Table 1 Summary of allelic heterogeneity in support of the common disease/common variant or multiallele/multilocus hypotheses

(a) Common disease/common variant hypothesis

Cardiovascular

APOE

*E4

Alzheimer

0.10-0.15

Early onset

Allele present in primates and all world

disease

(Caucasian)

populations; possible interaction with

dietary fats; may account for 20% of

Alzheimer disease

Age-related

0.10-0.15

Decreased risk

Well-established protective effect on

macular

age-related macular degeneration

degeneration

Cardiovascular

0.10-0.15

Increased risk

Accounts for 10-16% of plasma

disease

cholesterol variance (western

populations); increases risk of

cardiovascular disease (odds ratio

approximately 1.5)

F5

R506Q

Venous

0.02-0.08

Increased risk

Carriers have around 10% lifetime risk

thrombosis

for significant venous thrombosis

Metabolic/

PPARG

P12A

Type 2 diabetes

0.85

Increased risk

Relative risk 1.25

nutritional

mellitus

(Caucasian)

CAPN10

Haplotypes

Type 2 diabetes

0.03-0.29 (low

Increased risk in

Complex risk haplotypes that may

112 and 121

mellitus

to high risk

121/112 haplotype

include several SNPs, including

populations)

heterozygotes

CAPN10-g.4852G/A (UCSNP-43)

HFE

C282Y

Haemochromatosis

0.05

Around 40% risk

High frequency in Caucasians, low in

(Caucasian)

for homozygotes

Asiatics (suggesting admixture), so it may

be a recent mutation (less than 50,000

years ago)

Cancer

ELAC2

S217L

Prostate cancer

0.30 and 0.04

Increased risk

Odds ratio 2.4-3.1

and A541T

(Caucasian)

BRCA2

N372H

Breast cancer

0.22-0.29

Increased risk

Relative risk = 1.31 for HH compared to

(Caucasian)

NN genotypes

Infectious/

MHC class I

HLA-B*2702,

Ankylosing

0.09

Increased risk

Odds ratio approximately 170, mechanism

inflammatory

04, 05

spondylitis

(Caucasian)

unclear; also associated with reactive

arthritis and uveitis; about 2% of B27-

positive carriers develop ankylosing

spondylitis

MHC class II

DQB1*0302-

Type 1 diabetes

0.05

Increased risk

Around 10% of heterozygotes for these

DRB1*0401/

mellitus

(European)

high risk haplotypes develop type 1

DQB1*0201-

diabetes mellitus; relative risk

approximately 20

DRB1*03

IL12B

3' UTR

Type 1 diabetes

0.79

Increased risk

Interaction with HLA; increased

allele 1

mellitus

(Caucasian)

expression of IL12B in vitro

G6PD

A^-

G6PD deficiency

Approximately

Decreased risk of

High allele frequency proposed to be

(V68M/N126D)

0.20 (West

severe malaria

due to balancing selection

African)

HBB

HbC (E6K)

Anaemia

0.09 (West

Decreased risk of

High allele frequency proposed to be

(homozygotes)

African)

severe malaria

due to balancing selection

CCR5

Δ32-CCR5

HIV-1

0.09

Decreased HIV-1

Recent origin - estimated approximately

transmission

(Caucasian)

transmission

700 years ago [13]

Developmental

PDGFRA

Promoter

Neural tube

0.23

Increased risk for

At least six polymorphic sites within

H1/H2α

defect

(Caucasian)

sporadic neural

each haplotype

haplotypes

tube defect

(b) Multilocus/multiallele hypothesis

Cardiovascular

LDLR

> 735 alleles

Coronary artery

All rare, except in

Increased risk of

disease

isolate or founder

coronary artery

populations

disease

APOB

> 24 alleles

Coronary artery

R3500Q 0.002,

Increased risk of

Single common R3500Q allele

disease

remainder rare

coronary artery

disease

Cancer

BRCA1

> 483 alleles

Familial breast-

All rare, except in

Increased risk

ovarian cancer

isolate or founder

populations

BRCA2

> 404 alleles

Familial breast

All rare, except in

Increased risk

Common N372H allele (frequency

cancer

isolate or founder

approximately 0.25) with relative

populations

risk 1.31

MLH1

> 143 alleles

Hereditary non-

All rare

Increased risk

polyposis colorectal

cancer (HNPCC)

MSH2

> 108 alleles

Hereditary non-

All rare

Increased risk

polyposis colorectal

cancer (HNPCC)

P53

> 144 alleles

Multiple cancers

All rare

Increased risk

Neurosensory

ABCA4

> 350 alleles

Stargardt disease,

Most rare, G863A

Increased risk

retinitis pigmentosa

allele approximately

0.014 (Europeans)

RHO

> 88 alleles

Retinitis pigmentosa,

All rare

Increased risk

congenital stationary

night blindness

GJB2

> 45 alleles

Non-syndromic

Most rare, 30delG

Increased risk

30delG absent from non-European

deafness

allele around 0.015

populations

(Europeans)

Metabolic/

CFTR

> 963 alleles

Cystic fibrosis

Most rare,

nutritional

ΔF508 accounts for

Increased risk ΔF508 allele recent

approximately 70%

-estimated to have arisen 3,000

of cystic fibrosis

years ago [14]

alleles in Caucasians