Detection of Fetomaternal Genotype Associations in Early-Onset Disorders: Evaluation of Different Methods and Their Application to Childhood Leukemia

Table 5

Distribution of CDKN2A rs36228834 and CDKN2B rs36229158 genotypes and associated risk estimates for pre-B ALL susceptibility among children.

Gene, DNA variant,	No. (%)				Log-linear regression analysis
and genotype	ALL patients	ALL mothers	ALL fathers	Controls	Model	Genotype	Child OR (95% CI)	𝑃
CDKN2A
rs36228834					Child versus Null	TA versus TT	2.48 (1.45–4.15)	.001
TT	266 (86.6)	160 (93.0)	149 (86.6)	298 (93.7)		AA versus TT	9.87 (0.89–109.69)
TA	39 (12.7)	12 (7.0)	22 (12.8)	19 (6.0)		TA/AA versus TT	2.56 (1.54–4.26)	<.0005
AA	2 (0.7)	0	1 (0.6)	1 (0.3)	Child + Mother versus Null	TA versus TT	3.13 (1.81–5.40)	<.0005
						AA versus TT	—
						TA/AA versus TT	2.56 (1.54–4.26)	<.0005
CDKN2B
rs36229158					Child versus Null	CT versus CC	1.77 (0.98–3.21)	.054
CC	277 (91.4)	164 (95.4)	155 (90.1)	302 (94.7)		TT versus CC	8.25 (0.75–91.3)
CT	24 (7.9)	8 (4.6)	16 (9.3)	16 (5.0)		CT/TT versus CC	1.86 (1.04–3.34)	.037
TT	2 (0.7)	0	1 (0.6)	1 (0.3)	Child + Mother versus Null	CT versus CC	2.32 (1.23–4.35)	.033
						TT versus CC	—
						CT/TT versus CC	2.44 (1.29–4.60)	.006

Percentages indicate number of individuals with a given genotype/total number of genotyped individuals. Risk estimation was performed using log-linear regression analysis as implemented in the LEM software. Child odd ratios were measured using regression models consisting of the child genotype effect only (Child versus Null) or both child and mother genotypes (Child + Mother versus Null). Mating symmetry (i.e., six mating-type parameters) was assumed at both loci. 𝑃 values of the Wald test provided by LEM are shown for either the 2 degree-of-freedom (2 child genotype effects) or 1 degree-of-freedom (1 child genotype effect resulting from the collapsed heterozygous/homozygous rare genotypes) tests. OR indicates odds ratio; CI: confidence interval.