upstream	—	—	3.9				—	—	3.3			AA	368	171 (165-177)	AA	536	164 (158-171)
rs5742614	Intron 1	—	—	1.8	CG	14	18 (−14 to 49)	1	1 (2)	11.5	CG, CC	124	8 (−6 to 23)
rs5742614	Intron 1	—	—	1.8				1	1 (2)	11.5			GG	385	172 (166-178)	GG	444	163 (156-170)
rs3729846	Exon 2	—	—	0				—	—	0.8	CT	9	33 (−16 to 82)
rs3729846	Exon 2	—	—	0				—	—	0.8			CC	399	172 (166-178)	CC	557	164 (158-170)
rs12821878	Intron 2	1	2 (1)	22.7	AA	21	0 (−26 to 27)	Outside	1 (3)	5.8	AG, AA	64	−15 (−34 to 5)
													AG	139	5 (−8 to 17)
													GG	237	171 (163-178)	GG	505	167 (160-173)
rs10860869	Intron 2	1	—	29.1	TT	31	−5 (−28 to 17)	Outside	2 (1)	32.3	TT	59	11 (−10 to 32)
													AT	170	6 (−6 to 18)	AT	249	12 (−1 to 25)
													AA	196	170 (162-179)	AA	262	158 (149-167)
rs1019731	Intron 2	1	2 (2)	12.3	AC, AA	93	10 (−4 to 23)	—	—	3.4	AC	39	−10 (−34 to 14)
rs1019731	Intron 2	1	2 (2)	12.3				—	—	3.4			CC	304	170 (164-177)	CC	528	165 (159-172)
rs7956547	Intron 2	1	2 (3)	27.3	CC	29	−5 (−28 to 18)	2	2 (2)	26.2	CC	43	8 (−16 to 32)
													CT	160	2 (−10 to 14)	CT	210	10 (−3 to 23)
													TT	209	172 (164-180)	TT	314	160 (152-168)
rs5742626	Intron 2	—	—	0.5	CT	4	−3 (−61 to 54)	2	2 (3)	7.2	CT, CC	78	−8 (−26 to 9)
rs5742626	Intron 2	—	—	0.5				2	2 (3)	7.2			TT	394	172 (166-178)	TT	491	166 (159-173)
rs17880975	Intron 2	—	—	0.1	AG	1	−78 (−193 to 37)	—	—	2.3	AG	26	8 (−21 to 38)
rs17880975	Intron 2	—	—	0.1				—	—	2.3			GG	395	173 (167-178)	GG	540	165 (158-171)
rs2033178	Intron 2	2	3 (1)	6.2	AG, AA	47	5 (−13 to 22)	—	—	4.7	AG, AA	50	−24 (−46 to −3)
rs2033178	Intron 2	2	3 (1)	6.2				—	—	4.7			GG	349	172 (166-178)	GG	513	167 (161-174)
rs17884646	Intron 2	—	—	0	TT	397	172 (166-178)	—	—	0	TT	570	165 (159-171)
rs5742657	Intron 2	—	—	2.2	AG, GG	17	18 (−11 to 46)	2	—	12.1	AG, GG	128	3 (−11 to 18)
rs5742657	Intron 2	—	—	2.2				2	—	12.1			AA	383	171 (166-177)	AA	440	164 (157-170)
rs5742663	Intron 2	—	—	0.1	GT	1	12 (−103 to 127)	2	—	11.6	GT, GG	123	8 (−6 to 23)
rs5742663	Intron 2	—	—	0.1				2	—	11.6			TT	396	172 (167-178)	TT	444	163 (156-170)
rs11829586	Intron 2	—	—	2.3	AG	18	16 (−12 to 43)	2	—	11.5	AG, AA	121	7 (−8 to 22)
rs11829586	Intron 2	—	—	2.3				2	—	11.5			GG	380	172 (166-178)	GG	445	163 (156-170)
rs4764884	Intron 2	2	—	25.7	TT	25	−16 (−40 to 8)	2	2 (4)	23.7	TT	34	10 (−16 to 36)
													CT	153	0 (−12 to 12)	CT	200	5 (−8 to 18)
													CC	218	173 (165-181)	CC	333	162 (154-170)
rs5742683	Intron 2	—	—	0.1	AG	1	12 (−102 to 127)	2	—	10.6	AG, GG	113	5 (−11 to 20)
rs5742683	Intron 2	—	—	0.1				2	—	10.6			AA	396	172 (166-178)	AA	454	164 (157-171)
rs17884626	Exon 3	—	—	0				—	—	1.0	CT	11	13 (−31 to 57)
rs17884626	Exon 3	—	—	0				—	—	1.0			CC	399	172 (167-178)	CC	559	164 (158-171)
rs5009837	Intron 3	2	—	30.3	TT	36	−6 (−27 to 15)	Outside	2 (5)	41.3	TT	105	8 (−9 to 26)
													CT	167	6 (−6 to 18)	CT	260	10 (−3 to 24)
													CC	192	170 (162-178)	CC	203	158 (148-168)
rs17727841	Intron 3	2	3 (2)	19.1	CC	15	−4 (−35 to 27)	—	—	4.7	CG, CC	49	23 (1-44)
													CG	123	−4 (−17 to 8)
													GG	261	174 (167-181)	GG	520	163 (156-169)
rs4764883	Intron 3	2	—	30.9	CC	37	−8 (−29 to 12)	3	—	45.8	TT	132	−12 (−29 to 5)
													CT	167	4 (−8 to 17)	CT	248	−11 (−25 to 3)
													TT	186	171 (163-179)	CC	180	173 (162-183)
rs9308315	Intron 3	2	—	28.2	AA	28	−16 (−39 to 7)	3	3 (1)	49.8	TT	150	−12 (−28 to 5)
													AT	166	3 (−9 to 15)	AT	262	−11 (−26 to 4)
													TT	201	172 (164-180)	AA	152	173 (161-185)
rs978458	Intron 3	2	3 (3)	28.0	TT	28	−13 (−37 to 10)	3	—	37.5	TT	83	9 (−10 to 28)
													CT	164	4 (−8 to 16)	CT	259	7 (−6 to 20)
													CC	202	172 (163-180)	CC	224	160 (151-170)
rs5742692	Intron 3	—	—	2.1				3	3 (2)	11.7	GG	11	14 (−31 to 58)
													AG	17	18 (−11 to 46)	AG	111	4 (−12 to 19)
													AA	382	171 (166-177)	AA	444	164 (157-170)
rs11111262	Intron 3	2	—	9.9	AG, AA	76	−4 (−19 to 10)	—	—	2.7	AG, AA	27	40 (11-68)
rs11111262	Intron 3	2	—	9.9				—	—	2.7			GG	321	173 (167-180)	GG	536	163 (157-169)
rs1520220	Intron 3	2	3 (4)	19.1	GG	13	−33 (−65 to 0)	3	3 (3)	34.7	GG	73	10 (−9 to 29)
													CG	124	7 (−6 to 19)	CG	250	6 (−7 to 19)
													CC	258	171 (164-178)	CC	245	161 (151-170)
rs3730204	Exon 4; 3′ untranslated	—	—	2.3	CT	18	−24 (−52 to 3)	—	—	0.3	CT	3	6 (−79 to 90)
rs3730204	Exon 4; 3′ untranslated	—	—	2.3				—	—	0.3			TT	378	173 (168-179)	TT	562	165 (159-171)
rs6214	Exon 4; 3′ untranslated	Outside	3 (5)	39.8	TT	67	17 (0-34)	Outside	3 (4)	45.2	CC	124	−3 (−20 to 14)
													CT	183	−2 (−14 to 11)	CT	263	−4 (−18 to 10)
													CC	148	170 (161-180)	TT	178	167 (156-178)
rs6219	Exon 4; 3′ untranslated	3	4 (1)	10.0	CT, TT	78	−6 (−20 to 9)	4	4 (1)	9.1	CT, TT	94	16 (−1 to 32)
rs6219	Exon 4; 3′ untranslated	3	4 (1)	10.0				4	4 (1)	9.1			CC	321	174 (167-180)	CC	475	162 (155-169)
rs2946834	Downstream	3	4 (2)	33.0	AA	39	−7 (−28 to 13)	4	4 (2)	49.3	AA	142	16 (0-33)
													AG	181	1 (−11 to 13)	AG	279	2 (−12 to 17)
													GG	175	172 (164-181)	GG	147	159 (147-171)

↵* Represent tag SNPs except for 2 SNPs that were selected a priori: rs3729846 (Thr⁵²Thr) and rs17884626 (Ala¹¹⁵Thr).
↵† LD blocks consist of SNPs with MAF ≥ 5% in strong LD (95% of pairwise SNP comparisons with one-sided 95% CIs for D′ within 0.70-0.98). Group refers to SNP combination for diplotype estimation; position refers to SNP order in each group. SNPs were excluded from diplotype estimation based on either Tagger algorithm (r² ≥ 0.8) or MAF < 5% for tag SNPs or MAF < 3% for SNPs selected a priori. For African Americans, rs9308315 was the substitute for rs4764883 (Hardy-Weinberg P < 0.01).
↵‡ Based on total n = 402 (Caucasians) and total n = 582 (African Americans).
↵§ Caucasians: n = 401, excluded 1 missing plasma IGF-I. African Americans: n = 574, excluded 8 missing plasma IGF-I.
↵∥ Mean plasma IGF-I levels for reference genotypes estimated from linear regression intercepts are italicized in the last row for each SNP. Mean differences in plasma IGF-I levels for heterozygous and homozygous variants relative to reference genotypes were estimated from β values in linear regression models.