Table 2 Association of the 3 principal... | American Society of Hematology

Table 2

Association of the 3 principal loci (BCL11A, HMIP, and the β-globin gene cluster) with HbF levels

Genetic variants tested				Tanzanian HbSS patients				British HbSS patients
Locus	SNP name	Position* on chromosome	Allele change	Minor allele frequency	Effect† of allele change	P	n	Minor allele frequency	Effect† of allele change	P‡	n
Chromosome 2
BCL11A	rs11886868	60 573 750	C → T	0.26	−0.406	3.0 × 10⁻³⁰	1000	0.29	−0.302	8.5 × 10⁻⁴	146
BCL11A	rs4671393	60 574 455	A → G	0.30	−0.412	3.9 × 10⁻²⁸	845	0.28	−0.440	3.7 × 10⁻⁶	145
Chromosome 6
HMIP-1	rs28384513	135 417 902	A → C	0.21	−0.146	1.9 × 10⁻⁴§	1021	0.21	+0.103	.36	142
HMIP-2	rs9376090	135 452 920	T → C	0.01	+0.471	.016	1021	0.02	+0.581	.058	147
HMIP-2	rs9399137	135 460 710	T → C	0.01	+0.668	8.3 × 10⁻⁶	975	0.07	+0.529	.006	126
HMIP-2	rs9389269	135 468 851	T → C	0.03	+0.400	1.4 × 10⁻⁵§	1016	0.04	+0.461	.031	146
HMIP-2	rs9402686	135 469 509	G → A	0.06	+0.342	1.6 × 10⁻⁴§	1013	0.04	+0.460	.031	146
HMIP-2	rs9494142	135 473 333	T → C	0.13	+0.085	.060	1014	0.10	+0.218	.127	144
Chromosome 11
HBG2	rs7482144‖	5 232 745	G → A	0.01	+0.562	1.6 × 10⁻⁴	991	0.07	+0.136	.43	147
OR51B5/6	rs5006884	5 329 827	C → T	0.05	+0.164	.024	957	0.13	+0.217	.15	145

Genetic variants tested				Tanzanian HbSS patients				British HbSS patients
Locus	SNP name	Position* on chromosome	Allele change	Minor allele frequency	Effect† of allele change	P	n	Minor allele frequency	Effect† of allele change	P‡	n
Chromosome 2
BCL11A	rs11886868	60 573 750	C → T	0.26	−0.406	3.0 × 10⁻³⁰	1000	0.29	−0.302	8.5 × 10⁻⁴	146
BCL11A	rs4671393	60 574 455	A → G	0.30	−0.412	3.9 × 10⁻²⁸	845	0.28	−0.440	3.7 × 10⁻⁶	145
Chromosome 6
HMIP-1	rs28384513	135 417 902	A → C	0.21	−0.146	1.9 × 10⁻⁴§	1021	0.21	+0.103	.36	142
HMIP-2	rs9376090	135 452 920	T → C	0.01	+0.471	.016	1021	0.02	+0.581	.058	147
HMIP-2	rs9399137	135 460 710	T → C	0.01	+0.668	8.3 × 10⁻⁶	975	0.07	+0.529	.006	126
HMIP-2	rs9389269	135 468 851	T → C	0.03	+0.400	1.4 × 10⁻⁵§	1016	0.04	+0.461	.031	146
HMIP-2	rs9402686	135 469 509	G → A	0.06	+0.342	1.6 × 10⁻⁴§	1013	0.04	+0.460	.031	146
HMIP-2	rs9494142	135 473 333	T → C	0.13	+0.085	.060	1014	0.10	+0.218	.127	144
Chromosome 11
HBG2	rs7482144‖	5 232 745	G → A	0.01	+0.562	1.6 × 10⁻⁴	991	0.07	+0.136	.43	147
OR51B5/6	rs5006884	5 329 827	C → T	0.05	+0.164	.024	957	0.13	+0.217	.15	145

Representative SNPs for BCL11A on chromosome 2, the HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6, and HBG2 on chromosome 11, which encodes Gγ-globin are shown. rs7482144 has been extensively studied as the Xmn1 ^Gγ-polymorphism, a component of the classic sickle haplotypes, where the alternative allele A is detected as positive (site present, Senegal and Arab/Indian haplotypes). Allele frequencies in the patient population were derived from all genotyped individuals (n > 1300).

The chromosomal position given here is based on the public human genome assembly National Center for Biotechnology Information 36.1 (University of California Santa Cruz, genome browser²¹).

†

“+” or “−” indicates whether the allele change elevates or depresses HbF (expressed as ln[% HbF]). The value reported here (the regression coefficient β) indicates by how much the trait value changes, on average, when one of the alleles in a genotype is changed. This is also referred to as the additive allelic effect.

‡

Although the allelic effect sizes (β) are often comparable between the 2 groups, P values are much larger in the British patients because of the smaller number of subjects studied.

Association with these makers remains significant at P < .001 after linkage disequilibrium with rs9399137 is taken into account (ie, these markers display HbF association independent of rs9399137).

‖

rs7482144 is also referred to as the Xmn1-Gγ site, where “+” indicates the alternative allele A.

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