. 2013 Apr 23;4:40. doi: 10.3389/fphar.2013.00040

Table 1.

Summary of published cystic fibrosis pulmonary modifiers.

Gene/locus	Genes involved	Variant aliases	Variant position (rs no.)	Phenotypes tested	Association p-value	Source n (reference)	Replication n (reference)	Tested, not replicated n (reference)
8.1AH	LTA TNF	+252 A > G −308 G > A	909253 1800629	FEV₁ % pred Chronic P. aeruginosa colonization	<0.04 0.99	404 (Corvol et al., 2012)
	HSP70-2 RAGE	1267 A > G −429 T > C	106158 1800625
8.1MHC	AGER HSP70-2	−429 T > C 1267 A > G	106158	Age at onset of colonization Frequency of colonization	0.036 0.012	72 (Laki et al., 2006)
	TNFA	G-308A
11p13	APIP EHF		12793173	FEV₁ % pred (adjusted)	3.34 × 10⁻⁸	1,978 (Wright et al., 2011)	557 (Wright et al., 2011)
19q13	hCFM1	APOC2, D19S219, D19S112 haplotype		FEV₁ % pred	0.779	197 sib pairs (Zielenski et al., 1999)
A1AT	SERPINA1	1237 G > A	11568814	FEV₁ % pred CXR score Age at onset of P. aeruginosa	0.368 0.813 0.146	157 (Mahadeva et al., 1998b)	716 (Frangolias et al., 2003)	124 (Henry et al., 2001) 320(Courtney et al., 2006) 808 (Drumm et al., 2005)
		S allele Z allele	17580 28929474	FEV₁% pred CXR score Age at onset of P. aeruginosa	0.043 0.127 0.899	157 (Mahadeva et al., 1998b)	215 (Doring et al., 1994) 79 (Mahadeva et al., 1998a)	124 (Henry et al., 2001) 269 (Meyer et al., 2002) 808 (Drumm et al., 2005)
ABCC1	MRP-1	4741 C > G	504348	Age at onset of P. aeruginosa Age at which FEV₁ < 60%	0.0644 <0.05	203 (Mafficini et al., 2011)
				FEV₁ % pred	0.52
ABO		T99T 21404 C > A	8176719 8176720 1053878	Pulmonary disease severity Age at onset of P. aeruginosa	No association No association	778 (Taylor-Cousar et al., 2009)
		R176G	7853989
		21583 T > A	8176740
		H219H	8176741
		P227P	8176742
			816750
		66119 G > A	8176472
ACE		Insertion or deletion		Age of first P. aeruginosa infection	0.9	261 (Arkwright et al., 2003)		808 (Drumm et al., 2005)
				Age at which FEV₁ < 50%	0.03 (0.04)^§
				Age of death	No association
ADRB2		Arg16Gly	1042713	FEV₁ % pred FVC	<0.05 <0.05	126 (Buscher et al., 2002)		808 (Drumm et al., 2005)
				Flows at lower lung volumes	<0.01
				5 year decline in pulmonary function	<0.01
		Gln27Glu Thr164Ile	1042714 1800888	Bronchodilator responses to albuterol	NS
				Pulmonary function	Reduced
AGER		−429T > C	1800625	FEV1 Kulich CF-specific percentile z-score	0.02 0.03	967 (Beucher et al., 2012)
				KNoRMA	0.03
AGTR2			1403543	FEV₁ % pred (adjusted)	1.61 × 10⁻⁵	1,978 (Wright et al., 2011)		557 (Wright et al., 2011)
AHRR			12188164	FEV₁% pred (adjusted)	5.92 × 10⁻⁴	1,978 (Wright et al., 2011)		557 (Wright et al., 2011)
C3		31778 G > A	393770	FEV₁ % pred	0.75 (0.05)	755 (Park et al., 2011)
		4023 T > G	11569393		0.66 (0.03)
		39718 G > A	7257062		0.78 (0.52)
CD14		−159 C > T		Pulmonary disease severity	No association	105 (Faria et al., 2009)
CDH8			11645366	FEV₁ % pred (adjusted)	1.23 × 10⁻⁵	1,978 (Wright et al., 2011)		557 (Wright et al., 2011)
CEACAM3	19q13		6508999–10414823	Disease severity	0.0469	37 nuclear families (Stanke et al., 2010)
CEACAM6	19q13		1549960–11548735	Disease severity	0.0106	37 nuclear families (Stanke et al., 2010)
CFB		7680 A > G	537160	FEV₁ % pred	0.50 (0.83)	755 (Park et al., 2011)
		10858 A > G	2072633		0.68 (0.74)
CLCN2	CLC-2	−693 A > G		FEV₁ % pred	0.72	74 (Blaisdell et al., 2004)
		358 G > C			0.32
		427 A > G			0.32
		1089 T > C			0.21
		1909 G > C			0.22
DCTN4		Any missense variant	11954652	Age at onset of chronic P. aeruginosa infection	0.05 0.002	91 (Emond et al., 2012)
			35772018	Age of first P. aeruginosa infection	0.01		645 (Emond et al., 2012)^⊙
				Age at onset of chronic P. aeruginosa infection	0.004		530^○
				Age at onset of mucoid P. aeruginosa infection	0.03
				Time from first detection of P. aeruginosa infection to mucoid P. aeruginosa	0.01
DEFB1		Frequent polymorphisms		Age of first P. aeruginosa infection	No association	210 (Vankeerberghen et al., 2005)	62 (Segat et al., 2010)	224 (Tesse et al., 2008) 92 (Crovella et al., 2011)⁺
				FEV₁%	No association
DEFB4		Genomic copy number (2–12) of repeat unit		Pulmonary disease (mean and current FEV₁, mean and current FVC)	No association	355 (Hollox et al., 2005)
EDNRA		6672 G > C	5335	Pulmonary function (FEV₁)	0.002	1,577 (Darrah et al., 2010)
EEA1			4760506	FEV₁ % pred (adjusted)	6.77 × 10⁻⁶	1,978 (Wright et al., 2011)		557 (Wright et al., 2011)
FCGR2	FcγRII	R131H		Chronic P. aeruginosa colonization	0.042	167 (De Rose et al., 2005)
FUT2		G428A	601338	Impairment of lung function (FEV₁)	0.569	806 (Taylor-Cousar et al., 2009)
FUT3		T59G	28362459	Impairment of lung function (FEV₁)	0.544	707 (Taylor-Cousar et al., 2009)
		T202C	812936		0.491
		C314T	778986		0.615
		T1067A	3894326		0.792
GCLC		(GAG)_n		FEV₁ % pred	0.097	440 (McKone et al., 2006)
					0.001 (mild)
					0.533 (severe)
GSTM1		GSTM1^0/ GSTM1^0		FEV₁ % pred	0.16	53 (Hull and Thomson, 1998)	194 (Baranov et al., 1996)	146 (Flamant et al., 2004)
				Chrispin–Norman score	0.02			808 (Drumm et al., 2005)
				Shwachman score	0.04		60 (Korytina et al., 2004)
				Positive for P. aeruginosa	0.12
				No. of ΔF508 homozygotes	0.43
GSTM3		GSTM3^*A	1799735	FEV₁	0.01	146 (Flamant et al., 2004)
		GSTM3^*B		FVC	0.002
GSTP1		1375 A > G	947894	Spirometry	NS	146 (Flamant et al., 2004)	808 (Drumm et al., 2005)	60 (Korytina et al., 2004)
		I105V
GSTT1		GSTT1^*0/		Spirometry	NS	146 (Flamant et al., 2004)
		GSTT1^*0
HFE		C282Y and/or H63D	1800562 and/or 1799945	Positive for P. aeruginosa	0.81	82 (Pratap et al., 2010)
				FEV₁% pred	0.03
				FVC% pred	0.02
				Annual change in FEV₁% pred	0.003
				Annual change in FVC% pred	0.001
HLA		DRA	9268905	FEV₁ % pred (adjusted)	1.42 × 10⁻⁵	1,978 (Wright et al., 2011)	557 (Wright et al., 2011)
		DR4		Chronic P. aeruginosa colonization	≤0.03	98 (Aron et al., 1999)		72 (Laki et al., 2006)
		DR7/DQA^*0201		Chronic P. aeruginosa colonization	<0.03
HMOX1		11354 A > G	2071749	FEV₁ % pred	0.01 (0.29)	755 (Park et al., 2011)
		4613 A > T	2071746		0.40 (0.03)
IFNG	IFNγ	+874 A > T		Age of first P. aeruginosa infection	No association	261 (Arkwright et al., 2003)
				Age at which FEV₁ < 50%	0.09
				Age of death	No association
IFRD1		57460 C > T	7817	Cross-sectional measures of lung function	0.004 (0.0168)^£	320 (Gu et al., 2009)
				Longitudinal measures of lung function	0.016 (0.0187)^£
				FEV₁% pred (adjusted)	No association	1,978 (Wright et al., 2011)
		47556 G > T	3807213	Longitudinal measures of lung function	0.080
		38923 C > T	6968084	Cross-sectional measures of lung function	0.082
IL8			2227306	Pulmonary disease severity	0.19	737	385 (Hillian et al., 2008)
			2227307		0.04	727
			2227543		0.06	732	329 (Corvol et al., 2008)^♦
		−251 A > T	4073		0.07	733 (Hillian et al., 2008)
IL-10		−592 CC/-	1800872	Pulmonary function decline	No association	261 (Arkwright et al., 2003)
		−592 CC/TA		Age of first P. aeruginosa or B. cepacia infection	No association
				Age of death	No association
		−1082 G > A	1800896	Colonization with A. fumigatus	0.06 (0.03)^§ 0.02 (0.01)^§	378 (Brouard et al., 2005)		808 (Drumm et al., 2005)
				Development of ABPA	No association
				Colonization with P. aeruginosa
KRT8/KRT18			1907671	Disease severity	Associates	49 (24 sib pairs) (Stanke et al., 2011)
			4300473		Associates
			8608		Associates
		7952 T > C	2035875		0.00131
			1907671-4300473- 2035878-2035875 haplotype	Disease severity	0.0051
			2638526	Disease severity	NS
			2070876		NS
KRT19		c.90T > C	11550883	Effective specific airway resistance	0.0093	95 (Gisler et al., 2012)
		c.179G > C	4602		0.0052
			11550883-4602 haplotype		0.0097
MASP-2		Exon 3 A > G, D120G	72550870	Pulmonary function	No association	112 (Carlsson et al., 2005)	109 (Olesen et al., 2006)
				Need for transplantation	No association
				Colonization with P. aeruginosa	0.04
				Lung function in patients colonized with S. aureus	0.04
MBL2		X1 – B (A > G) X1 – C (A > G) X1 – D (C > T) (A/A, A/O, O/O) −221 G > C (X/Y)	1800450 1800451 5030737 7096206	FEV₁% FVC% Age of onset of P. aeruginosa	0.003 0.03 0.07	149 (Garred et al., 1999)	164 (Gabolde et al., 1999) 179 (Yarden et al., 2004) 298 (Davies et al., 2004)^Θ 47 (Trevisiol et al., 2005) 135 (Choi et al., 2006) 254 (Buranawuti et al., 2007)	112 (Carlsson et al., 2005) 260 (Davies et al., 2004)^Θ 47 (Trevisiol et al., 2005) 808 (Drumm et al., 2005) 105 (Faria et al., 2009) 788 (McDougal et al., 2010) 123 (Olesen et al., 2006)
				Lung function	No association	112 (Carlsson et al., 2005)	105 (Faria et al., 2009)
		−550 G > C (H/L)		Colonization	No association
MIF		−794 presence of absence of 5-CATT		Colonization with P. aeruginosa	0.004	167 (Plant et al., 2005)
				Colonization with S. aureus	0.50
				Colonization with Candida	0.36
				FEV₁ ≥ 80%	0.14
NOS1		(AAT)_9–15		Colonization with P. aeruginosa	0.0358	75 (Grasemann et al., 2000)	40 (Grasemann et al., 2002)
				Mean FE_NO	0.027
		(GT)_18–36		Colonization with A. fumigatus	0.8505 0.025	59 (Texereau et al., 2004)
				5 year decline of pulmonary function
NOS3		894 G > T		FE_NO	0.07 (0.02 in females)	70 (Grasemann et al., 2003)
				FEV₁	0.08 (in females)
				Colonization with P. aeruginosa	<0.05
		T5220G	1799983	Impairment of lung function (FEV₁)	0.54	808 (Drumm et al., 2005)
PPP2R1A		c.^*465T > A	2162779	Functional residual capacity	0.0033	95 (Gisler et al., 2012)
PPP2R4		c.−185A > C	3118625	FEV1	0.0048	95 (Gisler et al., 2012)
				Lung clearance index	0.0059
				Effective specific airway resistance	0.0064
SCNN1B	ENaCβ	T313M 938 C > T G589S 1765 G > A		Disease severity		56 (Viel et al., 2008)
SCNN1G	ENaCγ	L481G 1442 T > A V546I 1636 G > A	5735–5723 haplotype	Disease severity		56 (Viel et al., 2008)
SERPINA3	ACT, A1ACT	T-15A	4934	FEV₁% pred	0.04	157 (Mahadeva et al., 2001)
				Radiography score	0.03
SFTPA1		6A³ (and 6A³/1A¹ haplotype)		FEV₁% pred	0.01	135 (Choi et al., 2006)
				DLCO	0.10
				ATS score	0.006
				AMA score	0.02
				Dyspnea score	0.20
				Physical score	0.002
				Severity score	0.005
SFTPA2		1A¹ (and 6A³/1A¹ haplotype)		FEV₁% pred	0.009	135 (Choi et al., 2006)
				DLCO	0.13
				ATS score	0.007
				AMA score	0.06
				Dyspnea score	0.07
				Physical score	0.12
				Severity score	0.10
SLC8A3			12883884	FEV₁% pred (adjusted)	1.20 × 10⁻⁶	1,978 (Wright et al., 2011)		557 (Wright et al., 2011)
SLC9A3		521096 C > T	4957061	Age of first P. aeruginosa infection	0.02	1,004
				Decline of lung function (FEV₁)	0.05	752 (Dorfman et al., 2011)
SNAP23		c.267-9T > C	9302112	FEF₅₀	0.0088	95 (Gisler et al., 2012)
				Functional residual capacity	0.011
				Volume of trapped gas	0.0043
TGFB1		codon 10 C29T	1800470	Age at which FEV₁ < 50% Age at which FVC < 70%	<0.02 <0.005	171 (Arkwright et al., 2000)^*	261 (Arkwright et al., 2003)	118 (Brazova et al., 2006) 1,978 (Wright et al., 2011)
		codon 25 G74C	1800471	Age at which FEV₁ < 50% Age at which FVC < 70%	NS NS		808 (Drumm et al., 2005)^*
		C-509T	1800469	Impairment of lung function (FEV₁)	0.006	808 (Drumm et al., 2005)	498 (Drumm et al., 2005) 329 (Corvol et al., 2008) 105 (Faria et al., 2009) 472 (Bremer et al., 2008)	254 (Buranawuti et al., 2007)
TLR4		D299G	4986790	Mean FEV₁% pred	0.55	100 (Urquhart et al., 2006)
				Mean FVC% pred	0.52
				Age of first P. aeruginosa infection	0.78
				Chrispin–Norman X-ray score	0.16
		2688 G > A	10759931	Rate of change of FEV₁% pred per year	0.12
				FEV₁ % pred	0.84 (0.55)	755 (Park et al., 2011)
TLR5		R392X	5744168	Mean FEV₁ % pred	0.77	2219 (Blohmke et al., 2010)
TNFA	TNFa	G-308A (TNF2)	1800629	Mean FEV₁% pred Mean Chrispin–Norman X-ray score	0.02 0.17	53 (Hull and Thomson, 1998) 180 (Yarden et al., 2005)		261 (Arkwright et al., 2003) 180 (Yarden et al., 2005) 53 (Schmitt-Grohe et al., 2006)
				Mean Shwachman score	0.17
				No. positive for P. aeruginosa	0.72			808 (Drumm et al., 2005)
		C-851T		Mean FEV₁% pred Age of first P. aeruginosa infection	0.25 0.60
		G-238A		Mean FEV₁% pred Age of first P. aeruginosa infection	0.8 0.64
		+691g ins/del		Mean FEV₁% pred Age of first P. aeruginosa infection	0.008 0.018
TNFR1	TNFRSF1A	intron 1 haplotype		Disease severity	Associates	37 sib pairs (Stanke et al., 2006)

^§The number in parenthesis indicates the p-value for the association found in F508del homozygotes.

Only multivariate p-values are reported. The number outside the parenthesis is the p-value for pediatrics and the number in parenthesis is the p-value for adults.

^⊙The association of missense variants with age at first P. aeruginosa-positive culture and age at onset of chronic P. aeruginosa was replicated in a population of only European American patients.

^○The association of missense variants with age at first P. aeruginosa-positive culture and age at onset of chronic P. aeruginosa was replicated in a population excluding patients with non-European ancestry.

⁺Found that only the c.−20G > A SNP associated with disease severity.

^£The number in parenthesis indicates the p-value after a Bonferroni correction.

^♦Found that −251 TT, +396TT, and +781CC may be associated with an earlier occurrence of chronic P. aeruginosa colonization, which is an indicator of disease severity, but this was not examined in the study by Hillian et al. (2008).

^ΘThe association of MBL2 deficiency alleles with indicators of pulmonary disease severity was replicated in a population of 298 adults, but refuted in a population of 260 children.

The Trevisiol et al. (2005) study replicated an association of MBL2 deficiency alleles with pulmonary function, but not with PA colonization.

*The study by Arkwright et al. (2000) found the severe variant at codon 10 to be T/T, but the study by Drumm et al. (2005) found the severe variant to be C/C at codon 10. A more detailed discussion of the TGB1 association with CF can be found in the text.