Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning

Table 1 Data of linkage analysis

Ref	Author	Year	Subject	Scope	Linkage loci for IBD	Linkage loci for CD	Linkage loci for UC
R26	Hugot JP	1996	Caucasian CD	Autosome		16q(IBD1) +
R27	Satsangi J	1996	Northern european IBD	Autosome	7 +, 12 +, 3 ±	7 ± , 12 ± , 3 ±	7 +
R28	Cho JH	1998	American IBDa	Genome	(3q +,1p ± )(non-Jewish), (3q ± ,4q ± )e	16 ±	——
R29	Ma Y	1999	American CDa	Genome		14q ± , 17q ±e, 5q ±e
R30	Hampe J	1999	European IBDb	Genome	1 ± , 6 ± , X ±	10 ± , 12 ± , 16 ±	4 ± , X ±
R31	Duerr RH	2000	American CDa	Genome		14q +
R32	Rioux JD	2000	Canadian IBD	Genome	19p+, 5q+, 3p ± , 6p ±	5q +f , 19p +	19p ±
R33	Fisher SA	2002	European IBD	Genome	(6p+,1+,14+,18+)(male)	6p + (male)	6p + (male)
R34	Brant SR	1998	American CDa	3,7,12,16		16q(IBD1) ±
R35	Rioux JD	1998	Toronto IBD	3,7,12,16	——	——	——
R36	Curran ME	1998	European IBDb	12,16	——	12q ±	——
R37	Annese V	1999	Italian IBD	3,6,7,12,16	16q ±	16q ±	16q ±
R38	Vermeire S	2000	Belgian CD	3,7,12,16		——
R39	Dechairo B	2001	European IBD	3,6,7,	6p +	——	——
R40	Paavola P	2001	Finnish IBD	1,3,7,12,14,16	——	——	——
R41	Gavanaugh J	2001	IBDc	12,16	16q +	16q +	——
R42	Ohmen JD	1996	American IBDa	16	——	16q ±e	——
R43	Parkes M	1996	English IBD	16	——	16q ±	——
R44	CavanaughJA	1998	Australian CD	16		16q +(IBD1)
R45	Mirza MM	1998	Northern european UC	16			16q ± (IBD1)
R46	Porabosco P	2000	Italian IBD	16	16q +	16q +	16q +
R47	Brant SR	2000	American CD	16		16q +f , 16q ±
R48	Akollar PN	2001	Jewish CD	16		16q +f
R49	Van Heel DA	2002	European CD	16		——
R50	Zouali H	2001	European CD	16		16q +
R51	Hampe J	2002	European IBD	16	16p ±	16q +, 16p ±	——
R52	Satsangi J	1996	European IBD	6(MHC-II)	——	——	6p(MHC-II) +
R53	Silverber MS	1999	Canadian CD	6		6p(MHC-II) ±
R54	Hampe J	1999	Northern european IBDb	6	6p+	6p +	6p +
R55	Yang H	1999	American CD	6		6p(MHC) +
R56	Duerr RH	1998	Northern american IBD	12	12q ±	——	——
R57	Yang H	1999	American IBD	12	——	12q ±	——
R58	Lesage S	2000	Northern european CDd	12		——
R59	Parkes M	2000	American IBD	12	12q+	——	12q +
R60	Hampe J	2001	Northern european IBDb	3	——	——	——
R61	Duerr RH	2002	American IBD	3	3p +	——	——
R62	Rioux JD	2001	American CD	5q		5q +
R63	Vermeire S	2001	Belgian CD	X		Xq ±

Note: CD, CD-only family; UC, UC-only family; IBD=UC+CD+mixed family; +, convincing linkage (LOD ≥ 3.0); ±, suggestive linkage (3.0 > LOD ≥ 2.0); ——, no suggestive linkage (LOD < 2.0);

^a, including Jewish;

^b, family from English, German and Dutch;

^c, family from Northern American, European and Australian;

^d, family from French and Belgian;

^e, linkage only for Jewish;

^f, linkage only for IBD with early onset.

Table 2 Data of association analysis for NOD2

Ref year author	Subject	Main conclusion
R65, 2001	Europe CD, UC	A. Find P241S, R432R, R675W, G881R, IVS8-133delAinSCT, 980fs etc.31 variants
Hugot, JP		B. R675W, G881R, 980fs with CD, not with UC
		C. CD-GRR 3.0 at SHEM, 38.0 at HOM, 44.0 at CHEM
R66, 2001	American CD	A. 3020insC with CD
Ogura Y		B. CD-GRR 1.5 at SHEM, 17.6 at HOM
R67, 2001	German, English CD	A. 3020insC with CD, not with UC
Hampe J	UC	B. CD-GRR 2.6 at SHEM, 42.1 at HOM
R68, 2002	Europe CD, UC	A. Find 67 sequence variants, 9 of which gene frequency > 5%
Lesage S		B. R702W, G908R, 3020insC with CD, not with UC
		C. Support gene-dosage effect
R69, 2002	Europe CD, UC	A. R702W, G908R, 3020insC with CD, especially ileum CD, not with UC
Cuthbert AP		B. P628S linkage disequilibrium with the other three mutations
		C. CD-GRR 3.0 at SHEM, > 22.0 at HOM or at CHEM
		D. Mutation frequency: familial CD > sporadic CD
R70, 2002	Dutch CD	A. 3020insC with CD, G2722C not with CD
Murillo L		B. No association with clinical phenotype
R71, 2002	German, Norwegian	A. R675W, G881R, 980fs with CD
Hampe J	CD	B. Especially with ileum CD
R72, 2002	Canadian CD	A. R702W, G908R, 1007fs with CD, especially ileum CD
Vermeire S		B. No difference between familial CD and sporadic CD
R73, 2002	German UC, CD	A. 3020insC with CD, not with UC
Radlmayr M		B. Association with fistula, fibrostenosis, ileocecum resection
R74, 2002	Japanese CD, UC	A. R675W, G881R, 3020insC not with CD or UC
Inoue N
R75, 2002	Europe CD	A. R675W, G881R, 3020insC with CD
Vermeire S		B. Not with effect of Infliximb
R76, 2002	American CD	A. R702W, G908R, 1007fs with CD
Abreu MT		B. With fibrostenosis
R77, 2002	English CD	A. R702W, G908R, 1007fs with CD, especially ileum CD
Ahmad T		B. 3020insC with early onset of CD
		C. CD-GRR 2.4 at SHEM, 9.8 at HOM, 29.3 at CHEM
R49, 2002	Europe CD	A. R702W, 1007fs with CD, linkage disequilibrium with P628S
Van heel DA		B. Support gene-dosage effect

Note: CD = Crohn disease; UC = ulcerative colitis; CD-GRR = CD-genotype relative risk; SHEM = simple heterogeneous mutation; HOM = Homozygous mutation; CHEM = complex heterogeneous mutation; P value is uniformly set at ≤ 0.05; Nomenclatures were not uniform among the studies, R675W = R702W, G881R = G908R, 1007fs = 980fs = 3020insC.

Table 3 Data of association analysis for HLA

Ref	Year	Author	Subject	Region	Association with CD	Association with UC
R83	1995	Duerr RH	American UC	HLA-DR2		DRB1*1601-
R84	1995	Nakajima A	Japanese CD	DR, DQ, DP	(DRB1*0405,0410,DQA1*03,DQB1
					*0401,0402)+, (DQA1*0102,DRB1*
					1501,1302,DQB1*0602) -
R85	1996	Reishagen M	German CD	DRB1, DQA1, DQB1	DRB1*07+, DRB1*03-
R86	1996	Hesresbach D	French CD	HLA-I, HLA-II, TAP	DRB1*1302+, DRB1*04+c
R52	1996	Satsangi J	Europe IBD	DRB, DQB		DRB1*103+, DRB1*12+
R87	1996	Danze PM	French CD	DRB1, DQB1	(DQB1*0501, DRB1*07, 01)+
					(DQB1*0602/0603, DRB1*03)-
R88	1996	Heresbach D	French UC	HLA-II, TAP		DRB1*03-
R89	1997	Bouma G	Dutch IBD	HLA-DR		DRB1*15+, DRB1*13-
R90	1998	Fernandez AM	Spanish UC	DRB1		DRB1*1501+, DRB1*
R91	1998	Cariappa A	American CD	DRB, DQB, DPB	Haplotype DRB3*0301/DRB1*1302+	1502(severe)+
R92	1999	Bouma G	Dutch UC	DR, TNF-α, LT-α		DRB1*0103+, DRB1*15(female)+
R93	1999	Yoshitake S	Japanese IBD	DQ, DR, DP	DQB1*0402+, DRB1*1502-	(DRB1*1502,DRB5*0102,
						DQA1*0103,DQB1*06011,
						DPA1*0201,DPB1*0901)+,
						(DRB4*0101,DQA1*0302) -
R94	1999	Stokkers PC	Meta-analysis	DR, DQ, TNF-α	(DR7,DRB3*0301,DQ4)+, (DR2,DR3)-	(DR2, DR9, DRB1*0103)+, DR4 -
R95	1999	Hirv K	Estonians UC	DR, DQ, TNF-α		DRB1*1501+
R96	2001	Seki SS	Japanese UC	HLA-I, HLA-II		(MICA-TM-STR6, B52, DR2)+
R97	2002	Lantermann A	IBDa	DPA1	DPA1*02021(German)+
R98	2002	Orchard TR	Europe IBD	HLA-B, DR, TNF-α	Uveitis with (B*27,B*58,DRB1*0103)
R77	2002	Ahmad T	CDb	HLA-I, HLA-II	(DRB1*0701,CW*0802)+,
				TNF-α, LT-α, HSP70	DRB1*0103(fistula)+, DRB1*1501-

Note: UC = Ulcerative colitis; CD = Crohn disease; IBD = UC+CD;

^a, German, South Africa and South Korea IBD;

^b, white people CD;

^c, DRB1*04 is only associated with CD with no effect to cortexin; P value is uniformly set at ≤ 0.05; +, Positive association; -, Negative association.